Therapeutic Algorithms in systemic sarcoma therapy

Transcription

1 Therapeutic Algorithms in systemic sarcoma therapy Ian Judson Sarcoma Unit Royal Marsden Hospital

2 What evidence do we have? What sorts of evidence are there? Experience personal, peers ( Bayesian ) Educational symposia - this is why you re here Clinical trials phase II, phase III Guidelines e.g. ESMO, NCCN Casali et al, Ann Oncol 2008;19(suppl 2)ii

3 What are the roles of chemotherapy for soft tissue sarcomas? Palliation of advanced local or metastatic disease Pre-operative treatment for large tumours? Adjuvant chemotherapy in large, high grade, extremity tumours? - still unproven

4 Palliative benefit of chemotherapy in soft tissue sarcomas RMH data from 488 patients treated with first line chemotherapy (doxorubicin, doxorubicin + ifosfamide, other) RR = 33% RR in synovial sarcoma = 53% Clinical benefit as defined by CR + PR + SD for 6 months = 45% Median duration of benefit = 9 months Median OS = 12 months Good prognostic factors: age <40, liposarcoma and synovial sarcoma Karavasilis et al Cancer 2008;112:1585

5 Overall benefit of palliative chemotherapy CR + PR + SD 6 months = 45% Karavasilis et al, Cancer 2008;112:1585 Survival by treatment 100 Single agent Combination chemotherapy 80 % Survival Years Median single agent 11 months vs combination 16 months, p= 0.003

6 Is combination chemotherapy more effective? Few randomised trials, none positive for combination therapy Many single institution studies claiming a benefit An EORTC from 15 years ago suggested no benefit

7 STUDY : DESIGN Study coordinator: A. Santoro Soft tissue sarcoma (histologically proven) Recurrent, metastatic or locally advanced No prior chemotherapy Randomization DOXORUBICIN 75 mg/m2 iv d.1 - q 3 wks DOX 50 mg/m2 iv IFOS 5 g/m2 iv d.1 - q 3 wks DOX 50 mg/m2 iv CPH, VCR, DTIC d.1,2,3 - q 3 wks 263 patients 258 patients 142 patients

8 STUDY : RESPONSE DOX DOX/IFOS CYVADIC C.R P.R N.C P.D Early dth Not eval C.R.+P.R. 23.3% 28.1% 28.4% 95% c.i % % % Santoro et al, J Clin Oncol 1995;13:1537

9 STUDY : SURVIVAL P = 0.97 (logrank test) DOX DOX/IFOS CYVADIC years Santoro et al, J Clin Oncol 1995;13:1537

10 STUDY : DESIGN Study coordinator: A. van Oosterom Soft tissue sarcoma (histologically proven) Recurrent, metastatic or locally advanced STRATIFICATION : - prior Doxorubicin or Epirubicin - no prior chemotherapy Randomization IFOSFAMIDE 5 g/m2.day 24 hrs infusion d 1 - q 3 wks 38 / 51 patients IFOSFAMIDE 3 g/m2.day 4 hrs infusion d 1, 2, 3 - q 3 wks 41 / 52 patients

11 STUDY : RESPONSE 5 g/m 2-1d 3 g/m 2-3d 1st line 2nd line 3 PR N=48-6 % RR Median: 37 wks 1 CR 1 PR N=36-6 % RR Median: 59 wks 12 PR N=48-25 % RR Median: 40 wks 1 CR 2 PR N=40-8 % RR Median: 51 wks Van Oosterom et al Eur J Cancer 2002;38:2397

12 STUDY : RESPONSE 5 g/m 2-1d 3 g/m 2-3d 1st line 2nd line 3 PR N=48-6 % RR Median: 37 wks 1 CR 1 PR N=36-6 % RR Median: 59 wks 12 PR N=48-25 % RR Median: 40 wks 1 CR 2 PR N=40-8 % RR Median: 51 wks Van Oosterom et al Eur J Cancer 2002;38:2397

13 Results of phase II trials of high dose ifosfamide combinations Author Regimen RR Patel Reichardt Leyvraz ifos 10 g/m 2 66% dox 75 mg/m 2 ifos 12.5 g/m 2 55% epi 90 mg/m 2 ifos 10 g/m 2 55% dox 90 mg/m 2

