Uterine Leiomyosarcoma: Discussion

1. Uterine Leiomyosarcoma: Discussion Martee L. Hensley, M.D. Attending Physician, Gynecologic Medical Oncology Memorial Sloan-Kettering Cancer Center Professor of Medicine Weill Cornell Medical College

2. Abstracts 010 and 011: Does morcellation surgery for uterine LMS affect outcome? • THE IMPACT OF OPERATIVE TECHNIQUES TO THE ONSET OF PERITONEAL TUMOR DISSEMINATION IN PATIENTS WITH UTERINE LEIOMYOSARCOMAS • F Menge; E Hartmann; M Mathew; B Kasper; P Hohenberger • IMPACT OF TUMOR MORCELLATION ON THE NATURAL HISTORY OF UTERINE LEIOMYOSARCOMA (ULMS) • C Serrano; T Oduyebo; J Manola; YFeng; M Muto; S George

3. Menge abstract summary • Detailed attention to the surgical techniques—included the “myoma drill” cases with morcellation cases • Total of 23 uLMS cases in 10 years • 6 morcellation cases compared with 15 non-morcellation (4 metastatic cases excluded) p = 0.08 --3 cases with “peritoneal only” recurrence

4. Serrano abstract summary • only intra-abdominal morcellation included • Reasonable case match for post-op management • 16 morcellation cases • Imbalance for BSO • RESULTS: • RFS is significantly poorer after morcellation • Recurrences are peritoneal • Significant prognostic factor in small multivariate analysis that included tumor size and mitotic rate

5. Tumor morcellation led to a decrease in Recurrence Free Survival (RFS) p-value = 0.034 Median RFS TAH = 25.7 months Median RFS Morcellation = 10.8 months

6. In perspective: • MSKCC retrospective of re-operation after SCH (n=12) or morcellation (n=5) procedures in pts found to have uterine malignancies (EmCa =8; LMS=5; ESS=3; CS=1) • 5 morcellation procedures; 4/5 underwent re-operation • 2/4 were upstaged due to finding of residual peritoneal disease at time of re-operation. • Both of the patients had uterine LMS • There were a total of 13 re-staging procedures; 2/13 patients (15%) were upstaged—both had uLMS Einstein, Int J Gynecol Cancer, 2007

7. In perspective: • Retrospective comparison of pelvic recurrence at 3 months among morcellation (n=34) and no-morcellation hysterectomy (n=89) in patients with uterine malignancies • Morcellation pts: pelvic recurrence 8.82% • Hysterectomy pts: pelvic recurrence 3.66% • P=0.25 Morice P, Gynaecol Oncol 2003

8. 0 10 20 30 40 50 60 70 80 90 100 Points Age at Diagnosis 20 25 30 35 40 45 50 55 60 65 70 75 80 85 Tumor Size (cm) 0 5 10 15 20 25 30 35 High Tumor Grade Low Yes Cervical Involvement No Yes Distant Metastases No Yes Loco-regional Metastases No Total Points 0 50 100 150 200 250 300 5-year Survival 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.05 Uterine LMSNomogram to predict 5 year OS C-index = 0.683 Zivanovic, Hensley. Cancer 2012

9. Discussion : • Easy for us to say, post-hoc, that morcellation is BAD • But can we conclude that morcellation SHOULD NOT BE DONE? Takamizawa, Gynecol Obstet Invest 1999

10. Research agenda? • Identify a reliable tool for discerning pre-operatively which leiomyomas have high likelihood of being uLMS (or other malignancy). • Imaging characteristics? Imaging modality? • Presentation? (bleeding v. not?) • Post-menopausal growing fibroid? • Nomogram of multiple pre-op features? • The challenge is the database—need all that information on thousands of patients when the incidence of malignancy is 0.4%

11. Abstracts 012 and 013: What are the systemic treatment options for uLMS • LMS-02: A PHASE II SINGLE-ARM MULTICENTER STUDY OF TRABECTEDIN IN COMBINATION WITH DOXORUBICIN AS FIRST LINE TREATMENT OF METASTATIC AND/OR LOCALLY ADVANCED LEIOMYOSARCOMA OF UTERINE (U-LMS) OR SOFT-TISSUE (ST-LMS) ORIGIN: RESULTS FROM BOTH COHORTS, FOR THE FRENCH SARCOMA GROUP (FSG) • F Duffaud; C Chevreau; N Penel,; ALe Cesne; CGuillemet; C Delcambre; AFloquet; D Cupissol; ARey; P Pautier • IMPACT OF CHEMOTHERAPY IN UTERINE SARCOMA (UTS): REVIEW OF 12 CLINICAL TRIALS FROM EORTC INVOLVING ADVANCED UTS COMPARED TO OTHER SOFT TISSUE SARCOMA (STS) • I Ray-Coquard,; A Natukunda; J-Y Blay; P Casali; I Judson; A Krarup Hansen; L Lindner; AP Dei Tos; H Gelderblom; S Marreaud; S Litiere; P Rutkowski; P Hohenberger; A Gronchi; Wvan der Graaf

12. Ray-Coquard EORTC retrospective study: outcomes in ut sarcomas • 225 pt with uterine sarcoma, 71% ut LMS (160 LMS pts) • Response to chemo higher (30%) among pts with high grade cancers v. low grade (13.5%) • Histologic grade and performance status were prognostic for OS among all the ut sarcoma pts • Responses higher with dox-based chemo compared with ifos alone • LMS responses were 20% v. 33% for other histologies

