referat peter reichardt vor ort.ppt [kompatibilitätsmodus] · • in cases of clinical suspicion...

Meet-the Expert-SessionSystemtherapie bei Weichteilsarkomen

Peter Reichardt

HELIOS Klinikum Berlin-Buch / Interdisziplinäre Onkologie / Onkologisches Zentrum Berlin-Buch / Sarkomzentrum Berlin-Brandenburg

1P. Reichardt HELIOS Klinikum Berlin-Buch / Interdisziplinäre Onkologie

1. Anstellungsverhältnis oder Führungsposition

keine

2. Beratungstätigkeit

Novartis, Pfizer, Bayer, PharmaMar, Ariad, Amgen, GlaxoSmithKline

3. Aktienbesitz

keiner

4. Honorare

Novartis, Pfizer, Bayer, PharmaMar, Amgen, GlaxoSmithKline

5. Finanzierung wissenschaftlicher Untersuchungen

Novartis

6. Gutachtertätigkeit

keine

7. Andere finanzielle Beziehungen

keine

Offenlegung potentieller Interessenkonflikte

2

Basics

• incidence 4-5/100.000

• approximately 1% of all adult cancers

• equal gender distribution

• ~10 % of patients present with metastatic disease at the time of diagnosis

• 40 to 60% of patients with localised, high-grade soft tissue sarcoma will develop metastases

• metastases occur primarily in the lungs, lymph node metastases very rare (exceptions: rhabdomyosarcoma, synovial sarcoma)

• median survival from time of diagnosis of metastatic disease around 12 months.

HELIOS Klinikum Berlin-Buch / Interdisziplinäre OnkologieP. Reichardt


Individual sarcoma histologies as proportion of all soft tissue sarcoma (STS) by age according to Surveillance, Epidemiology and EndResults (SEER) data,1975-1999

Parham et al. ASCO 2011


Soft tissue sarcoma (STS) and bone sarcoma (bone) incidence by ageaccording to Surveillance, Epidemiology, and EndResults (SEER) data

Parham et al. ASCO 2011


Diagnostic Procedures

• in cases of clinical suspicion of soft tissue sarcoma, primary imaging is mandatory (MRI method of choice)

• histological verification of diagnosis with core needle biopsy or incisional biopsy (considering the definitive surgical procedure)

• staging: CT of lungs mandatory, further imaging according to clinical findings


Lipoma

Dediff. liposarcoma

Imaging / Biopsy


Pleomorphic liposarcoma (G3)

Biopsy / Surgery

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Surgical Treatment

• radical surgery

• marginal resection with 90% local recurrence

• re-resection in case of R1/R2 if possible



O‘ Sullivan et. al. 2003

• „tumor capsule“ is frontline of sarcoma

• in 66% of patients, tumor cells are found in peritumoral edema

Risc of local recurrence

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Radiotherapy

• 60-70 Gy postoperative radiation achieves local control rates of 70-90% after R1-resection

• significantly improved local control rate with postoperative radiation, no improvement of overall survival

• no radiation after radical surgery or stage 1A tumors

• always radiation after surgery for local recurrence



Isolated limb perfusion (ILP)


before after

before after

ILP – clinical results


MRI before ILP MRI after ILP



PET before ILP PET after ILP



Stojadinovic et al. J Clin Oncol 2002; 20: 4344–52

STS: Survival by Stage of Disease


Classical active agents: Anthracyclines, ifosfamide, DTIC

More recent agents: Trabectedin, pazopanib

Unregistered agents: Gemcitabine, docetaxel, trofosfamide, temozolomide

Systemic therapy


• Combination of doxorubicin or epirubicin with ifosfamide + DTIC results in response rates of up to 50 % (appr. 10% CR)

• Significantly higher response rate and progression-free survival compared to single agent therapy

• Significantly higher toxicity

• No significant improvement of overall survival in first-line therapy so far

Combination chemotherapy in first line


• Standard chemotherapy is based on anthracyclines as first line treatment.

• As of today, there is no formal demonstration that multiagent chemotherapy is superior to single-agent chemotherapy with doxorubicin alone in terms of OS.

• However, a higher response rate may be expected, in particular in a number of sensitive histological types.

