Are there benefits from chemotherapy to early endometrial cancer Are there benefits from chemotherapy to early endometrial cancer? Ursula Matulonis, M.D. Associate Professor of Medicine, Harvard Medical School Director/Program Leader, Medical Gynecologic Oncology Dana-Farber Cancer Institute Boston MA Email: Umatulonis@partners.org

Risk categories for recurrence Low Risk no poor prognostic features Intermediate Risk deep myometrial invasion presence of lymphovascular invasion high grade or rare tumor histology High Risk positive nodes extrauterine disease Creasman WT, et al. AJ Obstet Gynecol 1999;181:31-34.

Type I vs. Type II endometrial cancer Type II: Serous --Lack of unopposed estrogen (atrophy) -- High grade, often with metastases --Poorer prognosis (more rare but causes a disproportionate number of deaths) Type I: Endometrioid --Unopposed estrogen (hyperplasia) -- Low to moderate grade, minimal myometrial invasion -- Good prognosis

NCCN guidelines for surgically staged stage I cancer +/- adverse factors Grade 1 Grade 2 Grade 3 Stage IA (<50% myometrial invasion) Adverse risk factors not present observe Observe or brachy Adverse risk factors present obs or brachy Obs or brachy +/- pelvic RT Stage IB (≥ 50% myometrial invasion) Adverse factors present Obs or pelvic RT and/or brachy +/- chemotherapy (cat 2B for chemotherapy) Adverse risk features: age, +LVI, tumor size, lower uterine (cervical/gland involvement) www.nccn.org

NCCN guidelines for stage II and IIIA IIIA: Tumor invades the serosa of the uterus and/or adnexae Grade 1 Grade 2 Grade 3 All Stage II Vag Brachy +/- pelvic RT Pelvic RT + vaginal brachy Pelvic RT + vag brachy +/- chemotherapy (category 2B) Stage IIIA Chemotherapy +/-RT or involved field RT +/- chemotherapy or pelvic RT +/- brachy Is +Peritoneal cytology an independent risk factor? In the absence of adverse pathological features (high grade tumors, deep invasion, serous or clear cell path or extrauterine disease spread), + cytology is not generally treated. Is intraluminal fallopian tube spread considered stage III? www.nccn.org

Surgically staged Stage IIIB or higher Treatment Stage IIIB Chemotherapy +/- RT Stage IIIC1 (+ pelvic nodes) Stage IIIC2 (+para-aortic nodes) Stage IVA, IVB (no gross residual cancer) www.nccn.org

Addition of chemotherapy to RT versus RT alone Results of 2 pooled studies: NSGO-EC-9501/EORTC-55991 (Nordic study) and MaNGO ILIADE-III 540 patients enrolled; 534 evaluable. Eur J of Cancer 46:2422, 2010

NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III (pooled data) **Nordic trial showed that addition of CT to RT was associated with a significant 36% reduction in the risk of relapse or death and a sig 49% reduction in the risk of death from endometrial cancer; MaNGO trial showed same direction but not significant. Eur J of Cancer 46:2422, 2010

Problems with these studies Nordic trial - study closed early because of poor accrual - chemotherapy could be given either before or after RT - RT is lower than standard of care (44Gy) - serous and clear cell cancers were allowed. - no standard chemotherapy regimen prescribed. MaNGO trial - higher staged cancers included - serous and clear cell excluded Other problems: pooled data of different stages, histologies, treatments. Eur J of Cancer 46:2422, 2010

Endometrial cancer: GOG 122 for advanced III/IV cancer Phase III study: GOG 122 Endometrial cancer: GOG 122 for advanced III/IV cancer Doxorubicin 60 mg/m2 Cisplatin 50 mg/m2 every 3 weeks x 8 cycles WART (AP/PA) 30 Gy x 20 = 150 Gy 15 Gy boost to pelvic +/- PA Primary endpoint: PFS Secondary endpoint: OS Median F/u: 60 months - 73% were stage III Maximum Doxorubicin total dose = 420 mg/m2 Randall et al, JCO 2006

Progression-free survival improved with chemotherapy: GOG 122 HR 0.71 (95% CI, 0.55 to 0.91; P = .007) J Clin Oncol; 24:36-44 2006

Survival better with chemotherapy: GOG 122 HR 0.68 (0.52-0.89; p<0.01) J Clin Oncol; 24:36-44 2006

Survival by treatment and stage Randall, M. E. et al. J Clin Oncol; 24:36-44 2006

Ongoing studies of adjuvant therapy for endometrial cancer

Danish study, n=678 (AGO, EORTC, MaNGO, and others) Stage I and II endometrial cancer treated with surgery. Phase III study, n = 678 Eligibility: Stage I grade 3 endometrioid adenocarcinoma Stage II endometrioid adenocarcinoma Stage I and II type 2 histology (clear cell, serous, squamous cell carcinoma, or undifferentiated carcinoma) Randomized to: 1) observation 2) 6 cycles of carboplatin and paclitaxel. NCT01244789

GOG 249: Phase III Pelvic RT optional vaginal cuff boost Endometrial cancer 1) stage I with high-intermediate risks with +/- cytology 2) stage II (any histology), +/- risk factors 3) stage I/II serous or clear cell cancers with neg cytology n= 562 Vaginal cuff brachy + 3 cycles of paclitaxel 175 mg/m2 + carboplatin AUC 6 High-intermediate risks: age ≥ 70 yrs with one risk factor age ≥ 50 yrs with 2 risk factors age ≥ 18 yrs with 3 risk factors Risk factors: grade 2 or 3 tumor +LVI outer ½ myometrial invasion NCT00807768

NCT00411138

GOG 258 GOG 258 Paclitaxel 175 mg/m2 Carboplatin AUC 6 q21 days x 6 cycles Endometrial cancer stage I-IV Volume directed RT + cisplatin 50 mg/m2 days 1, 28 followed by: Paclitaxel 175 mg/m2 Carboplatin AUC 5 q21 days x 4 cycles Opened: 6/29/09 Phase III N=804 NCT00942357

Incorporation of bevacizumab into early stage endometrial cancer treatment No extrauterine disease outside of the pelvis NCT01005329

Conclusions When does our group use adjuvant chemotherapy for endometrial cancer and What type of chemotherapy? 1) Use IV carboplatin and paclitaxel 2) Sequential therapy 3) Clinical situations: Stage III or higher regardless of histology, Type II tumors (serous, clear cell) (any stage) Uterine carcinosarcomas As part of a clinical trial Follow the NCCN guidelines