13. Median OS 10.9 months among the 225 ut sarcoma pts v. 11.7 for other STS types • Median PFS 4.1 months ut sarcoma v. 3.71 other STS • Response to chemotherapy 23% among uterine sarcoma patients

14. In perspective: • 1977-2001 data window allows for long follow-up but limits treatment regimens to dox, ifos, CYVADIC • Possibility for changes over time in response definitions, histologic diagnoses, and grading changes • Some similarities to findings of nomogram for OS in ut LMS • Grade matters • We can all agree that better treatments are needed • We must recognize the challenges in agreeing on grade in LMS

15. In perspective: • Median OS 10.1 months (range 9 to 11.9) in this dox and ifos-treated group with 0 prior regimens • SARC 001 (gem v. gem-doce, 0-3 prior) • Median OS 17.9 months with gem-doc v. 11.5 months with gem • Evolution of both the efficacy of agents and supportive care improvements over 3 decades influence interpretation of these data

16. Gem v. Gem-Docetaxel in STS • Odds that Gem-Doce is superior to Gem for PFS = 98% • Odds that Gem-Doce is superior to Gem for OS=97% Maki, Hensley, J Clin Oncol 2007

17. LMS-02A phase II single-arm multicenter study of Trabectedin in combination with Doxorubicin as first-line treatment of metastatic and/or locally advanced leiomyosarcoma of uterine (U-LMS) or Soft Tissue (ST-LMS) origin: Results from both cohorts F.Duffaud, C. Chevreau, N. Penel, A. Le Cesne, C. Guillemet, C. Delcambre, A. Floquet, D. Cupissol, B. Lacas, P. Pautier French Sarcoma Group

18. LMS02–uterine results • Response (44 pts): • 25 PR ORR : 56.8% • 13 stable diseases • Disease control rate :86% • Median duration of response : 5.5 months(3.8 – 6.6) • PFS rate at 12 weeks: 84 %[95% CI : 73%-94%]

19. LMS 02–discussion • Important objective RR per RECIST for 1rst line therapy in LMS • Compare favorably with other combinations for U-LMS Doxo-Ifo1; U-LMS 1rst line ORR: 30%, DCR : 82% Gem-Tax2; U-LMS 1rst line ORR: 36%, m PFS = 4.4 mo • Compare favorably with other combinations for ST-LMS Ifo- containing3; all-LMS 1rst line ORR: 17%, • High rates of disease control and of PFS in both cohorts of LMS • 86% and 92% of DCR, PFS rates at 3 mo of 84% and 92%, for Uterine and Soft Tissue cohorts respectively • Supports the hypothesis that Doxo + Trab is an active regimen,in both cohorts of LMS • Van Glabbecke 20025, active agents 1rst line for LMS : 3 mo PFR ≥58% and 6 mo PFR >40% → Efficacy results of Doxo →Trab combi are very encouraging in U- and ST-LMS 1Sutton G Gynecol Oncol 1996, 2 Hensley Gynecol Oncol 2008, 3 Sleijfer S, EJC 2010 46: 72-83, 5Van Glabbecke M, EJC 2002 38:543

20. LMS 02–discussion • Though well tolerated, Doxo + Trab is toxic but manageable in 1st line • Less toxic than Doxo (75 mg) + Ifo (10 g),EORTC 62012 studya • 46% febrile neutropenia, 35% anemia gr3-4, 33% thombocytopenia gr3-4 • Compare favorably with Gem (900 mg)+Tax (100 mg),Hensleyb et al. 2008 • for anemia and thrombocytopenia (24% anemia gr3, 14.5% thombocytopenia gr3-4 ) • but 6% febrile neutropenia with Doxo+Trab vs. 0% with Gem+Tax, but in 45pts • LMS02 results different than GEIS-20 study results • GEIS-20: Doxo vs. Trab → Doxocombi(Martin-Proto et al. ECCO meeting 2013) • Combination not superior to Doxo alone (ORR : 13% and 20% , mPFS 5.7 and 5.6 mo, for Combi and Doxo respectively) • Trab → Doxo, all sarcoma subtypes, too small population • Define appropriate 1st line regimen in LMS only • A randomized phase III study, in 1st line, in LMS only, comparing best combinations regimens, is urgently needed, with new active combination drugs a Judson I. Ann Oncol LBA7 ESMO 2012; b Hensley M. Gyn Oncol 2008

21. So many choices: 1st line treatment, metastatic ut LMS, good PS, organ function, large volume lung and peritoneal mets • Gemcitabine • Gemcitabine-docetaxel • Doxorubicin • Doxorubicin-ifosfamide • Ifosfamide • Trabectedin • Trabectedin-doxorubicin • Liposomal doxorubicin • Pazopanib • Dacarbazine • 3-drug combinations

22. Where shall we focus our efforts? The n=1 approach The n=1001 approach • Genomic profiling of the great responder • Since there is not likely one driver for every uLMS, try to find the one driver for each one? • If you find the driver, will you have a drug? And how soon until • Target mutation • Oncogene bypass • Feedback upregulation • Prospective randomized trials with overall survival or at least PFS endpoints • Aim to define best first- and second-line therapies for uLMS • Dox-Trab v. Gem-Doc • Dox-Trab v. Dox • Gem-doce-placebo v. Gem-doce-bev • Ad infinitum for questions • BUT not for patients!

23. In the end-- The bad guy: The good guys: Photo, Smithsonian Marine Station

24. Acknowledgments • Dr. Maki and CTOS for this invitation • Authors and presenters of Abstracts 010, 011, 012, 013 for providing abstracts and slides for review • The women who face the challenges of this disease every day—