• Multiagent chemotherapy with adequate-dose anthracyclines plus ifosfamide may be the treatment of choice, particularly when a tumour response is felt to be potentially advantageous and patient performance status is good.

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First-line treatment of STS


• In angiosarcoma, taxanes are an alternative option, given their high antitumour activity in this specific histological type. An alternative option is gemcitabine + docetaxel.

• Doxorubicin plus dacarbazine is an option for multiagent first-line chemotherapy in leiomyosarcoma, where the activity of ifosfamide is far less convincing in available retrospective evidence, or in solitary fibrous tumour.

• Imatinib is standard medical therapy for those rare patients with dermatofibrosarcoma protuberans who are not amenable to non-mutilating surgery or with metastases deserving medical therapy.

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First-line treatment of STS


• Patients who have already received chemotherapy may be treated with ifosfamide, if they did not progress on it previously. High-dose ifosfamide (around 14 g/m²) may be an option also for patients who have already received standard-dose ifosfamide.

• Trabectedin is a second-line option and is approved for advanced previously treated STS in the EU. It has proved effective in leiomyosarcoma and liposarcoma. In myxoid liposarcoma, a high antitumour activity was described. A peculiar pattern of tumour response has been reported, with an early phase of tissue changes preceding tumour shrinkage. Clinical benefit with trabectedin was also obtained in other histological types.

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Treatment of anthracycline-refractory STS


• One trial showed that gemcitabine + docetaxel is more effective than gemcitabine alone as second-line chemotherapy, with special reference to leiomyosarcoma and undifferentiated pleomorphic sarcoma, but data are conflicting and toxicity is different. Gemcitabine was shown to have anti-tumour activity in leiomyosarcoma and angiosarcoma also as a single agent.

• Dacarbazine has some activity as a second-line therapy (mostly in leiomyosarcoma and solitary fibrous tumour). The combination of dacarbazine and gemcitabine was shown to improve the OS and PFS over dacarbazine in a randomised trial.

• A randomised trial showed a benefit in PFS averaging 3months for pazopanib given up to progression to advanced, previously treated, STS patients (excluding liposarcomas). Thus, it is an option in non-adipogenic STS.

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Treatment of anthracycline-refractory STS


Maki RG et al., J Clin Oncol 2007

Combination CT in refractory STS gemcitabine/docetaxel


Combination CT in refractory STS gemcitabine/DTIC

Garcia Del Muro et al., J Clin Oncol 2011


Le Cesne et al. J Clin Oncol 2005; 23(3): 576–84; Yovine et al. J Clin Oncol 2004; 22(5): 890–9; Garcia-Carbonero et al. J Clin Oncol; 2004: 22 (8): 1480–90; Le Cesne et al. AACR-NCI-EORTC Clin Cancer Res Vol 9 (16) Suppl, Abstract A31

Refractory STS: pooled analysis of phase II–trials with trabectedin


Single agent in refractory STS Pazopanib

van Der Graaf et al., Lancet 2012


Long term responders and survivors on pazopanib for soft tissue sarcomas (STS). Subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072

Kasper et al. 2014, Annals of Oncology; 1-6, 25: 719-724, 2014;

• 36% of patients with PFS >6 Monate

• 34% of patients with OS >18 Monate

• Prognostic factors for PFS and OS

- good Perfomance Status

- low/ intermediate tumor grade)

- normal baseline hemoglobin level


Current questions in advanced STS: Choosing the best treatment

• What is the PS of the patient?

• What is the specific disease stage or the amount of disease?

• What is the goal of treatment?

• What is the specific STS subtype?


• Goal 1: Make an advanced tumour resectable- Treatment with high probability of RECIST responses- High toxicity acceptable

Choosing the best treatment in refractory STS:Different agents for different goals

• Goal 3: Stabilization of the tumour with a good QoL- High tumour control rate

- RECIST response not necessary

- Long term benefit

- Well tolerated therapy

• Goal 2: Control symptomatic disease- Treatment with high probability of RECIST responses

- Toxicity acceptable

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Taxonomy of soft tissue sarcoma

Taylor et al., Nat Rev Oncology 2011


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Distribution of histological subtypes

• Distribution of histological types: % of all sarcomas diagnosed in 3 European regions (Aquitaine and Rhône-Alpes in France, Veneto in Italy; 2005-2008):

• Four major histological types in the 3 registries: GISTs, leiomyosarcomas (non uterine and uterine), liposarcomas and unclassified sarcomas.

