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Retroperitoneal disease
Testicle only
Extra-retroperitoneal disease or S2/S3 markers
Non-pulmonary visceral mets: bone, liver, etc.
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AJCC 1997 Testis Tümör Evrelemesi Primer Tümör
• pT1. Testis ve epididime kısıtlı tümör ve lvi yok; tümör tunika albugineaya invaze olabilir ama t vajinalise değil.
• pT2. Testis ve epididime kısıtlı
tümör ve lvi var veya tunika albugineayı aşan ve t vajinalise invaze olan tümör.
• pT3. Spermatik kord invazyonu, lvi
var veya yok. • pT4. Skrotum invazyonu, lvi var
veya yok.
Embriyonel karsinom, VI (+)
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Erken Evre NSGCT Klinik Evreleme
Retroperiton, doğru evrelemenin en zor yapıldığı alandır Klinik Evre I hastaların %30’u düşük evrelenmiştir RPLND (patolojik II) izlem çalışmaları Klinik Evre IIA hastaların %30’u gerçekte pN0 MSKCC % 35 Indiana % 23 SNTCG % 38 Sistemik evreleme önemli ölçüde düzeldi
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Okült Sistemik Hastalığı Saptamak
Orşiyektomi sonrası normal AFP ve/veya HCG IS ve IIA (S1) olanları dışla: ↑ AFP and/or HCG
genelde okült sistemik hastalığı gösterir Davis B et al; J Urol 152: 111,1994
Sheinfeld J et al; Proc ASCO, 1999 Rabbani F et al; J Clin Oncol 19: 2020, 2001
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Germ Hücreli Tümörler Doğal Seyir
Primer tümör
Retroperitoneal lenf nodları
Uzak metastaz
~10%
~90%
Retroperiton: ilk ve sıklıkla tek metastaz sahası
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Evre 1 NSTT’de tedavi seçenekleri
• RPLND • İzlem
• Primer kemoterapi
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Klinik Evre I NSGCT İzlem
Değerlendirilen hasta sayısı 2,222
NED olan hastalar 2,169 ( 98% )
Relaps sayısı (tüm hastalar) 585 ( 26% )
CS IA (LVI yok) ( 15% )
Relapsa kadar zaman (ay) ~7 (4-13)
Ortanca izlem (ay) 21-135
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Klinik Evre I NSGCT İzlem
• Relaps: %80-90 ilk yıl; %98 ilk 2 yıl
• Relaps bölgesi: Retroperiton en sık akciğer tutulumu veya marker yüksekliği de olabilir, ama
sadece birisi daha az sıklıkla diğer organlar nadir
• Relapsı öngören faktörler: lenfovasküler invazyon ECA T2 - 4
Kemoterapi almamış relaps gösteren hastalarının kür şansı fevkalade
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Evre I NSGCT, Relapsı ne öngörebilir?
RELAPSE mean
vasc. Inv. (+) 36-96% 52%
vasc. Inv. (-) 10-69% 22%
(Klepp, J Clin Oncol, 8:509, 1990) (Moul, Cancer Res 54:362, 1994)
(Leivovitch, J Clin Oncol 16:261, 1998) (Heidenreich, Cancer 83:1002, 1998)
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NSGCT İzlem
Yıl STM, CXR Vizitler arası ay
Abdominal/pelvik BT Aylar
1 1-2 2-3
2 2 3-4
3 3 4
4 4 6
5 6 12
6+ 12 12 Journal of NCCN 2006; 4: 1047
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Hacettepe deneyimi
140 hasta Evre 1 NSTT Şubat 1978 ile Mayıs 2000 8 (%6) takibe uymamış Median yaş: 28 (16-52) y Median takip: 38 (9-265) ay
Ozen et al: Eur Urol, 2001
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Patolojik tip # %
Miks germ hücreli 90 68
Embriyonal karsinom 22 17
Teratokarsinom 19 14
Yolk sac tümör 1 1
Total 132 100
Hastaların histopatolojik özellikleri
Ozen et al: Eur Urol, 2001
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İzlem
Relaps 32 (24%) hastada görüldü. Relapslar 2-23 ay arasında görüldü. Bunların 28’inde(%87) relaps ilk yıl içinde
idi. 1 hasta kaybedildi.
