Prof Dr REJİN KEBUDİ
İstanbul Uumlniversitesi Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml Pediatrik Hematoloji-Onkoloji Bilim Dalı
NF-1 ve TUumlMOumlRLER Periferik sinir sistemi Tm
Noumlrofibromlar plexiform noumlrofibromlar MPSKT
Merkezi Sinir Sistemi Tm Optik gliom Beyin Sapı Gliomları Yuumlksek gradlı gliomlar
Diğer Tm bull Feokromositoma bull Rabdomyosarkoma bull Gastrointestinal Stromal Tuumlmoumlrler bull Gastrik Karsinoid Tuumlmoumlr bull Glomus tuumlmoumlruuml bull Juumlvenil Myelomonositik Loumlsemi bull Meme kanseri
Kebudi R Neurofibromatosis and Cancer Turk Arch Ped 2008 43 80-3 Kebudi R Optic Pathway Gliomas Oncopedia Chapter 2008
OPTİK GLİOMLAR (OG) OG ccedilocukluk ccedilağı beyin tm lerinin 5
60 ı lt 5 yaş
Histoloji sıklıkla LGG ccediloğu pilositik
Genelde non-infiltratif yavaş buumlyuumlme paterni
50 sı optik sinirndashkiazma boumllgesinde diğer 50 sinde
hipotalamik tutulumoptik yolak tutulumu var bazen
frontal lob talamus diğer orta hat yapıları hatta beyin
sapı ve beyincik de tutulabilir
Yalnız unilateralbilateral optik sinir tutulumu daha ccedilok NF1 hastalarında halbuki kiazma tutulumu NF1 olmayan hastalarda daha sıktır
NF-1 olgularında OG daha yavaş seyreder
NF1 ve OG
NF1 de MSS tm leri goumlruumllebilir
NF1 de en sık goumlruumllen MSS tm OG
OG nadir ccedilocukluk ccedilağı beyin tm lerinin 1- 5
OG hastalarında NF1 prevalansı 50
NF1 hastalarında OG prevalansı 5
NF1 hastalarında hayat boyu OG gelişme riski 10-20
NF li hastalarda-goumlz noumlroloji endokrin onkoloji ortopedi konsultasyonları
SIOP-LGG1 ccedilalışması NF1 durumu tek anlamlı iyi prognostik parametre
OG-KLİNİK BULGU VE BELİRTİLER Tuumlmoumlruumln yerleşim yerine goumlre değişir
Optik sinir tutulumugoumlrsel bozukluklar (goumlrmede azalma aferent pupiller bozukluk optik atrofi papilloumldem strabismus goumlrme alanırenk bozuklukları proptosis
Optik sinirin frontal youmlnde tutulumu Ekzoftalmi
Kiazmatik-hipotalamik tm goumlrsel bozukluklar hidrosefali fokal noumlrolojik bozukluk kişilik ve intelektuel değişiklikler endokrin bozukluklar panhipopituitarizm diabetes insipidus diensefalik sendrom goumlruumllebilir
NF1 ve OG NF1(von Recklinghausenrsquos hst) prevalans 1 4000
ldquoNIH Consensus Development Statementrdquo
NF 1 tanısı iccedilin gt 2 kriter
gt 6 sutlu kahve lekeleri (cocukta gt0-5 cm erişkinde gt1-5 cm)-cafeacute-au-lait spots
gt 2 neurofibroma veya 1 plexiform neurofibroma
Axilleringuinal boumllge ccedilillenme
OPG
gt 2 Lisch noduumlluuml (iris hamartomu)
iskelet sistemi displazisi- sfenoid displazi uzun kemik korteks incelmesi
1 derece akrabada NF1
OG-TANI MRI veya CT optik sinirde tubular kalınlaşma fusiform
ters hilal şekli MRI tanı ve takipte tercih edilir
Tanı oumlzellikle NF1 hastalarında klinik ve radyolojik bulgularla konur
NF1 ve OG NF1 tm baskılayıcı geni (17q112) 1990 da klonlandı
Bu gen ras protein aktivitesini baskılayan ldquoneurofibrominrdquo isimli GTPaz aktive edici proteini (GAP) kodlar
Norofibromin hucre buyume ve ccediloğalmasını duzenleyen bir serintreonin kinaz olan MTORrsquou (mammolian target of rapamycin) da kontrol eder NF1 le ilişkili tuumlmoumlrlerde aktive MTOR saptanmıştır In vitro astrositlerin buyumesini engelleyen MTOR inhibitoru rapamisinin tedavide rolu olabilir
DODGE SINIFLAMASI Dodge I Tm optik sinirde Dodge 2 Kiazma tutulmuş Dodge 3 Tm optik traktusta H + hipotalamus LM+leptomeningeal Tutulum NF1 +
OG- TEDAVİ OG klinik gidişi farklı Tumor yıllarca stabil kalabilirhızla progresespontan regrese olabilir NF1 de OG daha iyi gidişli Uzun yıllar yaşıyabilir hayat kalitesi oumlnemli Orbita lezyonu goumlrsel kayıp azyoksa tedavi gerekmez Goumlrsel kayıp progresif ancak ccedilok yavaşsa radyolojik olarak intrakanalikuumller
veya intrakranial uzanım yoksa tedavi gerekmez
Bazı hastalarda hızlı radyolojik progresyon intrakranial uzanım varsa tedavi
Tedavi endikasyonları Vizyonda bozulma Diensefalik sendrom Tm progresyon bulguları (klinik radyolojik)
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti
ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
NF-1 ve TUumlMOumlRLER Periferik sinir sistemi Tm
Noumlrofibromlar plexiform noumlrofibromlar MPSKT
Merkezi Sinir Sistemi Tm Optik gliom Beyin Sapı Gliomları Yuumlksek gradlı gliomlar
Diğer Tm bull Feokromositoma bull Rabdomyosarkoma bull Gastrointestinal Stromal Tuumlmoumlrler bull Gastrik Karsinoid Tuumlmoumlr bull Glomus tuumlmoumlruuml bull Juumlvenil Myelomonositik Loumlsemi bull Meme kanseri
Kebudi R Neurofibromatosis and Cancer Turk Arch Ped 2008 43 80-3 Kebudi R Optic Pathway Gliomas Oncopedia Chapter 2008
OPTİK GLİOMLAR (OG) OG ccedilocukluk ccedilağı beyin tm lerinin 5
60 ı lt 5 yaş
Histoloji sıklıkla LGG ccediloğu pilositik
Genelde non-infiltratif yavaş buumlyuumlme paterni
50 sı optik sinirndashkiazma boumllgesinde diğer 50 sinde
hipotalamik tutulumoptik yolak tutulumu var bazen
frontal lob talamus diğer orta hat yapıları hatta beyin
sapı ve beyincik de tutulabilir
Yalnız unilateralbilateral optik sinir tutulumu daha ccedilok NF1 hastalarında halbuki kiazma tutulumu NF1 olmayan hastalarda daha sıktır
