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
I will divide my discussion into two parts—first a discussion of the two papers asking whether morcellation surgery affects outcomes for women with uterine LMS; and second a discussion of systemic treatment options for LMS

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
All 17 patients had uterine cancers, including a case of synchronous ovarian cancer. Eight (47%) had endometrioid histology, including the patient with both uterine and ovarian synchronous cancer, 5 had leiomyosarcoma (29%), 3 had low grade endometrial stromal sarcoma (18%), and 1 had carcinosarcoma (6%).
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. Uterine LMS Nomogram to predict 5 year OS
Points 10 20 30 40 50 60 70 80 90
100
Age at Diagnosis 25 35 45 55 65 75 85
Tumor Size (cm) 5 15
Tumor Grade
Low
High
Cervical Involvement No
Yes
Distant Metastases
Loco-regional Metastases
Total Points
150
200
250
300
5-year Survival
0.05
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
In this nomogram built to predict OS (not PFS or peritoneal recurrence we inlcuded “tumor rupture” as a potential predictive variable.
Tumor rupture was not a parameter in the final model, but this could have been due to: small number of pts with this parameter, or the use of OS as the endpoint, or the fact that other variables subsumed the influence of rubture.
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?
Among 923 women undergoing hysterectomy for presumed benign leiomyomas, only 4 had malignancies found (2 endometrial carcinoma, 1 LMS, and 1 ESS)
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
I will divide my discussion into two parts—first a discussion of the two papers asking whether morcellation surgery affects outcomes for women with uterine LMS; and second a discussion of systemic treatment options for LMS

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

14. In perspective:
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 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
Gemcitabine (n=49)
Gemcitabine-Docetaxel (n=73)
RECIST response 8%
16%
PFS, median
3 mo
6.2 mo
OS, median
11.5 mo
17.9 mo
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. F.Duffaud, C. Chevreau, N. Penel, A. Le Cesne,
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
F.Duffaud, C. Chevreau, N. Penel, A. Le Cesne,
C. Guillemet, C. Delcambre, A. Floquet, D. Cupissol, B. Lacas, P. Pautier
So, what about new combinations?
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 : 72-83,
5Van Glabbecke M, EJC :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 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 → Doxo combi (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
This bottom point focusses the question—what is the best first line systemic therapy?
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:
In the end, we try to make all our stories simple, with bad guys and good guys—and from these abstracts it is pretty easy to see who is who, but we all know that good novels have very complext haraters and so we have more reading and researching to do.
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—