Özen et al: Eur Urol,
2001
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Diğer izlem çalışmaları
Ülke &Yazar
# İzlem(ay)
Relaps Ex
Hollanda 126 42 28 1Danimarka 150 64 30 0R.M 132 30 27 1MSKCC 102 82 25 3MRC 396 48 25 5Ozen 140 32 24 1
%26 %1.2
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HÜTF’de relaps özellikleri Relaps % 24 oranında görülmüştür. Relapsın median zamanı 4 aydır. 23 aydan sonra relaps görülmemiştir. %56 oranında relaps RP’da
görülmüştür.
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RELAPS ZAMANI
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23RELAPS
0
2
4
6
8
RELAPS
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23RELAPS
AYLAR
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HÜTF İzlem protokolü 1. yıl 1.5 ayda AC, FM, TB 3 ayda USG, 6 ayda BT 2.yıl 2.5 ayda AC, FM, TB 5 ayda USG 3.yıl 4.5 ayda AC, FM, TB, USG 4.yıl 6 ayda AC, FM, TB, USG 5+yıl Yılda AC,FM,TB,USG
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RPLND Cerrahi Teknikte Evrim
Yazar Yıl Teknik
Lewis 1948 Tam bilateral (suprahilar)
Whitmore 1955 Modifiye bilateral
Lange 1982 Modifiye template Jewett 1987 Sinir koruyucu
Donohue 1990 Sinir koruyucu
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Bilateral RPLND Modified RPLND
“RP node sampling”
Suprahilar İnfrahilar
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Donohue J et al, J Urol 128, 1982
SAĞ
SOL
B-1 B-2 B-3
B-1 B-2 B-3
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RPLND “Mapping Study” Donohue J et al J Urol 128, 1982
“Landing zone” konsepti
Suprahilar metastazlar, düşük hacimli hastalıkta nadir
Karşı tarafa geçiş: LN hacmi ile orantılı olarak artar B3 > B2 > B1 Sağ >> Sol Kontralateral iliak çok nadiren etkilenir
Teratom 26/104 (%25). Pür ECA olan 3/49 (%6) dahil
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RPLND Modifiye Template
SAĞ SOL
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Sinir Koruyucu RPLND
left renal vein
IVC
hypogastric plexus
aorta
Left psoas
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1°RPLND Hasta Özellikleri
1989-2004 n = 500 Ortalama yaş 30.4 Lateralite R – 270 L – 230 Klinik Evre I – 364 IIA – 136 Yüksek STM - 20
ORŞİYEKTOMİ PATOLOJİSİ EC – 421 (pür EC 73)
LVI – 305 Teratom – 255
PATOLOJİK EVRE II -- 192
pN1 92 (48%) pN2/3 100 (52%)
RETROPERİTON PATOLOJİSİ Canlı GCT 175 (91%)
Teratom (herhangi) 44 (23%) Sadece Teratom 17 (9%)
Postop kemo 106 (55%)
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Evre I NSGCT, RPLND • RPLND sonrası relaps oranı% 6-15 olup
nadiren RPdadır
ref. N relapse retroperitonealHermans, 2000 292 10% 2.7%
Donohue, 1994 266 12% 0
Heritz, 1994 36 11% 0
de Bruin, 1993 27 0% 0
Ritchie, 1990 64 6%
Pizzocaro, 1985 71 15% 0
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RPLND YAZAR RELAPS (%) # İzlem (ay)
Pizzacaro 14.5 66 40Richie 6 64 38Jewett 11 36 44Donohue* 10.2 292 71McLeod 10.2 264 63
*Hermans et al, J Urol, 2000
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Evre I NSGCT, RPLND morbidite / mortalite
• %3-23 morbidite • Antegrad ejakülasyon (%75-94) • Geç yan etkiler (ileus)>%2
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Laparoskopik RPLND: AUA 2007 Abstrak 1004 Pizzocaro G et al
1999 – 2000
Klinik IA ( n = 8 )
2’sinde pozitif nod Adjuvan kemo yok
HER İKİSİ’nde de karaciğer met gelişti !!