NF-1 olgularında OG daha yavaş seyreder
NF1 ve OG
NF1 de MSS tm leri goumlruumllebilir
NF1 de en sık goumlruumllen MSS tm OG
OG nadir ccedilocukluk ccedilağı beyin tm lerinin 1- 5
OG hastalarında NF1 prevalansı 50
NF1 hastalarında OG prevalansı 5
NF1 hastalarında hayat boyu OG gelişme riski 10-20
NF li hastalarda-goumlz noumlroloji endokrin onkoloji ortopedi konsultasyonları
SIOP-LGG1 ccedilalışması NF1 durumu tek anlamlı iyi prognostik parametre
OG-KLİNİK BULGU VE BELİRTİLER Tuumlmoumlruumln yerleşim yerine goumlre değişir
Optik sinir tutulumugoumlrsel bozukluklar (goumlrmede azalma aferent pupiller bozukluk optik atrofi papilloumldem strabismus goumlrme alanırenk bozuklukları proptosis
Optik sinirin frontal youmlnde tutulumu Ekzoftalmi
Kiazmatik-hipotalamik tm goumlrsel bozukluklar hidrosefali fokal noumlrolojik bozukluk kişilik ve intelektuel değişiklikler endokrin bozukluklar panhipopituitarizm diabetes insipidus diensefalik sendrom goumlruumllebilir
NF1 ve OG NF1(von Recklinghausenrsquos hst) prevalans 1 4000
ldquoNIH Consensus Development Statementrdquo
NF 1 tanısı iccedilin gt 2 kriter
gt 6 sutlu kahve lekeleri (cocukta gt0-5 cm erişkinde gt1-5 cm)-cafeacute-au-lait spots
gt 2 neurofibroma veya 1 plexiform neurofibroma
Axilleringuinal boumllge ccedilillenme
OPG
gt 2 Lisch noduumlluuml (iris hamartomu)
iskelet sistemi displazisi- sfenoid displazi uzun kemik korteks incelmesi
1 derece akrabada NF1
OG-TANI MRI veya CT optik sinirde tubular kalınlaşma fusiform
ters hilal şekli MRI tanı ve takipte tercih edilir
Tanı oumlzellikle NF1 hastalarında klinik ve radyolojik bulgularla konur
NF1 ve OG NF1 tm baskılayıcı geni (17q112) 1990 da klonlandı
Bu gen ras protein aktivitesini baskılayan ldquoneurofibrominrdquo isimli GTPaz aktive edici proteini (GAP) kodlar
Norofibromin hucre buyume ve ccediloğalmasını duzenleyen bir serintreonin kinaz olan MTORrsquou (mammolian target of rapamycin) da kontrol eder NF1 le ilişkili tuumlmoumlrlerde aktive MTOR saptanmıştır In vitro astrositlerin buyumesini engelleyen MTOR inhibitoru rapamisinin tedavide rolu olabilir
DODGE SINIFLAMASI Dodge I Tm optik sinirde Dodge 2 Kiazma tutulmuş Dodge 3 Tm optik traktusta H + hipotalamus LM+leptomeningeal Tutulum NF1 +
OG- TEDAVİ OG klinik gidişi farklı Tumor yıllarca stabil kalabilirhızla progresespontan regrese olabilir NF1 de OG daha iyi gidişli Uzun yıllar yaşıyabilir hayat kalitesi oumlnemli Orbita lezyonu goumlrsel kayıp azyoksa tedavi gerekmez Goumlrsel kayıp progresif ancak ccedilok yavaşsa radyolojik olarak intrakanalikuumller
veya intrakranial uzanım yoksa tedavi gerekmez
Bazı hastalarda hızlı radyolojik progresyon intrakranial uzanım varsa tedavi
Tedavi endikasyonları Vizyonda bozulma Diensefalik sendrom Tm progresyon bulguları (klinik radyolojik)
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti
ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OPTİK GLİOMLAR (OG) OG ccedilocukluk ccedilağı beyin tm lerinin 5
60 ı lt 5 yaş
Histoloji sıklıkla LGG ccediloğu pilositik
Genelde non-infiltratif yavaş buumlyuumlme paterni
50 sı optik sinirndashkiazma boumllgesinde diğer 50 sinde
hipotalamik tutulumoptik yolak tutulumu var bazen
frontal lob talamus diğer orta hat yapıları hatta beyin
sapı ve beyincik de tutulabilir
Yalnız unilateralbilateral optik sinir tutulumu daha ccedilok NF1 hastalarında halbuki kiazma tutulumu NF1 olmayan hastalarda daha sıktır
NF-1 olgularında OG daha yavaş seyreder
NF1 ve OG
NF1 de MSS tm leri goumlruumllebilir
NF1 de en sık goumlruumllen MSS tm OG
OG nadir ccedilocukluk ccedilağı beyin tm lerinin 1- 5
OG hastalarında NF1 prevalansı 50
NF1 hastalarında OG prevalansı 5
NF1 hastalarında hayat boyu OG gelişme riski 10-20
NF li hastalarda-goumlz noumlroloji endokrin onkoloji ortopedi konsultasyonları
SIOP-LGG1 ccedilalışması NF1 durumu tek anlamlı iyi prognostik parametre
OG-KLİNİK BULGU VE BELİRTİLER Tuumlmoumlruumln yerleşim yerine goumlre değişir
Optik sinir tutulumugoumlrsel bozukluklar (goumlrmede azalma aferent pupiller bozukluk optik atrofi papilloumldem strabismus goumlrme alanırenk bozuklukları proptosis
Optik sinirin frontal youmlnde tutulumu Ekzoftalmi
Kiazmatik-hipotalamik tm goumlrsel bozukluklar hidrosefali fokal noumlrolojik bozukluk kişilik ve intelektuel değişiklikler endokrin bozukluklar panhipopituitarizm diabetes insipidus diensefalik sendrom goumlruumllebilir
NF1 ve OG NF1(von Recklinghausenrsquos hst) prevalans 1 4000
ldquoNIH Consensus Development Statementrdquo
NF 1 tanısı iccedilin gt 2 kriter
gt 6 sutlu kahve lekeleri (cocukta gt0-5 cm erişkinde gt1-5 cm)-cafeacute-au-lait spots
gt 2 neurofibroma veya 1 plexiform neurofibroma
Axilleringuinal boumllge ccedilillenme
OPG
gt 2 Lisch noduumlluuml (iris hamartomu)
iskelet sistemi displazisi- sfenoid displazi uzun kemik korteks incelmesi
1 derece akrabada NF1
OG-TANI MRI veya CT optik sinirde tubular kalınlaşma fusiform
ters hilal şekli MRI tanı ve takipte tercih edilir
Tanı oumlzellikle NF1 hastalarında klinik ve radyolojik bulgularla konur
NF1 ve OG NF1 tm baskılayıcı geni (17q112) 1990 da klonlandı