60% of all sarcomas

Mastrangelo G, et al. Cancer. 2012 Apr 19. doi: 10.1002/cncr.27555.


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STS – subtype-specific treatment

• combination chemotherapy with curative intent

• ifosfamide in synovial sarcoma

• trofosfamide in elderly / unfit patients

• taxanes in angiosarcoma

• hormonal therapy in endometrial stromal sarcoma of uterus

• gemcitabin / docetaxel in leiomyosarcoma (Uterus)

• trabectedin in leiomyosarcoma, liposarcomas, and TRS

• topo I – inhibitors in rhabdomyosarkoma and Ewing tumors

• sorafenib in angiosarcoma

• IGF1RAB in Ewing tumors, DSRCT, SFT

• etc.HELIOS Klinikum Berlin-Buch / Interdisziplinäre OnkologieP. Reichardt

32

Leiomyosarcoma (LMS)

Mastrangelo G, et al. Cancer. 2012 Apr 19. doi: 10.1002/cncr.27555; Matushansky I, et al. Am J Cancer. 2006;5(2):81-91; Eriksson M. Ann Oncol. 2010; 21(7):vii270–6; Sleijfer S, et al. Eur J Cancer. 2010;46:72–83.

• One of the most common subtypes: accounting for about 16% of all soft tissue sarcomas.

• Approximately half of all patients despite adequate local control of their disease will develop distant metastasis.

• Retrospective, exploratory analysis performed in 1,337 advanced STS patients who received first-line ifosfamide-containing chemotherapy (660 patients treated with doxorubicin monotherapy as comparators).

• Patients with leiomyosarcoma did not benefit from ifosfamide, with a decreased OS (P = 0.0247).


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Leiomyosarcoma (LMS)

• Retrospective study of 22 chemotherapy naive patients treated with the combination of doxorubicin/dacarbazine (60 mg/m2 Day 1/450 mg/m2 Day 1, 2 Q 3 weeks).

• A total of 105 cycles were administered with a median number of 6 cycles.

• EFFICACY:

- Median PFS = 15.1 months

- Median OS = 33.9 months

- Best response: PR (n=6.27%)

- Clinical benefit rate = 95% (only one patient progressed while on chemotherapy)

Rahal C, et al. ECCO-ESMO. 2013: Abs Nº 3837


34P. Reichardt HELIOS Klinikum Berlin-Buch / Interdisziplinäre Onkologie7B. L. Samuels, J Clin Oncol 28:15s, 2010 (suppl; abstr 10027)

Trabectedin as single agent for advanced soft tissue sarcomas failing standard of care

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Myxoid liposarcomas

• In myxoid liposarcomas, trabectedin can be the treatment of choice:

• In 51 pre-treated myxoid liposarcomapatients:

• ORR: 51%

• Tumour Control Rate: 90%

• Median PFS: 14.0 months

• PFS at 6 months: 88%

• In a phase II trial, 23 patients received trabectedin as neoadjuvant treatment:

• pCR (pathological complete response, complete disappearance of tumor tissue) =13%• PR=24%• No patients had disease progression from onset of study treatment to curative surgery

Eriksson M. Ann Oncol. 2010; 21(7):vii270–6; Grosso F, et al. The Lancet Oncol. 2007;8(7):595-602; Gronchi A, et al. Ann Oncol. 2012;23(3):771-6


36

Angiosarcoma

• Taxanes (paclitaxel or docetaxel) seem to be the drugs of first-line choice:

• In a study of patients with cutaneous sarcoma, eight of nine treated with paclitaxel and six of nine patients treated with docetaxel responded to treatment.

• In a larger retrospective study of 32 patients with angiosarcoma, 20 patients (63%) responded to paclitaxel treatment, with a progression-free survival of 7.6 months.