?? Pnömoperiton etkisi
MSKCC (IA,IB,IS,IIA) 1° RPLND : 0/577 karaciğer met
İngilizce literatüre göre, %96’dan fazla PS II hasta lap-RPLND’den sonra BEP x 2 alır, bu nedenle etkinlik değerlendirilemez. Birçok seride terapötik intent de eksiktir.
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P = 0.0033
1 x PEB (n = 174)
RPLND (n = 173)
ACT Çok merkezli çalışma: 60 merkez 19 merkez….1 hasta 11 merkez ….2 hasta 4 merkez …...3 hasta 1 merkez …….68 hasta Aynı grup tersiyer merkezlerde %1.2 RP rekürrensi bildirdi
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Klinik Evre I NSGCT RPLND mi BEP x 1 mi?
382 hasta randomize (ITT) LVI ~ 43% (CS IB)
Ortanca takip 4.7 yıl 35 hasta çıkarıldı (protokol violasyonu, seminom – 7)
347 hasta protokole göre tedavi edildi (ATP)
BEP x 1 n = 174
2 relaps
İpsilateral RPLND n = 174
32 (18%) pN+
IIA – 25 IIB – 6 IIC – 1
BEP x 2
141 (82%) pN0
13 relaps RP – 7
Skrotal – 2 Akciğer - 4 Albers et al JCO 2008
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Erken Evre NSGCT 1° RPLND
• En doğru (N) kategorizasyonu sağlar
• Düşük hacimli birçok hastada küratiftir (pN1)
• Mortalite yoktur; morbidite minimaldir
• Sinir koruyucu: Antegrad ejakülasyon >95%
• Retroperitonda geç relaps potansiyeli azalır
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RPLND
Evre I Seminom dışı tümörler arasında yanlızca pür matür teratomda ilk seçenek RPLND’dir.
Zira teratomlarda tanı anında %20’yi bulan okült retroperitoneal metastaz mevcuttur.
Rabbani,Urology,2003
Heidenreich,Eur.Urol.2006
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ACGME – RRC Analiz
2000 – 2004 (RPLND: 781 – 924) 108 program, 232 asistan
• uzman olanların 50%’si < 2 RPLND Yapmış ve 1 tane 1. assitans yapmış • %10’u ise hiç görmemiş
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Primer kemoterapi
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Kemoterapi
Cerrahiden korur Etkin Psikolojik stresi azaltır
Prognostik kriterler? Fazladan tedavi Kemonun morbiditesi Sekonder kanserler? Relaps sonrası kemo etkisi? Yinede %5 relaps
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Evre I NSGCT: primer kemoterapi
ref. N Criteria Scheme Relapse
Gimmi, 1990 41 embr.carc. or >pT1 BEP/PVB 0%
Studer, 1993 42vasc.invasion,
>pT1, embr.carc.
2xBEP/PVB 2.5%
Kratzik, 1996 87 vasc.invasion BEP 4.6%
Pont, 1996 29 vasc.invasion 2 x BEP 6.9%
Studer, 2000 59vasc.invasion,
>pT1, embr.carc.
2xBEP/PVB 3.4%
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Evre 1 yüksek risk NSGCT EC ve / veya VI
Relapse Unnec.CT(% of total
population of clinical stage 1)
stage 1 high risk surveillance 50% 0%(40-50% of clinical stage 1)
RPLND N- 20-25% 0%(40-50%)
N+ CT- 2-42% 0%(50-60%) CT+ 0-6% ~15%
primary CT 0-7% ~50%
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Germ Hücreli Tümörler Kemoterapi elimizi güçlendirmektedir
Kür Oranları — İyi Risk: > 90% Orta Risk: 75% Kötü Risk: 45%
(JCO 1997; 15:594)
Kanıta-Dayalı Tedavi Önerileri
IGCCCG’ye Göre Tedavide Anahtar İlaç İlk basamak tedavi:
Sisplatin (100 mg/m2) + Etoposid +/- Bleomisin
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Kemoterapi madem bu kadar etkili neden herkeze vermiyoruz?
1. Toksisite sadece akut değil geç ve hatta kalıcı ve hatta öldürücü olabilir 2. Her zaman Teratoma olasılığı
düşünülmelidir.