Bu gen ras protein aktivitesini baskılayan ldquoneurofibrominrdquo isimli GTPaz aktive edici proteini (GAP) kodlar
Norofibromin hucre buyume ve ccediloğalmasını duzenleyen bir serintreonin kinaz olan MTORrsquou (mammolian target of rapamycin) da kontrol eder NF1 le ilişkili tuumlmoumlrlerde aktive MTOR saptanmıştır In vitro astrositlerin buyumesini engelleyen MTOR inhibitoru rapamisinin tedavide rolu olabilir
DODGE SINIFLAMASI Dodge I Tm optik sinirde Dodge 2 Kiazma tutulmuş Dodge 3 Tm optik traktusta H + hipotalamus LM+leptomeningeal Tutulum NF1 +
OG- TEDAVİ OG klinik gidişi farklı Tumor yıllarca stabil kalabilirhızla progresespontan regrese olabilir NF1 de OG daha iyi gidişli Uzun yıllar yaşıyabilir hayat kalitesi oumlnemli Orbita lezyonu goumlrsel kayıp azyoksa tedavi gerekmez Goumlrsel kayıp progresif ancak ccedilok yavaşsa radyolojik olarak intrakanalikuumller
veya intrakranial uzanım yoksa tedavi gerekmez
Bazı hastalarda hızlı radyolojik progresyon intrakranial uzanım varsa tedavi
Tedavi endikasyonları Vizyonda bozulma Diensefalik sendrom Tm progresyon bulguları (klinik radyolojik)
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti
ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
NF1 ve OG
NF1 de MSS tm leri goumlruumllebilir
NF1 de en sık goumlruumllen MSS tm OG
OG nadir ccedilocukluk ccedilağı beyin tm lerinin 1- 5
OG hastalarında NF1 prevalansı 50
NF1 hastalarında OG prevalansı 5
NF1 hastalarında hayat boyu OG gelişme riski 10-20
NF li hastalarda-goumlz noumlroloji endokrin onkoloji ortopedi konsultasyonları
SIOP-LGG1 ccedilalışması NF1 durumu tek anlamlı iyi prognostik parametre
OG-KLİNİK BULGU VE BELİRTİLER Tuumlmoumlruumln yerleşim yerine goumlre değişir
Optik sinir tutulumugoumlrsel bozukluklar (goumlrmede azalma aferent pupiller bozukluk optik atrofi papilloumldem strabismus goumlrme alanırenk bozuklukları proptosis
Optik sinirin frontal youmlnde tutulumu Ekzoftalmi
Kiazmatik-hipotalamik tm goumlrsel bozukluklar hidrosefali fokal noumlrolojik bozukluk kişilik ve intelektuel değişiklikler endokrin bozukluklar panhipopituitarizm diabetes insipidus diensefalik sendrom goumlruumllebilir
NF1 ve OG NF1(von Recklinghausenrsquos hst) prevalans 1 4000
ldquoNIH Consensus Development Statementrdquo
NF 1 tanısı iccedilin gt 2 kriter
gt 6 sutlu kahve lekeleri (cocukta gt0-5 cm erişkinde gt1-5 cm)-cafeacute-au-lait spots
gt 2 neurofibroma veya 1 plexiform neurofibroma
Axilleringuinal boumllge ccedilillenme
OPG
gt 2 Lisch noduumlluuml (iris hamartomu)
iskelet sistemi displazisi- sfenoid displazi uzun kemik korteks incelmesi
1 derece akrabada NF1
OG-TANI MRI veya CT optik sinirde tubular kalınlaşma fusiform
ters hilal şekli MRI tanı ve takipte tercih edilir
Tanı oumlzellikle NF1 hastalarında klinik ve radyolojik bulgularla konur
NF1 ve OG NF1 tm baskılayıcı geni (17q112) 1990 da klonlandı
Bu gen ras protein aktivitesini baskılayan ldquoneurofibrominrdquo isimli GTPaz aktive edici proteini (GAP) kodlar
Norofibromin hucre buyume ve ccediloğalmasını duzenleyen bir serintreonin kinaz olan MTORrsquou (mammolian target of rapamycin) da kontrol eder NF1 le ilişkili tuumlmoumlrlerde aktive MTOR saptanmıştır In vitro astrositlerin buyumesini engelleyen MTOR inhibitoru rapamisinin tedavide rolu olabilir
DODGE SINIFLAMASI Dodge I Tm optik sinirde Dodge 2 Kiazma tutulmuş Dodge 3 Tm optik traktusta H + hipotalamus LM+leptomeningeal Tutulum NF1 +
OG- TEDAVİ OG klinik gidişi farklı Tumor yıllarca stabil kalabilirhızla progresespontan regrese olabilir NF1 de OG daha iyi gidişli Uzun yıllar yaşıyabilir hayat kalitesi oumlnemli Orbita lezyonu goumlrsel kayıp azyoksa tedavi gerekmez Goumlrsel kayıp progresif ancak ccedilok yavaşsa radyolojik olarak intrakanalikuumller
veya intrakranial uzanım yoksa tedavi gerekmez
Bazı hastalarda hızlı radyolojik progresyon intrakranial uzanım varsa tedavi
Tedavi endikasyonları Vizyonda bozulma Diensefalik sendrom Tm progresyon bulguları (klinik radyolojik)
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti
ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OG-KLİNİK BULGU VE BELİRTİLER Tuumlmoumlruumln yerleşim yerine goumlre değişir
Optik sinir tutulumugoumlrsel bozukluklar (goumlrmede azalma aferent pupiller bozukluk optik atrofi papilloumldem strabismus goumlrme alanırenk bozuklukları proptosis
Optik sinirin frontal youmlnde tutulumu Ekzoftalmi
Kiazmatik-hipotalamik tm goumlrsel bozukluklar hidrosefali fokal noumlrolojik bozukluk kişilik ve intelektuel değişiklikler endokrin bozukluklar panhipopituitarizm diabetes insipidus diensefalik sendrom goumlruumllebilir
NF1 ve OG NF1(von Recklinghausenrsquos hst) prevalans 1 4000
ldquoNIH Consensus Development Statementrdquo
NF 1 tanısı iccedilin gt 2 kriter
gt 6 sutlu kahve lekeleri (cocukta gt0-5 cm erişkinde gt1-5 cm)-cafeacute-au-lait spots
gt 2 neurofibroma veya 1 plexiform neurofibroma
Axilleringuinal boumllge ccedilillenme
OPG
gt 2 Lisch noduumlluuml (iris hamartomu)
iskelet sistemi displazisi- sfenoid displazi uzun kemik korteks incelmesi
1 derece akrabada NF1
OG-TANI MRI veya CT optik sinirde tubular kalınlaşma fusiform
