State of the Science: Current status of research relevant to GCT GCT Survivors Weekend April 16, 2011

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1 State of the Science: Current status of research relevant to GCT GCT Survivors Weekend April 16, 2011 Jubilee Brown, M.D. Associate Professor UT M.D. Anderson Cancer Center

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3 Ovarian Cancer 21,880 new cases projected for 2010» 25,580 in ,850 deaths in US for 2010» 16,090 in % of all cancers 6% of all deaths -Jemal A, CA Cancer J Clin, 2010

4 Ovarian Cancer 90% are epithelial ovarian tumors 7% are sex cord-stromal tumors Different from more common epithelial type» Typical ovarian cancer research does not apply

5 WHO Classification (1973) Epithelial Sex cord-stromal Germ cell Soft tissue tumors not specific to the ovary Unclassified Secondary (metastatic) Tumor-like conditions (pregnancy luteoma, etc.)

6 WHO Classification - SCST Granulosa stromal cell» Granulosa cell» Thecoma-fibroma Androblastomas; Lipid Sertoli-Leydig cell cell Gynandroblastoma Unclassified

7 Adult GCT

8 Angiogenesis CD31: High MVD score, mean MVD of 48.4 CD31: Low MVD score, mean MVD of 7.4

9 The Story of GCT Research

10 Surgical Therapy - standard Childbearing complete: complete hysterectomy Fertility desired: Take out the involved tube and ovary BUT conserve the other normal ovary and the uterus in patients with limited disease Staging is still necessary Gershenson DM (2005) JNCI Monographs 34:43-7

11 Conservative Management

12 Post-surgical therapy Limited information Most institutions have only a few patients Published studies are limited» Combine histologic subtypes» Recommendations for rare tumors based on limited data Tend to progress or recur over many years even decades; need long-term follow-up

13 Post-surgical therapy How do you get past the pile of piranhas to see what s really there?

14 Post-surgical therapy: Sertoli-Leydig Cell Tumors Over 90% are Stage IA tumors Stage correlates with grade:» 100% of well differentiated tumors are stage IA» Only 52% of poorly differentiated tumors are stage IA Higher grade is associated with malignant behavior» 10% intermediate, 60% poorly diff, 20% retiform/heterologous show malignant behavior Recommendation is to treat:» Any patient with stage IC or greater» Poorly differentiated tumors of any stage (including IA)» Heterologous elements of any stage (including IA) -Brown J, Gershenson DM (2006) Treatment for Rare Ovarian Malignancies. M. D. Anderson Cancer Care Series Gynecologic Cancer. Springer-Verlag -Gordon MD, Ireland K (1995) Clin Lab Med 15:595

15 DATA - Platinum Slayton/GOG FAC 3/7 CR Schwartz 1976 FAC 2 CR Jacobs Doxo/Cis 2 PR Camlibel 1983 CAP 1 CR Kaye 1986 CAP 1 CR Neville 1984 Altretamine/Cis 2 PR

16 Treatment Surgery BVP (Colombo, Zambetti) 9/11 responses, severe toxicity BEP (Gershenson)

17 Gershenson BEP 9 patients with advanced SCST 83% 1 (Bleomycin, etoposide, cisplatin) RR / 7 durable remissions -Gershenson DM et al (1996) Obstet Gynecol 87:

18 Homesley (GOG 115) BEP x 4 75 patients, 18 excluded 57 patients Stage II IV disease 61% Grade 4 myelotoxicity -Homesley HD et al (1999). Gynecol Oncol 72:

19 BEP Regimen Bleomycin 20 units/m2 q week x 9 w Yielded 2 fatalities, so Bleomycin 20 units/m2 q 3 weeks x 4 Etoposide Cisplatin 75 mg/m2 QD x 5d q3w x 4 20 mg/m2 d1-5 q3w x 4

20 Bleomycin Discontinue if» DLCO decreases by 30%» Rales» Lack of expansion on examination

21 Homesley (GOG 115) % 69% had negative 2nd look surgery of advanced stage primary & 51% of patients with recurrence remained progression free

22 GOG 115 (Homesley) 6 complete responders had 24.4 month duration of response Only one with advanced disease had durable remission 4 pulmonary toxicity (2 deaths)