14 Is this a real improvement -do we need a randomised trial?

15 Impact of case selection Case selection has enormous impact This is the likely reason for very high response rates in single centre phase II trials, we can all obtain response rates like this by selecting young, fit patients with rapidly growing disease, such as synovial sarcoma

16 PROTOCOL 62012: Randomized trial of single agent doxorubicin versus doxorubicin/ifosfamide SC: I. Judson Eligibility: High grade STS (2-3) Age No previous chemo for adv/met dis WHO PS < 2 Will this be the definitive trial? DESIGN Randomization Doxorubicin 75 mg/m² d 1 Or as a 72 hour Contin. i.v. infusion Doxorubicin 25 mg/m² d 1-3 Ifosfamide 2.5 g/m² d 1-4 Neulasta 6mg s.c Day 5 Stratification: Age (<50 vs 50) PS (0 vs 1) Liver mets (0 vs +) Histological grade (2 vs 3)

17 Accrual Graph pts (05/03/10) Accrual of study Theoretical Study Expected today: 450 Observed today: 440 Expected 1y: 73 Observed 1y: 25 Expected 2y: 173 Observed 2y: /03/04 6/03/05 6/03/06 6/03/07 5/03/08 5/03/09 5/03/10

18 What about disease heterogeneity?

19 Overall survival in advanced STS 1.2 treated with chemotherapy leiomyo mfh synovial lipo fibro van Glabbeke et al, J Clin Oncol 1999;17:150

20 Conclusions from EORTC data Early survival advantage for synovial sarcoma, possibly due to increased sensitivity to chemotherapy Long term advantage for liposarcoma, possibly due to more indolent behaviour or pattern of disease spread

21 What subtypes are particularly sensitive to chemotherapy? Most sensitive subtypes appear to be: Synovial sarcoma Myxoid/round cell liposarcoma Uterine leiomyosarcoma Other? But N.B. data are sparse on individual disease outcomes

22 When is chemotherapy unhelpful? Some diseases are unresponsive to cytotoxic chemotherapy including: Alveolar soft part sarcoma Clear cell sarcoma Solitary fibrous tumour Endometrial stromal sarcoma

23 What is the role of ifosfamide? Combination therapy with doxorubicin If aim of treatment is maximum tumour regression, e.g. pre-op, for rapid symptom relief, if no other adjuvant treatment possible Second line therapy after single agent doxorubicin But not for all diseases, effective against synovial sarcoma, less effective against leiomyosarcoma and liposarcoma

24 RMH data on treatment of synovial sarcoma Regimen Result Ifos / dox RR 58.6% Doxorubicin RR 25% Ifosfamide RR 25% Other RR 50% Ifos/Dox vs Dox Ifos/Dox vs Ifos Ifos/Dox vs other Dox vs Ifos p=0.06 p=0.025 p=0.76 p=1.00 From Spurrell et al Ann Oncol 2005;16: see also Sleijfer et al, Retrospective analysis of ifosfamide in EORTC trials Eur J Cancer 2010;46:72-83

25 Responses to doxorubicin alone or in combination with ifosfamide Sleijfer et al Eur J Cancer 2010;46:72-83 Disease type Doxorubicin alone Ifosfamide regimen Leiomyosarcoma Synovial Sarcoma Liposarcoma GIST 9 9 Other 19 30

26 Other effective agents Gemcitabine / gemcitabine + docetaxel, especially for leiomyosarcoma Paclitaxel for angiosarcoma Trabectedin for dox + ifos refractory sarcomas, especially leiomyosarcoma, liposarcoma and synovial sarcoma Aromatase inhibitors for ER+ / PgR+ endometrial stromal sarcoma (ESS)

27 Gemcitabine +/- docetaxel First reported to be active in leiomyosarcomas (mainly uterine) by Martee Hensley, MSKCC Activity in STS confirmed by SARC trial (Maki et al), survival advantage for combination In leiomyosarcomas French group appear to have demonstrated that gemcitabine alone is as good (more intensive regimen) UK GeDDiS trial will compare gemcitabine + docetaxel with doxorubicin as first line therapy for STS

28 Hensley et al reported response rate of 53% in LMS (mainly uterine) to gemcitabine + docetaxel (J Clin Oncol 2002;20:2824) Duration of best response Progression-free survival