ters hilal şekli MRI tanı ve takipte tercih edilir
Tanı oumlzellikle NF1 hastalarında klinik ve radyolojik bulgularla konur
NF1 ve OG NF1 tm baskılayıcı geni (17q112) 1990 da klonlandı
Bu gen ras protein aktivitesini baskılayan ldquoneurofibrominrdquo isimli GTPaz aktive edici proteini (GAP) kodlar
Norofibromin hucre buyume ve ccediloğalmasını duzenleyen bir serintreonin kinaz olan MTORrsquou (mammolian target of rapamycin) da kontrol eder NF1 le ilişkili tuumlmoumlrlerde aktive MTOR saptanmıştır In vitro astrositlerin buyumesini engelleyen MTOR inhibitoru rapamisinin tedavide rolu olabilir
DODGE SINIFLAMASI Dodge I Tm optik sinirde Dodge 2 Kiazma tutulmuş Dodge 3 Tm optik traktusta H + hipotalamus LM+leptomeningeal Tutulum NF1 +
OG- TEDAVİ OG klinik gidişi farklı Tumor yıllarca stabil kalabilirhızla progresespontan regrese olabilir NF1 de OG daha iyi gidişli Uzun yıllar yaşıyabilir hayat kalitesi oumlnemli Orbita lezyonu goumlrsel kayıp azyoksa tedavi gerekmez Goumlrsel kayıp progresif ancak ccedilok yavaşsa radyolojik olarak intrakanalikuumller
veya intrakranial uzanım yoksa tedavi gerekmez
Bazı hastalarda hızlı radyolojik progresyon intrakranial uzanım varsa tedavi
Tedavi endikasyonları Vizyonda bozulma Diensefalik sendrom Tm progresyon bulguları (klinik radyolojik)
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti
ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
NF1 ve OG NF1(von Recklinghausenrsquos hst) prevalans 1 4000
ldquoNIH Consensus Development Statementrdquo
NF 1 tanısı iccedilin gt 2 kriter
gt 6 sutlu kahve lekeleri (cocukta gt0-5 cm erişkinde gt1-5 cm)-cafeacute-au-lait spots
gt 2 neurofibroma veya 1 plexiform neurofibroma
Axilleringuinal boumllge ccedilillenme
OPG
gt 2 Lisch noduumlluuml (iris hamartomu)
iskelet sistemi displazisi- sfenoid displazi uzun kemik korteks incelmesi
1 derece akrabada NF1
OG-TANI MRI veya CT optik sinirde tubular kalınlaşma fusiform
ters hilal şekli MRI tanı ve takipte tercih edilir
Tanı oumlzellikle NF1 hastalarında klinik ve radyolojik bulgularla konur
NF1 ve OG NF1 tm baskılayıcı geni (17q112) 1990 da klonlandı
Bu gen ras protein aktivitesini baskılayan ldquoneurofibrominrdquo isimli GTPaz aktive edici proteini (GAP) kodlar
Norofibromin hucre buyume ve ccediloğalmasını duzenleyen bir serintreonin kinaz olan MTORrsquou (mammolian target of rapamycin) da kontrol eder NF1 le ilişkili tuumlmoumlrlerde aktive MTOR saptanmıştır In vitro astrositlerin buyumesini engelleyen MTOR inhibitoru rapamisinin tedavide rolu olabilir
DODGE SINIFLAMASI Dodge I Tm optik sinirde Dodge 2 Kiazma tutulmuş Dodge 3 Tm optik traktusta H + hipotalamus LM+leptomeningeal Tutulum NF1 +
OG- TEDAVİ OG klinik gidişi farklı Tumor yıllarca stabil kalabilirhızla progresespontan regrese olabilir NF1 de OG daha iyi gidişli Uzun yıllar yaşıyabilir hayat kalitesi oumlnemli Orbita lezyonu goumlrsel kayıp azyoksa tedavi gerekmez Goumlrsel kayıp progresif ancak ccedilok yavaşsa radyolojik olarak intrakanalikuumller
veya intrakranial uzanım yoksa tedavi gerekmez
Bazı hastalarda hızlı radyolojik progresyon intrakranial uzanım varsa tedavi
Tedavi endikasyonları Vizyonda bozulma Diensefalik sendrom Tm progresyon bulguları (klinik radyolojik)
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti
ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OG-TANI MRI veya CT optik sinirde tubular kalınlaşma fusiform
ters hilal şekli MRI tanı ve takipte tercih edilir
Tanı oumlzellikle NF1 hastalarında klinik ve radyolojik bulgularla konur
NF1 ve OG NF1 tm baskılayıcı geni (17q112) 1990 da klonlandı
Bu gen ras protein aktivitesini baskılayan ldquoneurofibrominrdquo isimli GTPaz aktive edici proteini (GAP) kodlar
Norofibromin hucre buyume ve ccediloğalmasını duzenleyen bir serintreonin kinaz olan MTORrsquou (mammolian target of rapamycin) da kontrol eder NF1 le ilişkili tuumlmoumlrlerde aktive MTOR saptanmıştır In vitro astrositlerin buyumesini engelleyen MTOR inhibitoru rapamisinin tedavide rolu olabilir
DODGE SINIFLAMASI Dodge I Tm optik sinirde Dodge 2 Kiazma tutulmuş Dodge 3 Tm optik traktusta H + hipotalamus LM+leptomeningeal Tutulum NF1 +
OG- TEDAVİ OG klinik gidişi farklı Tumor yıllarca stabil kalabilirhızla progresespontan regrese olabilir NF1 de OG daha iyi gidişli Uzun yıllar yaşıyabilir hayat kalitesi oumlnemli Orbita lezyonu goumlrsel kayıp azyoksa tedavi gerekmez Goumlrsel kayıp progresif ancak ccedilok yavaşsa radyolojik olarak intrakanalikuumller
veya intrakranial uzanım yoksa tedavi gerekmez
Bazı hastalarda hızlı radyolojik progresyon intrakranial uzanım varsa tedavi
Tedavi endikasyonları Vizyonda bozulma Diensefalik sendrom Tm progresyon bulguları (klinik radyolojik)
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti
ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
NF1 ve OG NF1 tm baskılayıcı geni (17q112) 1990 da klonlandı
Bu gen ras protein aktivitesini baskılayan ldquoneurofibrominrdquo isimli GTPaz aktive edici proteini (GAP) kodlar