23 Problems with BEP Limited response to toxic chemotherapy Duration of response was 24 months Only 1 of 7 patients with advanced disease had durable remission Severe pulmonary fibrosis from bleomycin deaths) Second malignancies leukemia Hematologic toxicity (2

24 First Investigation The activity of taxanes in the treatment of sex cord-stromal ovarian tumors Purpose: To determine the efficacy and side effects of taxane-based chemotherapy for SCST -Brown J et al (2004) J Clin Oncol 22:

25 Taxanes in SCST 222 patients with SCST; 44 received a taxane 11 newly diagnosed» 9 adjuvant: Median PFS and OS not reached at 51 months» 2 with measurable disease: 1 CR, 1 not evaluable» Overall: PFS 34 months with median F\U 90 months 37 patients with recurrent disease (7 NMD, 30 MD)» NMD: 86% remained progression free, PFS 34 months» MD: 60% remained progression free, RR 42%, PFS 20 months -Brown J et al (2004) J Clin Oncol 22:

26 Taxanes in SCST Toxicity»»»»» Neutropenia (n = 6) Anemia (n = 1) Thrombocytopenia (n = 1) Myelodysplasia (n = 1) Hypersensitivity (n = 1) -Brown J et al (2004) J Clin Oncol 22:

27 Taxanes in SCST Conclusions:» Taxanes appear to have efficacy in treating SCST» Toxicity appears to be limited and acceptable -Brown J et al (2004) J Clin Oncol 22:

28 Next Investigation The activity of taxanes compared with BEP in the treatment of sex cord-stromal ovarian tumors Purpose: To compare the use of taxanes +/platinum with BEP in patients with SCST -Brown J et al (2005) Gynecol Oncol 97:

29 Newly Diagnosed Patients 22 patients: 11 BEP, 11 Taxane Length of F/U: 87 months BEP Taxane P NED 9/11 (82%) 9/11 (82%) 1 PFS 46 m NR (52+ m) OS 97 m NR (52+ m) 0.994

30 Recurrent Measurable Disease 37 patients: 7 BEP, 30 Taxane BEP n = 7 Taxanes n = 30 P CR 2 2 PR 3 9 Stable 0 6 Prog 2 12 RR 72% 37% FTP 72% 57% 0.727

31 Presence of platinum important! No platinum: Total response rate: 18% Platinum: Total response rate: 54% Compared with 18%, P = Comparing tx episodes, P = 0.027

32 Toxicity BEP (5/21 patients)» 3 pulmonary fibrosis,» 2 grade 4 neutropenia Taxane (6/44 patients)» 4 grade 4 neutropenia» 1 hypersensitivity» 1 myelodysplasia DLCO

33 Conclusions Taxane-based chemotherapy appears to be as effective as BEP for newly diagnosed and recurrent SCST Taxane-based chemotherapy may be less toxic than BEP for SCST This warrants further study

34 GOG 264 A Randomized Phase II Trial of Paclitaxel and Carboplatin versus Bleomycin, Etoposide, and Cisplatin for Newly Diagnosed Advanced Stage and Recurrent Chemonaive Sex CordStromal Tumors of the Ovary

35 GOG 264

36 GOG 264 Opened February 2010 Accrual: Push 4/128 to open! International Finally, tumors interest support and funding for rare

37 Recurrent disease? GOG 187 opened November 2000 Single agent paclitaxel» First-line (newly diagnosed) arm 0/45 patients accrued, so replaced with GOG 251» Second-line (recurrent) arm 28/45 patients accrued

38 What about something informed by science? Something novel No natural lymphatic supply to granulosa cells May rely on angiogenesis for vascular supply Anecdotally, very few instances of LN mets

39 LN metastasis is extremely rare in SCSTs It many not be necessary to include routine lymphadenectomy in the staging of patients with SCSTs Nodal metastasis may be a secondary event

40 Patterns of metastasis in SCSTs: Can routine staging lymphadenectomy be omitted? 257 evaluable patients 111 had complete or partial staging procedure 52% had LN removed (n = 58 patients) None had positive nodes 117 patients eventually developed recurrent disease» Only 6 patients (5.1%) had nodal metastases

41 Patterns of metastasis in SCSTs: Can routine staging lymphadenectomy be omitted? Conclusions» LN metastasis is extremely rare in SCSTs» It may not be necessary to include routine lymphadenectomy in the staging of patients with SCSTs» Our findings suggest that nodal metastasis is a secondary event Brown J, et al. Gynecol Oncol, 113:86-90, 4/2009.

