Chemotherapy for endometrial cancer Amelia Jernigan MD Assistant

+ Chemotherapy for endometrial cancer Amelia Jernigan, MD Assistant Professor of Gynecologic Oncology LSU-New Orleans November 11, 2016

+ Objectives n To review the types of endometrial cancers and general approaches to treatment n Type II (grade III, UPSC, Carcinosarcoma, clear cell) n Review the role of chemotherapy in the treatment of endometrial cancer in the following settings n Adjuvant n Recurrent/metastatic n Neoadjuvant n To discuss emerging therapeutic approaches & exciting developments

+ Types of uterine tumors Endometrial cancers: Type I: G 1 -2 endometrioid Type II: UPSC Clear cell Carcinosarcoma Stromal cancers Leiomyosarcoma Endometrial stromal sarcoma Undifferentiated endometrial sarcoma Adenosarcoma

+ Endometrial cancer n 4 th most common cancer in women n Most common gynecologic malignancy n ~400 K cases last year n Most early stage (and those tend to do pretty well); advanced disease is associated with poor outcomes

+ Staging (out with the old & in with the new – but ya gotta know both!)

+ Endometrial cancer stage & Survival Heintz APM, et al. J Epid Biostat 2001

+ Treatment for early stage disease n Surgery n TAH n BSO (usually) n Lymph node assessment n Strategies n Fertility preservation option: n No LND n D&C q 3 months n Selective LND based on intraoperative findings n n LND for everyone Progesterone (megace, medroxyprogesterone, Mirena IUD) n Sentinel lymph node biopsy RISK OF PELVIC LN METASTASIS Invasion Grade 1 Grade 2 Grade 3 Endometrium Inner 1/3 Middle 1/3 Outer 1/3 0% 3% 0% 11% 3% 5% 9% 19% 0% 9% 5% 34% Creaseman WT Cancer 1987; Mariani Gyn Onc 2008

+ Adjuvant therapy for early stage disease – high intermediate risk? PORTEC 1 n n Included: Stage I EC: G 1 -2 >50%, G 2 -3 <50% Excluded: serous, clear cell n TAH, BSO, no LND n No adj t vs RT n 8 year LRR 4% vs 14% (p<0. 001), OS no difference, increased morbidity n HIR: >60, G 3, Outer half GOG-99 n Included: Stage IB, IC, IIA (occult), IIB (occult). n Excluded: serous, clear cell n TAH/BSO Lymph node sampling n No adj tx vs RT n HIR: RF – G 2 -3, LVI+, outer 1/3 n Any age – all 3 risk factors n 50 -69 – 2 risk factors n >=70 – any risk factor n Risk of recurrence was lower in the HIR group; did not set out to or show difference in OS.

+ Vaginal cuff brachytherapy n PORTEC 2: n Stage IBG 3, ICG 1 -2 >60 yoa, IIAG 1 -2, G 3 >1/2 invasion n EBRT vs Brachytherapy n No difference in vaginal recurrence or distant recurrence. More pelvic recurrence (3. 5% vs 0. 6%) n No difference in OS (but much death is due to intercurrent diseaes)

+ The role of chemotherapy n Hogberg trial n Two RCT: NSGO-EC 9501/EORTC-55991 & MANGO-ILIADE-III n Stage I-III EC, no residual tumor, and high risk disease n Randomized: RT with or without sequential chemotherapy n ~ 36% reduction in risk of relapse or death (p = 0. 07 combined, sig for NSGO but not MANGO)

+ The role of chemotherapy (GOG 249) No difference in outcome. Would more cycles of chemo have made a difference?

+ What about chemo. RT and more chemo? – RTOG 9708 n Phase II clinical trial n High risk EC (g 2 -3 with >50% MI, cervical stromal invasion or pelvic confined extrauterine disease) n Cis 50 mg/msq D 1 & 28 during RT (45 Gy) to pelvis followed by vaginal brachyteherapy and then cis 50 mg/msq and paclitaxel 175 mg/msq every 4 weeks for 4 cycles n At 4 years: pelvic, regional and distant reucurence rates – 2%, 2% and 19% n 4 year OS and DFS: 85% and 81% n 4 year OS and DFS for stage III patients: 77 % 72%; no recurrences for stage IC-IIA ***

+ What about cis-RT, with Bev? RTOG 0921 n Phase II clinical trial n 30 High risk EC s/p hyst and LND 1+ RF (grade 3 >50% MI; g 2 -3 with cervical stromal invasion, known extrauterine disease) n bevacizimab + cisplatin + IMRT carbo/taxol x 4 cycles n Primary endpoint: Grade 3+ adverse events (23. 3%) n 2 year OS 96. 7% & DFS 79% Viswanathan Cancer 2015