Norofibromin hucre buyume ve ccediloğalmasını duzenleyen bir serintreonin kinaz olan MTORrsquou (mammolian target of rapamycin) da kontrol eder NF1 le ilişkili tuumlmoumlrlerde aktive MTOR saptanmıştır In vitro astrositlerin buyumesini engelleyen MTOR inhibitoru rapamisinin tedavide rolu olabilir
DODGE SINIFLAMASI Dodge I Tm optik sinirde Dodge 2 Kiazma tutulmuş Dodge 3 Tm optik traktusta H + hipotalamus LM+leptomeningeal Tutulum NF1 +
OG- TEDAVİ OG klinik gidişi farklı Tumor yıllarca stabil kalabilirhızla progresespontan regrese olabilir NF1 de OG daha iyi gidişli Uzun yıllar yaşıyabilir hayat kalitesi oumlnemli Orbita lezyonu goumlrsel kayıp azyoksa tedavi gerekmez Goumlrsel kayıp progresif ancak ccedilok yavaşsa radyolojik olarak intrakanalikuumller
veya intrakranial uzanım yoksa tedavi gerekmez
Bazı hastalarda hızlı radyolojik progresyon intrakranial uzanım varsa tedavi
Tedavi endikasyonları Vizyonda bozulma Diensefalik sendrom Tm progresyon bulguları (klinik radyolojik)
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti
ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
DODGE SINIFLAMASI Dodge I Tm optik sinirde Dodge 2 Kiazma tutulmuş Dodge 3 Tm optik traktusta H + hipotalamus LM+leptomeningeal Tutulum NF1 +
OG- TEDAVİ OG klinik gidişi farklı Tumor yıllarca stabil kalabilirhızla progresespontan regrese olabilir NF1 de OG daha iyi gidişli Uzun yıllar yaşıyabilir hayat kalitesi oumlnemli Orbita lezyonu goumlrsel kayıp azyoksa tedavi gerekmez Goumlrsel kayıp progresif ancak ccedilok yavaşsa radyolojik olarak intrakanalikuumller
veya intrakranial uzanım yoksa tedavi gerekmez
Bazı hastalarda hızlı radyolojik progresyon intrakranial uzanım varsa tedavi
Tedavi endikasyonları Vizyonda bozulma Diensefalik sendrom Tm progresyon bulguları (klinik radyolojik)
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti
ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OG- TEDAVİ OG klinik gidişi farklı Tumor yıllarca stabil kalabilirhızla progresespontan regrese olabilir NF1 de OG daha iyi gidişli Uzun yıllar yaşıyabilir hayat kalitesi oumlnemli Orbita lezyonu goumlrsel kayıp azyoksa tedavi gerekmez Goumlrsel kayıp progresif ancak ccedilok yavaşsa radyolojik olarak intrakanalikuumller
veya intrakranial uzanım yoksa tedavi gerekmez
Bazı hastalarda hızlı radyolojik progresyon intrakranial uzanım varsa tedavi
Tedavi endikasyonları Vizyonda bozulma Diensefalik sendrom Tm progresyon bulguları (klinik radyolojik)
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti
ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OG- TEDAVİ
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OG- TEDAVİ
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OG- TEDAVİ (CerrahiRT) Geccedilmişte RT anrezektabl LGG da ldquoaltın standardrdquo dı
RT OG da stabilizasyonklinik duumlzelme (25 goumlrmede duumlzelme) sağlayabilir RT ile 10 yıl PFS 70-95
RT NF1rsquoli hastalarda Moya Moya sendromu
RT endokrinkemiklere yan etkisi ikincil malignite riski
İngilterersquode 5880 ccedilocuk NF1 + OPG değerlendirildi
RT + 18 hastanın 9 unda 12 SMN
RT - 40 hastanın 8 inde 9 SMN
RT alanlarda SMN RR 3 X
Cerrahinin kiazma + hipotalamusa uzanan tm de rolu kısıtlı (goumlrsel ve noumlrolojik morbiditede artış)
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OG- TEDAVİ-RT RT noumlrokognitif ve serebrovaskuumller komplikasyonlar
nedeniyle lt 5yaş iccedilin oumlnerilmez
Son yıllarda 8-10 yaş hatta gt10 yaşta da oumlnce KT oumlnerilmekte
Chong Al et alhellipBouffet E) Optic pathway gliomas in adolescence time to
challenge treatment choices NeuroOncol 2013 33 hst 1990-2006 gt10 yaş lt 10 yaş kadar etkin
RT-kiazmahiopalamusa- konformal -3D-CRT IMRT stereotactic RT proton
Doz 50-54 Gy 180 cGyfr genelde
Jenkin D Angyalfi S Becke L et al Optic glioma in children surveillance resection or irradiation Int J Radiat Oncol Biol Phys 199325215ndash25 Merchant TE Kun LE Wu S Xiong X Sanford RA Boop FA 2009 Phase II trial of conformal radiation therapy for pediatric low-grade glioma J ClinOncol 27 3598ndash3604
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OG- Kemoterapi KT kuumlccediluumlk ccedilocuklarda ( hatta gt 10 yaşta) semptomatik
progresif hastalıkta endike
Tedavi amacı genelde kuumlratif değildir tm buumlyuumlmesini durdurup belirti ve bulguları rahatlatmak nadiren kuumlccediluumlltmek
Bu şekilde RT geciktirilebilir kulanılmasına gerek kalmayabilir
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Packer R et al 1988 vincristine - actinomycin D ilk başarılı sonuccedillar lt 5 yaş ldquochiasmatic hypothalamic gliomrdquo median 4 yıl FU 625 PFS hiccedil RT almadılar
Ancak 7 yılda 13 uuml progresyonsuz sağ idi
Packer 1997 vincristine- carboplatin (tek carbo yanıtı) 2 kuumlre yanıt varsa 18 ay
50 ccedilocuk (21 NF1) 78 SDPR
En sık kullanılan protokol vincristine and carboplatin
SIOP-LGG 1996 VCR carboplatin
SIOP-LGG 2004 semptomatikPD 18 ay KT NF - ise gt 8 yaşRT lt8 yaş VCR carboplatin etoposid
NF + ise VCR carboplatin
OG- Kemoterapi
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
J Neurosurg 1997 May86(5)747-54 Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas Packer RJ1 Ater J Allen J Phillips P Geyer R Nicholson HS Jakacki R Kurczynski E Needle M Finlay