42 If LN metastasis is rare and distant metastasis is common Characterize lymphatic supply to granulosa cell tumors and SCSTs Characterize angiogenesis may play a prominent role» Tumors are highly vascular» Distant metastases are common

43 CT of Pelvis

44 PET/CT: Sertoli-Leydig

45 We know these tumors are vascular:

46 We know these tumors are vascular:

47 We know these tumors are vascular:

48 What does that mean clinically? 80 tumor samples from 65 patients Stained for CD31 (MVD), VEGF, and D2-40 (LVD) Correlated with clinical data

49 Clinical relevance of angiogenesis and lymphangiogenesis in SCSTs D2-40 (lymphatic marker)» Most tumors had absent or low LVD» Clinically, only 3 patients of 65 stained slides had LN metastases (recurrent disease)» 3 tumors with nodal metastasis had LVD of 38.5 vessels/hpf» Tumors without nodal metastasis had LVD of 2.7 vessels/hpf (p < 0.001)

50 Clinical relevance of angiogenesis and lymphangiogenesis in SCSTs VEGF» Present in 99% of all samples to some degree» Overexpressed in 35% of samples» Related to high MVD

51 VEGF Overexpression and Angiogenesis VEGF: Overexpression with high score of 12 VEGF: No overexpression with low overall score of 4

52 Why is VEGF important? Because we have anti-vegf Bevacizumab (Avastin) is a monoclonal antibody that targets VEGF!

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54 But does VEGF mean that there are really more blood vessels? CD31: High MVD score, mean MVD of 48.4 CD31: Low MVD score, mean MVD of 7.4

55 What does that tell us about GCT behavior? CD31 (MVD)» High MVD in 41% of samples; associated with» Shorter DFS (16.7 vs months, p = )» Increased risk of recurrence (p < 0.04)» Shorter OS (108.6 vs m, p < 0.001)» Related to VEGF expression (p = 0.009)» Associated with distant metastasis (p < 0.001)

56 Question: If angiogenesis is important, does that translate clinically?

57 8 patients underwent treatment with Avastin for recurrent disease» 1 CR» 2 PRs» 2 stable» 3 progressed Response rate 38%, clinical benefit rate of 63% PFS 7.2 months, OS after bev of 23.6 months -Tao X, Brown J et al (2009) Gynecol Oncol 114:

58 GOG 251 A Phase II Study of Bevacizumab in the Treatment of Recurrent Sex Cord-Stromal Ovarian Tumors» Accrual complete (36 patients) as of January 31, 2011» Will have the results very shortly.» Designing next trial

59 Featured Poster Presentation Secondary cytoreductive surgery: A key tool in the management of recurrent ovarian sex cordstromal tumors D. Namaky1, P. Ramirez2, M. Munsell2, A. Nick2, D. Gershenson2, J. Brown2 Good Samaritan Hospital, Cincinnati, OH, 2University of Texas M.D. Anderson Cancer Center, Houston, TX 1 Rationale: What is the role of surgery when GCT recurs?

60 Results 105 patients Median progression-free survival (PFS) 33.1 months Median overall survival months Successful in achieving an optimal result (<1 cm left) in 75% of patients!

61 Results

62 Results 71.7% of patients (n=76) recurred more than once» 66.2% of these patients had multiple surgeries Each time, the cancer-free interval was shorter More likely to come back in a distant site at the second recurrence (24%) vs. the first recurrence (15%)» Helps with knowing where to look» Surgery may be useful over and over again!

63 Conclusions Most patients with recurrent ovarian sex cord-stromal tumors can be optimally cytoreduced Secondary cytoreductive surgery should be considered as a treatment option for selected patients with recurrent disease

64 Juvenile Granulosa Cell Tumor

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66 Research Requires Funding! NCI» Cooperative groups GOG» SPOREs, PPG, R01, R21 Industry Foundations» Foundation for Women s Cancer» OCRF Local institutions

67 Thank you!

68 Acknowledgements David M. Gershenson, M.D. Michael T. Deavers, M.D. Anil K. Sood, M.D. Ljiljana Milojevic

69 Acknowledgements