+ The role of chemotherapy (PORTEC 3) n Stage IA with invasion, G 3 +LVI; Stage IBg 3, Stage IIIA or IIIC, or IIIB if parametrial invasion only; Stage IA with invasion, IB , II, or III with serous or clear cell n Randomized to two groups: n Radiation (48. 6 Gy in 1. 8 Gy/fx, EBRT) n Radiation and chemo (48. 6 Gy in 1. 8 Gy/fx, EBRT with cis 50 mg/msq IV t cycles during RT carbo AUC 5 & paclitaxel 175 mg/msq q 3 wks x 4 cycles)

+ Treatment for advanced stage disease n Surgery: n Debulking gross disease when you can n Chemotherapy has trumped radiation

+ Advanced EC – Combo chemotherapy: GOG 48 n 387 women with advanced or PFS 3. 2 n vs Conclusion: Doxorubicin + 3. 9 months recurrent EC RCT cyclophosphamide appears to OS 6. 9 vs 7. 3 amonths offer small advantage over n Doxorubicin 60 mg/msq q 3 wks alone in management 21 doxorubicin days n Doxorubicin 60 mg/msq + of EC at the expense of more More myelosuppression Cyclophosphamide 500 frequent myelosuppression mg/msq q 3 wks More and GI toxicity Clinically significant? Need more active single agent!! Thigpen et al. JCO 1994

+ Advanced EC: what about cis? GOG 107 n 281 patients with advanced or recurrent EC randomized n n Doxorubicin 60 mg/msq q 3 wks D Response Cis+D 8% Complete 19% 17% Partial 23% D: 3. 8 months 75% None 58% D: 9. 2 5. 7 months Doxorubicin 60 mg/msq q 3 D+Cis: months wks and cisplatin 50 mg/msq. D + Cisp: 9. 0 months q 3 wks n Combination arm with more n G 4 leukopenia (28% vs 7. 4%) n G 3&4 anemia (19% & 5. 4% vs 4% & 0%) n G 3&4 Thrombocytopenia (8. 5% & 5. 4% vs 1. 3% & 0. 7%) n Nausea & vomiting New Standard Thigpen et al. JCO 2004

+ Advanced EC: what about taxol? – GOG 163 n N Randomized phase II study n n Doxorubicin 60 mg/msq + cisplatin 50 mg/msq Doxorubicin 50 mg/msq + paclitaxel 150 mg/msq (24 h)+ filgrastim 5 mcg/d d 3 -12 Fleming Annals of Oncology 2004 RR PFS OS D+cis 157 40% 7. 2 12. 6 D+Ptx 160 43% 6 14. 6

+ Advanced EC: back to taxol – GOG 177 n RR PFS OS AP 34% 5. 3 12. 3 TAP 57% 8. 3 15. 3 263 women n n Doxorubicin 60 mg/msq + cisplatin 50 mg/msq Doxorubicin 50 mg/msq, cisplatin 50 mg/msq, pacitaxel 160 mg/msq, filgrastim Fleming JCO 2004

+ Chemo or RT? n Susumi et al (JGOG 2033) n 385 women with stage IC-III endometrioid adenocarcinoma to WPR vs TAP, 5 yr PFS 83. 4 vs 81. 8% n BUT, for IC over age of 70 with grade 3 EC OR stage IIIIIA, chemo resulted in better PFS (83. 8% vs 66. 2%, p=0. 024) and OS (89. 7% vs 73. 6%, p=0. 006) n GOG 184 n 552 women wit stage III disease debulked to maximum residual of 2 cm or less followed by n volume directed RT vs TAP n Similar 3 year DFS (62 vs 64%) n If there was gross residual disease at enrollment, TAP a/w 50% reduction in risk of relapse or death.

+ Advanced EC – WAI vs AP – GOG 122 Chemotherapy standard adjuvant treatment over WAI BUT reductions in morbidity are much needed

+ Advanced EC – So why Carbo/Taxol? GOG 209 Noninferiority RCT: 1300 women stage III/IV/Recurrent EC Carbo/taxol vis TAP q 3 wk x 7 cycles Same ORR: 51% Same PFS: 13 months Similar OS (37 v 40 monts) Less g 2+ toxicity (neuropathy, thrombocytopenia, emesis, diarrhea, metabolic derrangements)

+ What about sequencing? n Retrospective data suggests that sandwich therapy may result in improve outcomes (OS, PFS) compared to chemo/radiation or radiation/chemo – but this has been difficult to reproduce Secord Gyn Onc 2009

