Radiation Oncology/Uterine Sarcoma/Leiomyosarcoma

Uterine Leiomyosarcoma Overview LMS account for ~25% of uterine sarcomas, which account for ~4% of uterine malignancies Presentation typically with vaginal bleeding, pelvic mass, and pain PET/CT useful based on anecdotal evidence Staging: based on endometrial CA; cervical LMS is considered Stage II Outcome prediction Mayo clinic risk assessment index (age, size, stage, grade) Prognostic index developed for soft tissue sarcomas does not apply to LMS (PMID 10717626) Surgery main treatment modality TAH standard component Lymph node dissection has not improved survival, but provides prognostic information Oophorectomy may not be necessary in premenopausal women, if ovaries are grossly normal Outcomes: Stage I-II LMS may be cured (15-year OS 40-50%) Stage III-IV LMS have very poor prognosis (5-year OS 15-30%) Adjuvant RT is controversial; Mayo data suggest significantly improved LC, but no impact on DFS or OS. Phase III EORTC trial in Stage I-II showed no impact on loco-regional control, PFS or OS for leiomyosarcoma (but LRR benefit for carcinosarcoma) Adjuvant chemotherapy is also controversial; doxorubicin-based regimens appear the most active, but have not resulted in significant survival benefit Localized LMS EORTC 55874 (1987-2000) -- observation vs. pelvic RT Randomized. 224 patients with high grade uterine sarcoma (leiomyosarcoma 46%, carcinosarcoma 41%, endometrial stromal sarcoma 13%), Stage I-II (LMS were all stage I using FIGO 2009 system), treated with TAH/BSO + washings (75%), nodal sampling optional (25%). Arm 1) observation vs. Arm 2) pelvic RT 50.4/28 Field: top border L4/L5, lower border lower margin of obturator foramina, posterior border S2/S3 2008 PMID 18378136 -- "Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: An European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874)." (Reed NS, Eur J Cancer. 2008 Mar 28 [Epub ahead of print]) Outcome: LRR only observation 18% vs. RT 3%, LRR at any time 40% vs. 21% (SS); no impact on PFS or OS By subset: No benefit for LMS, improved local control for CS Conclusion: Pelvic RT improves local control but not PFS or OS for carcinosarcoma, there is no benefit in leiomyosarcoma Minnesota, 2005 (1972-1998) PMID 15923804 -- "On the apparent failure of adjuvant pelvic radiotherapy to improve survival for women with uterine sarcomas confined to the uterus." (Dusenbery KE, Am J Clin Oncol. 2005 Jun;28(3):295-300.) Retrospective. 49 patients with Stage I-II (20 LMS, 18 homologous mullerian, 11 heterologous mullerian) DFS: LMS 5-years 40%, 15-years 40%; Mullerian 5-years 65%, 15-years 61%. Failures mostly distant Toxicity: 3 SBO, 1 sigmoid colon obstruction Conclusion: adjuvant pelvic RT efficacious; frequent peritoneal failures suggest role for abdominal RT; better systemic therapy needed Gustave-Roussy, 2004 PMID 15571617 -- "Adjuvant chemotherapy with cisplatin, ifosfamide, and doxorubicin followed by radiotherapy in localized uterine sarcomas: results of a case-control study with radiotherapy alone." (Pautier P, Int J Gynecol Cancer. 2004 Nov-Dec;14(6):1112-7.) Case-control. 18 patients with chemo followed by RT vs. 16 patients RT alone vs. 2 patient no therapy Conclusion: Adjuvant chemo followed by RT is feasible; PIII trial ongoing in France All stages SARCGYN trial; 2013 PMID 23139262 -- "A randomized clinical trial of adjuvant chemotherapy with doxorubicin, ifosfamide, and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas (SARCGYN study). A study of the French Sarcoma Group." (Pautier P, Ann Oncol. 2013 Apr;24(4):1099-104. doi: 10.1093/annonc/mds545. Epub 2012 Nov 8.) Randomized. 81 patients with LMS (48%), carcinosarcoma (23%), undifferentiated sarcoma (11%). Stage I (64%). Both arms surgery + pelvic RT. Randomized to observation vs chemotherapy with doxorubicin / ifosfamide / cisplatin x 4 cycles. Stopped early due to lack of recruitment. Median F/U 4.3 years Outcome: 3-year OS: chemo-RT 81% vs RT only 69% (NS); DFS 55% vs 41% (SS). Toxicity: Grade 3+ thrombopenia 76%, febrile neutropenia 22%, two toxic deaths Conclusion: chemotherapy increases disease-free survival Princess Margaret; 2013 (1998 - 2008) PMID 23705661 -- "Postoperative radiotherapy improves local control and survival in patients with uterine leiomyosarcoma." (Wong P, Radiat Oncol. 2013 May 24;8:128. doi: 10.1186/1748-717X-8-128.) Retrospective. 69 patients, primary uterine LMS with hysterectomy. Pelvic RT 45 Gy in 32 patients (46%). Median F/U 5 years Outcome: LR observation 39% vs RT 19% (SS); 3-year OS 69% vs 35% (SS) univariate, persisted on multivariate. Positive SM increased odds of LR (HR 5.6). Large tumor size and Stage II-IV associated with development of distant mets Conclusion: Postoperative pelvic RT reduces LR and improves OS of patients with uterine LMS Dijon, 2005 (France) (1966-2001) PMID 15837053 -- "The role of surgery and treatment trends in uterine sarcoma." (Benoit L, Eur J Surg Oncol. 