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