J Reaman G Boyett JM Abstract The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided There
has been increased interest in the use of chemotherapy for young children but little information concerning the long-term efficacy of such treatment Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy The patients were followed for a median of 30 months from diagnosis with 31 patients followed for more than 3 years Fifty-eight children had diencephalic tumors 12 had brainstem gliomas and three had diffuse leptomeningeal gliomas Forty-four (56) of 78 patients showed an objective response to treatment Progression-free survival rates were 75 +- 6 at 2 years and 68 +- 7 at 3 years There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year progression-free survival 79 +- 11 vs 75 +- 6 respectively) The histological subtype of the tumor its location and its maximum response to chemotherapy did not have an impact on the duration of disease control The only significant prognostic factor was age children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +- 7 compared with a rate of 39 +- 21 in older children (p lt 001) Treatment with carboplatin and vincristine is effective especially in younger children in controlling newly diagnosed progressive low-grade gliomas
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Klin Padiatr 2000 Jul-Aug212(4)177-84 [HIT-LGG effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report] Gnekow AK1 Kaatsch P Kortmann R Wiestler OD Abstract BACKGROUND The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children
with progressive low grade glioma at an age under 5 years and in older children upon individual decision PATIENTS AND METHOD Until October 10th 1999 402 patients from 69 hospitals were registered 130 children with progressive tumors were treated
after a median observation time of 5 months 46 patients received primary radiotherapy and 84 primary chemotherapy A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1 4 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53
RESULTS Of 84 patients in the chemotherapy arm of the study (49 male 35 female 23 NF I median age 299 years) 36 received treatment
at diagnosis and 43 after a median observation time of 197 months 943 achieved a clinical and neuroradiological response according to protocol criteria (5 CR 30 PROR 31 SD) after a median of 51 months 4 tumors showed primary progression (9 too early 5 not known) Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy after a median delay of 256 months at a median age of 60 years At a median observation time of 210 months 6 children are in CR 11 in PR 48 have SD 4 tumors are progressive and 3 children died of their tumor (9 too early 3 not known) PFS is at 72 after 36 months 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely
CONCLUSIONS Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children
with progressive low-grade glioma The high rate of hypersensitivity reactions has to prompt future modifications of treatment
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Eur J Paediatr Neurol 20026(4)207-12 Visual pathway glioma in children treated with chemotherapy Demaerel P1 de Ruyter N Casteels I Renard M Uyttebroeck A van Gool S Abstract Visual pathway gliomas occur predominantly in young children Chemotherapy has been
increasingly used as a first-line treatment because of the complications caused by radiotherapy and surgery Nine children between 6 months and 9 years (median age of 48 years) were treated with vincristine and carboplatin according to the SIOP (Socieacuteteacute Internationale dOncologie Peacutediatrique) low-grade glioma 1996 protocol Five patients had evidence of neurofibromatosis type 1 Magnetic resonance imaging (MRI) and ophthalmological assessment were performed during and after treatment There was a positive response in all children (100) Three patients developed progressive disease between 8 and 12 months after ceasing treatment One of them being only 25 years old was again treated by chemotherapy with partial response on MRI Patients with neurofibromatosis type 1 never developed progressive disease Our data suggest that chemotherapy is an effective treatment option in young children with visual pathwaygliomas MRI is an important means of monitoring the tumour response provided that a rigid imaging protocol is used to detect the early tumoral changes
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
SIOP LGG 2004
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
KT ile HOG da genelde SD+PR 62- 83
KT sırası veya sonrası 30-35 PD
ABD-COG-LGG randomize vincristine carboplatin vs
TPCV ( 6-thioguanine procarbazine cisplatin vincristine) (modifiye 6-thioguanine procarbazine dibromodulcitol CCNU and vincristine (TPCDV)
Fransa-BB-SFOP- alterne kuumlrler carboplatin-procarbazin cispatin-VP16
vincristin-cyclophosphamide
Diğer ajanlarcisplatin-vincristine temozolamide oral etoposide tamoxifen ve carboplatinum vinblastin vinorelbine
OG- Kemoterapi
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