29 Refractory STS Gemcitabine v Gemcitabine/Docetaxel Maki et al J Clin Oncol 2007;25:2755 R Gemcitabine 10 mg/m 2 /min at 1200 mg/m 2 over 120 min days 1 & 8, q 21 days Gemcitabine 900 mg/m 2 days 1 & 8 + docetaxel 100 mg/m 2 day 8, q 21 days

30 But data are conflicting Randomised trial in leiomyosarcoma - French Sarcoma Group Randomise Gemcitabine 1000 mg/m 2 over 100 min days 1,8,15 - q 28d Gemcitabine 900 mg/m 2 over 90 min days 1 & 8 + docetaxel 100 mg/m 2 day 8 q 21d No difference between 2 arms Duffaud et al J Clin Oncol 2008;26(suppl): abstr 10511

31 But data are conflicting Randomised trial in leiomyosarcoma - French Sarcoma Group Randomise Gemcitabine 1000 mg/m 2 over 100 min days 1,8,15 - q 28d Gemcitabine 900 mg/m 2 over 90 min days 1 & 8 + docetaxel 100 mg/m 2 day 8 q 21d No difference between 2 arms Duffaud et al J Clin Oncol 2008;26(suppl): abstr 10511

32 Pooled analysis Progression-free survival 100% UTERINE - PFS 80% 60% 40% 55% 63% 46% 50% median PFS G : 4.9 months (CI95%: ) G + D : 6 months (CI95%: ) 20% 18% 28% G + D At risk 0% Months since 1st course G 3 32

33 Uterine leiomyosarcoma: response to 6 cycles gemcitabine + docetaxel Nov 2010 Feb 2011

34 How do we use gemcitabine + docetaxel? Used in refractory metastatic STS Probably most effective against leiomyosarcomas Uterine sarcomas often sensitive, dramatic responses observed Is gemcitabine alone as good currently unclear?

35 Paclitaxel in angiosarcoma different types of evidence Schlemmer et al Eur J Cancer 2008;44:2433 Retrospective analysis by EORTC RR 62%, 75% for scalp angiosarcoma Median time to progression 7.6 months Penel et al J Clin Oncol 2008;26:5269 Prospective phase II trial by French group RR 18.5% Median time to progression 4 months

36 How do we use paclitaxel? First or second line therapy for angiosarcoma, both visceral (heart, spleen, liver) and cutaneous (UV related scalp and face in the elderly, radiation induced chest wall) Usually given by weekly injection, e.g mg/m 2 Low toxicity, well tolerated in the elderly

37 Other drugs for angiosarcoma Pegylated liposomal doxorubicin (Caelyx) Low cardiotoxicity can be maintained for a long time re-treatment is possible can be given to patients with cardiac or pulmonary artery primaries who will receive radiotherapy to the heart accumulates in skin, so very helpful for cutaneous lesions

38 Trabectedin (ET-743) Yondelis Tetrahydroisoquinoline alkaloid Ecteinascidia turbinata CHMP approval 20th September 2007: «Trabectedin is indicated for the treatment of patients with ASTS, after failure of anthracyclines and ifosfamide or who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients» Approved by NICE on cost-sharing basis

39 Trabectedin in myxoid liposarcoma

40 Trabectedin in myxoid liposarcoma e.g. initial reduction in tumour density then slow onset PR 0 +2 c +5 c Is this related to mechanism of action - inhibition of transcription factors activated by translocation? +8 c +11 c

41 Trabectedin (ET-743, Yondelis) in leiomyosarcoma and liposarcoma

42 How do we use trabectedin in practice? Favoured subtypes are leiomyosarcoma, liposarcoma and synovial sarcoma Within leiomyosarcomas seems to be particularly useful for uterine LMS Within liposarcomas it appears to be particularly active against myxoid / round cell liposarcoma, although this was not apparent in the randomised study Key advantage is lack of cumulative toxicity

43 Hormone sensitive sarcomas Endometrial stromal sarcomas, and some low grade ER/PR expressing leiomyosarcomas, respond to oestrogen deprivation In premenopausal women GnRH agonists or oophorectomy In postmenopausal women aromatase inhibitors, or progestogens Usual therapy is letrozole 2.5 mg o.d.