+ Advanced EC – bev? n GOG n 53 women up to 2 prior treatments bev 15 mg/msq q 3 wks n ORR 15%, 36% PFS at 6 months n GOG 86 P: RCT 349 women: carbo/taxol/bev, carbo/taxol/temsirolimus, carbo/ixabepilone/bev OS benefit compared to hx reference (GOG 209) n ORR: 59. 5%, 55. 3%, 52. 9% n OS 34 mo with c/t/bev in this trial vs 23 mo in GOG 209. The other two arms both had OS of 25 mo. Aghajanian JCO 2011; ASCO abstract n MITO END-2 Trial n 108 women with <=1 prior platinum based regimen with progression > 6 months after first line therapy completed carbo/taxol and randomized to bev or not n Tx with bev resulted in: n Higher ORR (71. 7% vs 54. 3%) n Better PFS (13 vs 8. 7 mo, HR 0. 59 95 CI 0. 35 -0. 98)) n No OS difference (22. 5 vs 18 mo, HR 0. 65, 95 CI 0. 311. 36)

+ Advanced EC – Hormonal therapy? Study Treatment Grade N RR Agent Avg dose RR% Podratz 1985 Progestins 1 2 3 10 71 73 40% 15% 2% Hydroxyprogesterone caproate 1 -3 g IM q wk 29% Megace 800 mg/d 1 2 3 14 17 27 37% g 1 -2 8% Medroxyprogesterone acetate 200 -1000 mg IM weekly or po daily 22% Lentz 1996 Megestrol acetate 40 -800 mg daily 20% Thigpen 1999 MPA 200 mg vs 1000 mg/d 1 2 3 59 113 127 37% 23% 9% Tamoxifen 20 -40 mg daily 10% Goserelin acetate 3. 6 mg SC montly 11% Tam 40 mg/d alt MPA 200 mg/d 1 2 3 15 17 27 Overa ll RR 33% Anastrazole 1 mg po daily 9% Arzoxifene 20 mg po daily 31% Megace 160 mg/d x 3 wk alt Tam 40 mg/d x 3 wk 1 2 3 16 17 22 38% 24% 22% Whitney 2004 Fiorica 2004 Barakat gynecologic oncology 2013

+ Single agent trials Agent RR Chyclophosphamdie 11% Fluorouracil 21% Chlorambucil 0% Methotrexate 6% Ifosfamide 14% 6 mercaptopurine 0% Hexamethylmelamine 17% Vincristine 16% Cisplatin 21 -25% Vinblastine 8% Carboplatin 28% Etoposide 3% Doxorubicin 26% Teniposide 9% Epirubicin 25% Topotecan 20% Liposomal doxorubicin 9. 5% Paclitaxel 27. 3% Pirarubicin 7% Docetaxel 21% Mitoxantrone 4% Ixabepilone 12% Barakat gynecologic oncology 2013

+ Special situations UPSC n n Fader – multiinstitutional, retrospective study of stage I UPSC s/p Staging – Obs vs RT vs Plat/tax chemo & RT But (p=0. 013) what about Chemotherapy fewer recurrences noninvasive, stage IA, n CT +/- RT: 11. 2% Recur completely staged n RT: 25% recur (NS vs CT +/-RT) patients? ? ? *** may not need n Obs: 30. 3% recur chemo*** Fader Cancer 2009; Mahdi Gyn Onc 2015

+ Special situations - UPSC n Serous cancers n Neoadjuvant response rates to carbo and taxol of 60 -70% n Surgical debulking and staging should be routinely performed when feasible n Platinum based chemotherapy should be considered in all patients n n …. ? Confined to a polyp and fully staged? ? Radiation?

+ Special situations - carcinosarcoma n GOG 150: Phase III RCT WAI vs Cis/Ifos/Mesna for stage I-IV uterine carcinosarcoma <1 cm residual n 232 women (206 eligable) n ½ early stage, ½ advanced n Adjusting for stage and age, recurrence rate 21% lower fro chemotherapy than WAI (NS)& estimated death rate was 29% lower with chemotherapy (p=0. 85) Regimen RR, PFS, OS Carbo/taxol 54%, 8 mo, 15 mo Ifos/taxol 45%, 8. 4 mo, 13. 5 mo Ifos/Cis 54% n GOG 261: awaiting results – carbo/taxol vs Ifos/taxol Wolfson Gyn Onc 2007/ GOG 232 B, GOG 161; GOG

+ Special circumstances – uterine carcinosarcoma n Topotecan may have promise in the recurrent setting n 51 women with recurrent or progressive Uterine carcinosarcoma n Topotecan 1. 5 mg/msq IV x 5 days every 3 weeks until progression or intolerance n 3 (6%) died after first tx n 5 complete responses (10%) n 13 stable disease (27%) Miller, Gyn Onc 2005

+ Special circumstances n Recurrence limited to the vagina n If no prior RT Most vaginal recurrences are salvageable, on long term (~15 year) follow up of PORTEC 1: n If prior RT n n If candidate, surgery (exenteration) n If not candidate for surgery Tailored RT or medical therapy Creutzberg IJROBP 2011 n Survival rates after vaginal recurrence were 70% for no tx and 38% for EBRT at 5 years & 51% vs 25% at 1 years.

+ Thanks!