OPTİK YOL GLİOMUNDA BİOLOJİK AJANLAR Sporadik OPGrsquode Vemurofenib paradoksik cevap
Sorafenib progresyon
NF-OPGrsquode Farnesiltransferaz inhibitoumlrleri
etkisiz
Tuumlm OPGrsquolerde Bevacizumabplusmnİrinotecan
konvansiyonel KTrsquoye uumlstuumln değil
Sievert AJ Lang SS Boucher KL Madsen PJ Slaunwhite E Choudhari Net al 2013 Paradoxical activation and RAF inhibitor resistance of BRAF proteinkinase fusions characterizing pediatric astrocytomas Proc Natl Acad Sci U SA 110 5957ndash5962 Karajannis MA Legault G Fisher MJ Milla SS Cohen KJ Wisoff JH et al2014 Phase II study of sorafenib in children with recurrent or progressivelow-grade astrocytomas Neuro Oncol 16 1408ndash1416 Widemann BC Salzer WL Arceci RJ Blaney SM Fox E End D et al 2006Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitortipifarnib in children with refractory solid tumors or neurofibromatosis type Iand plexiform neurofibromas J Clin Oncol 24 507ndash516 Gururangan S Fangusaro J Poussaint TY McLendon RE Onar-Thomas A WuS et al 2014 Efficacy of bevacizumab plus irinotecan in children withrecurrent low-grade gliomasmdasha pediatric brain tumor consortium studyNeuro Oncol 16 310ndash317
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Yanıt Oranları
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Vakaların 1 3 uuml
olaysız yaşıyor
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Sirolimus
Erlotinib
Packer ve ark nuumlks duumlşuumlk dereceli gliomlu hastalarda 28 guumln boyunca Erlotinib (Tarceva) ve beraberinde Rapamisinrsquoi kullandıkları ve NFrsquoli 7 hastanın da bulunduğu ccedilalışmada olguların hepsinde stabil hastalık veya kuumlccediluumllme sağlamışlardır
Everolimus (RAD001) ikinci nesil bir oral mTOR inhibitoumlruuml (rapalog) olup refrakter veya ilerleyen duumlşuumlk dereceli gliomlarda (OPGrsquoler de dahil) denenmektedir (NCT01158651)
Gottfried ON Viskochil DH Couldwell WT Neurofibromatosis Type 1 and tumorigenesis molecular mechanisms and therapeutic implications Neurosurg Focus 201028 (1)E8
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
COG Protocol ACNS1022-Phase II Randomized Trial of Lenalidomide in Pediatric Patients with Recurrent Refractory or Progressive Juvenile Pilocytic Astrocytoma and Optic Pathway Gliomas
Lenalidomide- oral- antiangiogenik and immunomodulatuar aktivite- Ccedilocuk CNS tm de etkili olabilir
Randomize ccedilalışma
Lenalidomide ndashya duumlşuumlk doz(20 mgm2 doz) ya yuumlksek doz (115 mgm2 doz) PO- 21 guumln-28 guumlnluumlk siklus
26 kuumlr (PDR a kadar)
Yanıt oranı
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
FARKLI TEDAVİ DENEMELERİhellip Brain 2016 Feb139(Pt 2)404-14
Nerve growth factor improves visual loss in childhood optic gliomas a randomized double-blind phase II clinical trial
Falsini B etal Riccardi R Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss
Presently there is no strategy to prevent visual loss in this kind of tumour This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients aged from 2 to 23 years with stable disease and severe visual loss Ten patients were randomly assigned to receive a single 10-day course of 05 mg murine nerve growth factor as eye drops while eight patients received placebo All patients were evaluated before and after treatment testing visual acuity visual field visual-evoked potentials optic coherence tomography electroretinographic photopic negative response and magnetic resonance imaging Post-treatment evaluations were repeated at 15 30 90 and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days) which were not observed in placebo-treated patients Furthermore in patients in whom visual fields could still be measured visual field worsening was only observed in placebo-treated cases while three of four nerve growth factor-treated subjects showed significant visual field enlargement This corresponded to improved visually guided behaviour as reported by the patients andor the caregivers There was no evidence of side effects related to nerve growth factor treatment Nerve growth factor eye drop administration appears a safe easy and effective strategy for the treatment of visual loss associated with opticpathway gliomas
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
NF-1 de oftalmolojik tarama
American Academy of Pediatrics (AAP) oumlnerileri
NF-1 1-7 yaş arası ccedilocuklara yılda bir 8-18 yaş arası 2 yılda bir oftalmolojik muayene Glioma insidensi 42 morbiditesi duumlşuumlk Asemptomatik hastalara rutin MR oumlnerilmemekte vizuumlel değişiklik sebat eden baş ağrıları konvulziyonlar baş ccedilevresinde belirgin artış kafada pleksiform noumlrofibrom NF1 tuumlm gende delesyon olanlara oumlnerilmekte OG saptanırsa ilk yıl 3 ayda bir kontrol
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
NF-1 de oftalmolojik tarama