• Biological therapies, in particular antiangiogenic therapies, offer hope for an angiosarcoma specific treatment, with further prospective studies needed to clarify treatment strategies:

• In a phase 2 study of single-agent bevacizumab in 29 patients with angiosarcoma three partial responses and 13 patients achieving stable disease were seen in 26 evaluable patients, suggesting significant activity.

• Partial responses were seen in four patients and one complete response was seen with sorafenib in a phase II trial, giving an overall-response rate of 14% with a median progression-free survival of 3,8 months.

Young RJ, et al. Lancet Oncol. 2010;11:983–91; Eriksson M. Ann Oncol. 2010; 21(7):vii270–6



• Mammalian target of rapamycin inhibitors in malignant perivascular epithelioid cell tumours (PEComas), which are often associated with the loss of tuberous sclerosis complex 1 (TSC1)/TSC2.

• Crizotinib in inflammatory myofibroblastic tumour associated with anaplastic lymphoma kinase translocations.

• Sunitinib and cediranib in alveolar soft part sarcoma, where the molecular target is as yet unclear.

• Sunitinib in solitary fibrous tumours, where the molecular target is as yet unclear.

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Molecular targeted agents


Solitary fibrous tumor

VEGFR-1 is found in 92% of SFTSawada et al., Pathology International 2002

39

Targeted therapy in alveolar soft part sarcoma

• ASPS account for appr. 1% of all STS• t(X;17)(p11;q25) translocation results in ASPL-TFE3 fusion gene,

which encodes for an aberrant transcription factor which leads to activation of MET

Tsuda M et al., Cancer Res 2007;67:919-929


40

Tivantinib in ASPS

Wagner et al., Cancer 2012

• Tivantinib (ARQ 197) is a selective inhibitor of MET• Phase II trial in MiT (microphthalmia transcription

factor-associated tumors)


41

Sunitinib malate in ASPS

Palassini et al., J Clin Oncol 28:7s, 2010 (suppl; abstr 10014)


42

Cediranib in ASPS

Kummar et al., J Clin Oncol 2011; 29 (suppl; abstr.10001)

• Cediranib is a potent inhibitor of VEGFR-1, -2, -3 tyrosine kinases

• Phase II trial to determine response rate

• 28 patients evaluable• 12 PR (43%)• 4 >20% reduction in target lesions 78% DCR at 6 months• 6 SD at 6 months


43

Crizotinib in inflammatory myofibroblastic tumor

ClinicalTrials.gov Identifier: NCT01524926

• Inflammatory myofibroblastic tumor is a mesenchymal neoplasm with an inflammatory infiltrate. Appr. 50% carry rearrangements of ALK.

• Crizotinib is a selective inhibitor of ALK.• Sustained partial response in a patients with ALK-translocated

IMT, no response in another patient without ALK translocation.

• CREATE: Cross-tumoral Phase 2 With Crizotinib• Locally Advanced and/or Metastatic Anaplastic Large Cell Lymphoma• Locally Advanced and/or Metastatic Inflammatory Myofibroblastic Tumor• Locally Advanced and/or Metastatic Papillary Renal Cell Carcinoma Type 1• Locally Advanced and/or Metastatic Alveolar Soft Part Sarcoma• Locally Advanced and/or Metastatic Clear Cell Sarcoma• Locally Advanced and/or Metastatic Alveolar Rhabdomyosarcoma

Butrynski JE et al., N Engl J Med 2010; 363: 1727–1733.


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mTOR Inhibition in PEComa

• PEComa family of tumors:

- Lymphangioleiomyomatosis

- Angiomyolipoma

- Clear cell „sugar“ tumor of the lung

- Clear cell myomelanocytic tumor

- PEComa (perivascular epithelioid cell tumor)


45

mTOR Inhibition in PEComa

• Tuberosis sclerosis complex:

- Mutation of TSC1 or TSC2 leads

to activation of mTOR pathway

• Responses to sirolimus in 3 consecutive patients with PEComa

• Response to temsirolimus in a patient with PEComaWagner A et al., J Clin Oncol 2010

Italiano A et al., Ann Oncol 2010

Agulnik M., Cancer 2011


46

Imatinib mesylate in advanced dermatofibro-sarcoma protuberans: pooled analysis of two phase II clinical trials.