44 Response of ESS to aromatase inhibitors experience at RMH Date of diagnosis Response to prior therapy Response to aromatase inhibitor Duration of response (months) 1990 PD on doxorubicin PR PD on tamoxifen and MPA PR in pelvis, liver and lungs SD on MPA several years SD MPA SD several yrs, with liver and lung surgery PR CR following surgery PD on zoladex, SD doxorubicin, PD carbo/taxol PD PD megestrol PR (also stopped HRT) PD on leuprorelin PD (since responded to MPA) N/A (for many yrs thought to have endometriosis) PR 16+ Response rate (assessable pts CR, PR, SD) = 75% Median response duration = 15 months (8-87)

45 Intravascular leiomyomatosis response to letrozole and goserelin July 2010 Feb 2011

46 Can we define the diversity of sarcomas at the molecular level? Chaotic karyotype, no easily defined molecular drivers (leiomyosarcoma, pleomorphic sarcoma) Characteristic chromosomal translocations (synovial sarcoma, myxoid liposarcoma) Activating mutations (GIST) Consistent chromosomal amplification (welldifferentiated / de-differentiated liposarcoma) Loss of suppressor gene function (PEComa)

47 Can we translate molecular information into clinical practice? In part... Chaotic karyotype not yet Translocations some progress Imatinib in DFSP, PVNS, angiogenesis inhibitors in alveolar soft part sarcoma, ALK inhibitors in IMT Activating mutations GIST, obviously with imatinib and other TKIs Chromosomal amplifications potentially CDK4 and MDM2 inhibitors in dediff lipo Loss of suppressor gene function TSC1/2 loss activating mtor pathway in PEComas, activity of rapamycins

48 28 year old man, slowly progressive lung disease, several operations for resection of brain metastases, on cediranib since December 2007 November 2007 September 2008

49 Response of metastatic synovial sarcoma to pazopanib ongoing March 2007 early 2009 Prior to start of pazopanib After 12 months on pazopanib

50 Fig 2. (A) Multiple, recurrent tumors of the scalp, and (B) clinical complete response maintained for more than 3 years on imatinib therapy Rutkowski, P. et al. J Clin Oncol; 28: Copyright American Society of Clinical Oncology

51 Response of PEComa to sirolimus Jan 2008 Sept 2010

52 Before giving treatment you have to answer these questions: 1. What is the aim of giving chemotherapy? Palliation to prevent progression or to relieve specific symptoms? Down-sizing, i.e. maximum possible tumour shrinkage Prevention of recurrence systemic, local 2. Does chemotherapy work in this disease? 3. Are there specific agents that might be best?

53 Therapeutic choices for first line therapy palliative setting Synovial sarcoma ifosfamide + doxorubicin or doxo alone, perhaps depends on age Leiomyosarcoma doxorubicin or gemcitabine-containing regimen Liposarcoma Myxoid/ round cell doxorubicin De-diff liposarcoma difficult, not very responsive Pleomorphic Possibly an advantage for ifosfamide regimen

54 Therapeutic choice need to obtain tumour shrinkage Synovial sarcoma, pleomorphic sarcomas Ifosfamide + doxorubicin Leiomyosarcoma Gemcitabine + docetaxel Pleomorphic sarcoma Ifosfamide + doxorubicin

55 Therapeutic choices special cases Angiosarcoma Weekly paclitaxel or Caelyx ER/PR expressing low grade gynae tumours or metastasising leiomyoma Aromatase inhibitors, GnRH agonists or both, depending on menopausal status PEComa Rapamycin (or analogue) Inoperable DFSP, PVNS Imatinib Alveolar soft part sarcoma Angiogenesis inhibitor

56 Second line Ifosfamide if doxorubicin used first line, except in case of leio and lipo Trabectedin for leiomyosarcoma and liposarcoma, and synovial sarcoma if ifos/dox used first line Gemcitabine +/- docetaxel for leiomyosarcoma Consider dacarbazine for uterine leio We are investigating infusional ifosfamide 14 g/m 2 over 14 days every 28 days

57 Conclusions Clearly, not all soft tissue sarcomas are alike in their molecular mechanisms of activation and response to systemic treatment You need to be clear about treatment intent Be aware of differential responsiveness to commonly used agents such as ifosfamide Note special regimens for diseases such as angiosarcoma and ESS

58 THANK YOU