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Toksisite 1. Pulmonary toksisite (BEPx4 = %1-2 ölüm) 2. B-K
Raynaud’s phenomenon: % 6-7 BEP alanlarda(NEJM 1987); Sadece Bleomisin alanlarda (de Wit, JCO, 1997)
3. Raynaud’s phenomenon (Ann Int Med, 1981) 4. Magnesium Kaybı → Raynaud’s. (Cancer, 1985) 5. Yüksek renin/aldosterone →?Vasküler toksisite (JCO, 1986)
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Vasküler Toksisite: Geç kemo toksisitesi
(Meinardi et al, JCO 2000)
MI 6/87 ( 7%) Yaş: 30-42: 7:1 Risk artımı
Ekzersiz ile ST çökmesi 6/55 (11%)
Kardiyak Risk Faktörleri: Chemo vs no chemo
Chol 79% vs 58% fark ; 21% BP 39% vs 13% fark; 26%
Raynaud’s 24% vs 0% Fark; %24
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(B)EP’in geç toksistesi – Leukemia Doza bağlı ve en düşük güvenli doz yok
(Includes other drugs)
(Schneider et al. JCO 1999; 17:3226)
=2(B)EP cycles =adjuvant
chemo
=4(B)EP cycles =initial chemo
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van den Belt-Dusebout, JCO; 25:4370, 2007
Chemo
RT
Surg only
RT+ Chemo
1. İkincil kanser ve CV hastalık riski en çok RT+KT
> RT > CT > Cerrahi
3. CV hastalık 10-15 y ikincil kanser 20-25 y sonra
İkinci Malignant Neoplasmlar (SMN) and Kardiyovasküler Hastalık (CVD)
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Evre 1 de KT
1. RPLND: A. p Evre 1 de ~%5-10 relaps. B. p Evre 2‘A da ~% 10-15 relaps C. Demek ki; bu hastaların %20-25’i KT alır. 2. İzlem = %30 relaps olur ve 3 kür KT gerekir. Bu
RPLNd’ye göre daha fazla KT demek 3. KT: %100 KT alir
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Evre 1, NSGCT primer kemoterapi
Surveillance RPLND prim.chemomean productivity loss per patient (weeks)
5.2-5.7 5.9-7.3 4.9-6.1
(Lashley, Urol Clin N Am 25:405, 1998)
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Hastalar neyi tercih ediyor?
Relaps riski Tercih
>50% Hemen tedavi: Kemo veya RPLND
40-50% Doktor karar versin
<40% Çoğunluk izlemi seçiyor
Stiggelbout et al: Eur J Cancer, 1996
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Doktorlar neyi seçiyor?
Hastalar kemoyu >%50 riskte tercih
etmelerine karşın, doktorlar relaps oranlarının %73’lere vardığında kemoyu tercih ediyor.
Stiggelbout et al: Eur J Cancer, 1996
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Bütün bu tartışmalar neden? Evrelendirmeyi iyi yapamıyoruz
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PET scan
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PET scanning and metastases detection
(Hain, Eur J Nucl Med 27:590, 2000)
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PET
(Leibovitch, J Urol 154:1759, 1995) (Saunders, Ann Thorac Surg, 67:790, 1999)
1. Detection limit of (spiral) CT: 1-1.5 cm
(?) at 3mm: sens.=90% BUT spec.=50% 2. PET detected cancer in normal sized LN
in lung cancer
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PET scanning and metastases detection in stage I and II
PET did not detect microscopic lesions (<0.5 cm)
however, all c-stage II lesions were correctly asigned
trials: AU, AH06/98, ongoing (n=312, 3-4 years) EORTC, high risk stage I patients
(Albers, Urology 53:808, 1999) (Cremerius, Urology 54:900, 1999)
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Evre I Seminom dışı
EAU VI (-) İzlem (B) VI (+) BEP x 2 (B) Ancak ! RPLND + KT (A)
NCCN IA İzlem / RPLND IB RPLND / BEPx2 İzlem IS EP x 4 / BEP x 3
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Risk faktörleri
EAU: VI PPV: % 53 % 50 EC % 70 MIB-1 PPV: % 64 EAU: pT1, VI (-) pT2-pT4 NCCN: IA: pT1, IB: pT2, pT3, pT4