Rutkowski P et al., J Clin Oncol 2010;28:1772-9

>90% t(17;22), resulting in COL1A1-PDGF-B fusion oncogene (upregulation of PDGFB gene)

autocrine and paracrine production of PDGF-B leads to activation of PDGFR-B McArthur et al., J Clin Oncol 2005

• SWOG-S0345 and EORTC 62027 closed after registration of imatinib in DFSP due to low accrual

• A total of 24 patients treated– 46 % partial remissions– 25 % stable disease– mPFS 1.7 years– no difference between 400 und 800 mg of imatinib



Meta-Analyse 1997


Adjuvant Chemotherapy for Adult Soft Tissue Sarcomas of the Extremities and Girdles: Results of the Italian Randomized Cooperative Trial

Frustaci et al., J Clin Oncol 2001

DFS OS


Meta-Analyse 2008 - OS

Pervaiz et al., Cancer 2008


Woll et al., Lancet Oncology 2012


Effect of adjuvant chemotherapy on survival in FNCLCC grade 3 soft tissue sarcomas: a multivariate analysis of the French Sarcoma Group Database.

• Retrospektive Analyse von 1.513 Patienten mit lokalisierten Weichteilsarkomen aus der Datenbank der French Sarcoma Group

• Zentraler Review von Histologie und Grading nach dem FNCLCC System

• Einfluss der adjuvanten Chemotherapie:- Medianes follow-up 9 Jahre- Bei der multivariaten Analyse zeigte sich ein signifikanter

Einflussauf das

5-Jahres MFS: 58 % versus 49 %, HR 0.7, p = 0.015-Jahres OS: 58 % versus 45 %, HR 0.6, p = 0.0002bei Patienten mit Grad 3 Sarkomen

- Kein Unterschied im MFS und OS bei Grad 2 Sarkomen

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Italiano et al., Ann Oncol 2010


Issels et al., Lancet Oncology 2010

Chemotherapy +/- regional hyperthermia


• There is no consensus on the current role of adjuvant chemotherapy.

• A meta-analysis found a statistically significant limited benefit in terms of both survival- and relapse-free survival.

• It is nknown whether adjuvant chemotherapy may be particularly beneficial in specific subgroups or even detrimental in others.

• Therefore, adjuvant chemotherapy is not standard treatment in adult-type STS. It can be proposed as an option to the high-risk individual patient (high-grade, deep, >5 cm tumour) for a shared decision-making with the patient or within clinical trials.

• In any case, adjuvant chemotherapy is not used in histological subtypes known to be insensitive to chemotherapy.

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Multimodality treatment of localized STS


• When employed, adjuvant chemotherapy should consist of the combination chemotherapy regimens proved to be most active in advanced disease.

• In one large randomised phase III study (in patients with G2–3, deep, >5 cm STSs), regional hyperthermia in addition to systemic chemotherapy was associated with a local progression-free survival (PFS) and DFS advantage.

9

Multimodality treatment of localized STS


• Metachronous (disease-free interval ≥1 year) resectable lung metastases without extrapulmonary disease are managed with surgery as standard treatment, if complete excision of all lesions is feasible.

• Chemotherapy may be added to surgery as an option, taking into account the prognostic factors (a short previous recurrence-free interval and a high number of lesions are adverse factors, encouraging the addition of chemotherapy), although there is a lack of formal evidence that this improves outcome [IV, B]. Chemotherapy is preferably given before surgery in order to assess tumour response and thus modulate treatment.

• In cases where lung metastases are synchronous, in the absence of extrapulmonary disease, standard treatment is chemotherapy. Surgery of completely resectable residual lung metastases may be offered as an option, especially when a tumor response is achieved.


„If you operate on patients who are more likely to survive, it is to beexpected that they survive longer than those you did not operate on.“


Conclusions

• Standard chemotherapy is based on anthracyclines as first line treatment.

• More recent treatment options is pretreated patients include trabectedin and pazopanib.

• There is more than one type of adult soft tissue sarcoma.

• Detection of molecular aberrations leads to identification of new treatment options.

• Adjuvant chemotherapy is not standard treatment in adult-type STS and can be proposed as an option to the high-risk individual patient.

referat peter reichardt vor ort.ppt [kompatibilitätsmodus] · • in cases of clinical suspicion...

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