2005 May;31(4):434-42.) Retrospective. 72 patients with uterine sarcomas (34 LMS, 25 mullerian, 12 ESS, 1 angiosarcoma). RT 55%. Chemo 37% 5-year OS: all 36%; Stage I 47%, Stage II 60%, Stage III/IV 15% Conclusion: surgery main treatment. Adjuvant therapies do not decrease DM or increase OS MGH, 2004 (1990-1999) PMID 14766261 -- "The treatment of uterine leiomyosarcoma. Results from a 10-year experience (1990-1999) at the Massachusetts General Hospital." (Dinh TA, Gynecol Oncol. 2004 Feb;92(2):648-52.) Retrospective. 27 patients. Most treated with multimodality therapy (surgery, chemotherapy, and/or RT) Sugery: if no visible disease post-op, better OS (SS) Adjuvant therapy: after optimal cytoreduction, no decrease in rate of recurrence Adjuvant chemo: minimally effective, with 80% progression of disease Conclusion: Deadly disease. Aggressive surgical cytoreduction should be the goal Mayo, 2003 (1976-1999) PMID 12798712 -- "Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy." (Giuntoli RL 2nd, Gynecol Oncol. 2003 Jun;89(3):460-9.) Retrospective. 208 patients with LMS. Median F/U 7.7 years Worse prognosis: high grade, advanced stage, oophorectomy worse DSS Pelvic RT: no impact on DSS (p=0.06) in multivariate analysis. Significantly decreased LR when further evaluated as 31 case-controls (70% Stage I) Ovarian resection no impact on survival Risk-assessment index developed: Age (>51): 1 point; Tumor size (>5cm): 1 point; Stage (II-IV): 1 point; Grade (2-4): 2 points Low risk = 0-1 points (n=22, no deaths, median survival >25 years), intermediate risk = 2-3 points (n=53, median survival 6.5 years), high risk = 4-5 points (n=81, median survival 2.1 years) Vienna, 1999 PMID 10419731 -- "Leiomyosarcoma of the uterus: a clinicopathologic multicenter study of 71 cases." (Mayerhofer K, Gynecol Oncol. 1999 Aug;74(2):196-201.) Retrospective. 71 patients. Median F/U 9 years Predictors: age (<50 better), tumor stage, LVI, mitotic count in Stage I Norwegian Radium Hospital, 1993 (1976-1985) PMID 11578330 -- "Leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS) of the uterus. A survey of patients treated in the Norwegian Radium Hospital 1976-1985." (Nordal RN, Int J Gynecol Cancer. 1993 Mar;3(2):110-115.) Retrospective. 127 patients with LMS or endometrial stromal sarcoma, 14 reclassified 5-year OS: LMS 39%, ESS 67% Prognosis: grade (Grade I-II similar prognosis as endometrial carcinoma, Grade III-IV 5-year OS 33%) Adjuvant chemo: no clear benefit Advanced LMS No good chemotherapy regimens available; minimal impact on survival Doxorubicin-based combinations appear the most active, and are typically used as first line Minnesota experience with RT not particularly successful Search continues ... GOG, 2005 PMID 15721421 -- "Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced leiomyosarcoma of the uterus: a Gynecologic Oncology Group study." (Sutton G, Gynecol Oncol. 2005 Mar;96(3):749-52.) Phase II. 35 patients. Liposomal doxorubicin 50mg/m2 IV. Conclusion: no benefit over standard doxorubicin GOG, 2005 PMID 16051328 -- "Phase II trial of dacarbazine, mitomycin, doxorubicin, and cisplatin with sargramostim in uterine leiomyosarcoma: a Gynecologic Oncology Group study." (Long HJ, Gynecol Oncol. 2005 Nov;99(2):339-42.) Phase II. 18 patients. DMAP + sargramostim. Conclusion: too complex and toxic. Study closed early Minnesota, 2004(1978-1997) PMID 15262141 -- "Limitations of adjuvant radiotherapy for uterine sarcomas spread beyond the uterus." (Dusenbery KE, Gynecol Oncol. 2004 Jul;94(1):191-6.) Retrospective. 19 women with advanced uterine sarcomas who received adjuvant RT. 7 adjuvant chemo. Survival: 1-year 67%, 5-year 33%; failures mostly distant Conclusion: prognosis if spread beyond uterus is poor GOG, 2003 PMID 12694653 -- "Evaluation of paclitaxel in previously treated leiomyosarcoma of the uterus: a gynecologic oncology group study." (Gallup DG, Gynecol Oncol. 2003 Apr;89(1):48-51.) Phase II. 48 patients. Paclitaxel 175 mg/m2 IV Conclusion: modest activity, minimal toxicity GOG, 2002 PMID 12051882 -- "Phase II study of mitomycin, doxorubicin, and cisplatin in the treatment of advanced uterine leiomyosarcoma: a Gynecologic Oncology Group study." (Edmonson JH, Gynecol Oncol. 2002 Jun;85(3):507-10.) Phase II. 35 patients, treated with MAP 1-6 cycles Conclusion: MAP is not remarkably active; significant (10/35) pulmonary toxicity GOG, 1999 PMID 10479491 -- "Phase II trial of paclitaxel in leiomyosarcoma of the uterus: a gynecologic oncology group study." (Sutton G, Gynecol Oncol. 1999 Sep;74(3):346-9.) Phase II. 34 women. Paclitaxel 175 mg/m2 IV. RT in 23% Conclusion: Limited activity; consider higher dose GOG, 1996 PMID 8751554 -- "Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study." (Sutton G, Gynecol Oncol. 1996 Aug;62(2):226-9.) Phase II. 34 women. Ifosfamide + doxorubicin Conclusion: Toxic, with moderate activity