bull NF1rsquoli hastaların OG iccedilin taranması Normal goumlz muayenesi olan asemptomatik hastada bazal kranyel goumlruumlntuumlleme veya VEP ldquovisual-evoked potentials ldquo oumlnerilmemektedir (A-III) lt8 yaş altında tuumlm hastalar yılda bir oftalmolojik muayene olmalıdır(A-II) Goumlrme keskinliği goumlrme alanının değerlendirilmesi renkli vizyon testleri pupillerin değerlendirilmesi goumlz kapakları okuler motilite iris ve fundus muayenesi Goumlrme alanlarının bilgisayarlı veya kinetik testi hasta guumlvenilirse yardımcı olabilir ancak gerekli değildir Bu değerlendirmelerin muumlmkuumlnse NF1 li kuumlccediluumlk ccedilocukların test edilmesinde yetenekli bir oftalmolog veya noumlro-oftalmolog tarafından yapılması oumlnerilmektedir
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Rejin Kebudi Samuray Tuncer Fatma Betul Cakır Omer Gorgun Fulya Yaman Ağaoğlu Inci Ayan Emin
Darendeliler
İstanbul Uumlniversitesi
Cerrahpaşa Tıp Fakuumlltesi amp Onkoloji Enstituumlsuuml
Pediatrik Hematoloji-Onkoloji Bilim dalı Radyasyon Onkolojisi BD ITF Oftalmoloji
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Demografik veriler
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml
N= 61 patiens (1990-2012 )
32 kız 29 erkek
Median yaş - 5 yaş (1 ay-19 yaş)
66 (40) NF-1
2 kardeş
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Kebudi RUpadhyaya MTuncer Set al A novel mutation in the NF-1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma Pediatric Blood and
Cancer 2008
NF EUROPE 2012 Istanbul
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
KLİNİK BULGULAR Goumlrsel bozukluklar
vizyonda azalmakayıp
strabismus
proptosis
KIBAS
başağrısı
kusma
nistagmus
konvulsiyon
endokrin bozukluklar
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Diensefalik sendrom Kebudi R Tuğcu D Ayan İ Gorgun O Diensefalik sendromlu bir olgu Cocuk Dergisi 2007 7 69-71
5 hastada Diensefalik sendrom (hipotalamic tumor) (failure to thrive emaciation-losing weight euphoria)
3 uumlnde leptomeningeal yayılım 2 si exitus diğer hastada diensefalik sendrom + yaygın spinal aks seeding metastaz vardı VC KT ile tam yanıt aldı halen yaşıyor
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Dodge Classification
13 (21) Dodge I (tumor confined to optic nerve only)
11 (18) patients bilateral involvement
27 (44) Dodge 2 (tumor involving the chiasm)
21 (34) Dodge 3 disease (tumor extended to the hypothalamus)
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
TEDAVİ
Median 38 ay takip (1 ay-24 yıl)
15 (25) hasta tedavisiz stabil hastalıkla takip edildi
TEDAVİ
Semptomatik ve Progresif hastalıkta verildi
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
TEDAVİ- Cerrahi Radyoterapi 18 (31) hastada cerrahi uygulandı
5 total
4 subtotal
9 VP şant 5 i ek tedavi almadı
6 hasta RT aldı
2 hasta primer RT aldı
3 RT ve KT
1 cerrahi ve RT
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
TEDAVİ-KEMOTERAPİ VCR 15 mgmsup2
Carboplatinum 560 mgmsup2
İlk 3 kuumlr 3 hf bir sonra 4 hf bir 12 kuumlr
38 hasta KT aldı
6 hasta C + KT
3 hasta RT + KT
29 hasta tek KT 37 vincristinecarboplatin (VC)
1 (vincristineCCNUCTX and PCZ)
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Tedavi sonuccedilları Tuumlm grup sağkalım 5 yıl 943
5 yr PFS NF+ 81 NF- 76
3138 KT ile hasta klinik yanıt stabil kaldı
738 KT altında PD (6 VC 1 diğer)
Goumlrme- sonuccedillar
23 hastada goumlrsel fonksiyonlar stabil
13 hastada goumlrsel fonksiyonlar da duumlzelme
4 diensefalik sendromtartı alımı noumlrolojik tabloda duumlzelme
Radyolojik
30 hasta stabil hastalık
5 inde kısmi regresyon
1 spinal aksta total regresyon
Endokrin takip 21 hastada endokrin sorunlar
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
The 5-year and 10-year PFS rates were 814 and 656 and 763 and 656 in NF-1 vs non-
NF-1 patients respectively
5 year progression free survival (months)
NF patient
Non NF patient
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
SONUCcedil OG oumlzellikle NF li hastalarda yıllarca stabilyavaş seyirli olabilir
Bir kısmı progrese olup semptomatik olabilir (visuel endokrin
bozukluk koumlrluumlk exitus)
Semptomatik progrese hastalarda kemoterapi (en sık kullanılan
vincristine-carboplatinum) etkindir ve iyi bir hayat kalitesi sağlar
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Tuumlrkiyersquoden deneyimler Varan A et alAm J Clin Oncol 2012
Hacettepe Uumlniversitesi Onkoloji Enst
N= 101 (1975-2008 )
Median yaş 6 (1 ay-18 yaş)
53 NF- 1
31 hypothalamic-chiasmatic
30 KT 49 C 40 RT
5 yr PFS 65 OS 88
10 yr PFS 54 OS 83
CDDP 100 mgm2 VP 16 100 mgm2 x 3 day every 28 days for 9 cycles or COPP
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Tuumlrkiyersquoden deneyimler Kebudi R et al 2012
İstanbul Uumlniversitesi Onkoloji Enstituumlsuuml ITF Goumlz
N= 61 ccedilocuk hasta (1990-2012 )
Median yaş 5 yaş (1 ay-19 yaş)
66 NF-1
5 inde diensefalik sendrom
34 - hipotalamus
3 leptomeningeal hastalık 2 si ex
5 yr PFS NF+ 81 NF- 76
38 hasta KT aldı
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Tuumlrkiyersquoden deneyimler Erkal HS et al 1997 Radiother Oncol Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy
Ankara Uumlniversitesi Rad Onk BD
N= 33 ccedilocuk hasta (1973-94) hepsi RT alan hasta
6 NF-1
24 OG 9 - kiazma-hipotalamus
5 yr 10 yıl PFS 82 77 5 ve 10 yıl S 93 ve 79
Teşekkuumlrler
Teşekkuumlrler