PRIMARY TREATMENT CLINICAL PRESENTATION INITIAL EVALUATION. Conclude procedure with/without lymph node dissection

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1 INITIAL EVALUATION History and Physical CXR Pathology review 1 Labs Consider CA125, and pre-operative imaging of abdomen and pelvis Screen for Lynch Syndrome by family history or molecular testing CLINICAL PRESENTATION Disease confined to uterus Stage II gross cervical involvement Hysterectomy 2, BSO and consider intraoperative frozen section and/or sentinel lymph node mapping 45 Gy pelvic radiotherapy plus brachytherapy (72 hours) PRIMARY TREATMENT Grade 1-2, less than or equal to 50% invasion and tumor diameter less than or equal to 2 cm Grade 1-2, greater than 50% invasion OR tumor diameter greater than 2 cm with any invasion OR Grade 3 and non-endometroid cell type (papillary serous, clear cell, carcinosarcoma) Conclude procedure with/without lymph node dissection Full staging with pelvic and para-aortic node sampling (omental biopsy for nonendometroid cell type) Hysterectomy 1, BSO with para-aortic node sampling (omental biopsy for non-endometroid cell type) Radical hysterectomy 2, BSO, pelvic and para-aortic node sampling and/or sentinel lymph node mapping (omental biopsy for non-endometroid cell type) See page 2 & 3 for Endometroid and Page 4 for Serous Cell Type Disease not confined to uterus Consider surgical debulking See page 3 for Endometroid and page 4 for Non-Endometroid Cell Type 1 Consider approved biomarkers, see Appendix A 2 Hysterectomy may be performed through open or minimally invasive techniques based on surgeon/patient discretion BSO = Bilateral Salpingo-Oophorectomy Please refer to American College of Obstetricians and Gynecologists (ACOG) Guidelines for referral.

2 STAGE 1 This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson, Stage 1A (less than 50%) myometrial invasion Adverse risk-factors 2 present? Yes No ADJUVANT THERAPY Grade 1 Observe or Vaginal brachytherapy Grade 2 Observe or Vaginal brachytherapy 3 and/or pelvic RT Grade 3 Vaginal brachytherapy 3 and/or pelvic RT Grade 1/Grade 2 Observe Grade 3 Observe or Vaginal brachytherapy Stage 1B (greater than or equal to 50%) myometrial invasion Adverse risk-factors 2 present? Yes No Grade 1/Grade 2 Vaginal brachytherapy 3 and/or pelvic RT Grade 3 Pelvic RT with or without chemotherapy 3 or vaginal brachytherapy plus chemotherapy Grade 1 Observe or Vaginal brachytherapy 3 Grade 2 Vaginal brachytherapy 3 Grade 3 Vaginal brachytherapy and/or Pelvic RT 3 Stage II 4 Vaginal brachytherapy and/or pelvic RT Pelvic RT with vaginal brachytherapy Pelvic RT with vaginal brachytherapy Grade 1 Grade 2 Grade 3 with or without chemotherapy 1 See Appendix B for FIGO Staging 2 Potential adverse risk factors include the following: Age, positive lymphovascular invasion, tumor size, and lower uterine (cervical/glandular) involvement. RT = radiotherapy 3 Preferred 4 Depends on depth of invasion in uterus and cervical stroma plus other risk factors

3 STAGE 1 ADJUVANT THERAPY Stage IIIA with serosal involvement 45 Gy pelvic radiotherapy and vaginal brachytherapy with or without concurrent chemotherapy with or without adjuvant chemotherapy 2 Stage IIIA with adnexal involvement Adjuvant chemotherapy 2 and consider vaginal brachytherapy Stage IIIB, Stage IIIC1 45 Gy pelvic radiotherapy and vaginal brachytherapy with or without concurrent chemotherapy followed by adjuvant chemotherapy 2 See surveillance on Page 5 Stage IIIC2 Extended-field radiotherapy and vaginal brachytherapy, with or without concurrent chemotherapy followed by adjuvant chemotherapy 2 Stage IV Chemotherapy 2 LVSI =Lymphovascular space invasion 1 See Appendix B for FIGO Staging 2 See Appendix C for Chemotherapy Regimens

4 STAGE 1 ADJUVANT THERAPY Stage IA (no invasion or superficial invasion) Vaginal brachytherapy 2 with or without concurrent chemotherapy followed by adjuvant chemotherapy 3 Stage IB Vaginal brachytherapy 2 or Pelvic RT 4 with or without concurrent chemotherapy followed by adjuvant chemotherapy 3 Stage II Stage IIIA Pelvic RT 2,4 or Vaginal brachytherapy with or without concurrent chemotherapy followed by adjuvant chemotherapy 3 Vaginal brachytherapy 2 with or without concurrent chemotherapy followed by adjuvant chemotherapy 3 See surveillance on Page 5 Stage IIIB Pelvic RT 2,4 or Vaginal brachytherapy with or without concurrent chemotherapy followed by adjuvant chemotherapy 3 Stage IIIC Disease present in ovaries? Yes No Chemotherapy 3 Pelvic RT 2,4 or Vaginal brachytherapy with or without concurrent chemotherapy followed by adjuvant chemotherapy 3 Stage VI Chemotherapy 3 LVSI =Lymphovascular space invasion 1 See Appendix B for FIGO Staging 2 Preferred 3 See Appendix C for Chemotherapy Regimens 4 Consider concurrent paclitaxel for disease confiend to the pelvie

5 SURVEILLANCE After completion of treatment Visits every 3-6 months for Years 1 and 2, then every 6 months for Year 3-5 Physical and pelvic exam every visit CA125 (if initially elevated) every visit Imaging as clinically indicated Systemic recurrence? Yes Chemotherapy 1 No isolated recurrence Consider radiotherapy and/or resection with or without chemotherapy Please refer to American College of Obstetricians and Gynecologists (ACOG) Guidelines for referral. LVSI =Lymphovascular space invasion 1 See Appendix C for Systemic Therapy

6 APPENDIX A: APPROVED BIOMARKERS BIOMARKER DISEASE SITE CELL TYPE FISH IMMUNOHISTOCHEMISTRY MOLECULAR Gynecology Ovarian and Uterine Carcinoma HER2/neu HER2/neu ER/PR MSI (MLH1, MSH2, MSH6, PMS2) PTEN BRAF V600E MSI by PCR MLH1 promoter hypermethylation if applicable KRAS mutation BRAF mutation TP53 PIK3CA mutation AKT1 mutation PTEN mutation Lynch Syndrome MSI (MLH1, MSH2, MSH6, PMS2) MSI by PCR MLH1 promoter hypermethylation if applicable 1 Literature support for MD Anderson approved Biomarkers is available and can be found under Clinical Management Algorithms Biomarkers MD Anderson Approved 1 Literature support for MD Anderson approved Biomarkers is available and can be found under Clinical Management Algorithms Biomarkers MD Anderson Approved

7 APPENDIX B: FIGO Staging Stage I 1 II 1 III 1 IV 1 Description Tumor confined to the corpus uteri IA: No or less than half myometrial invasion IB: Invasion equal to or more than half of the myometrium Tumor invades cervical stroma, but does not extend beyond the uterus 2 Local and/or regional spread of the tumor IIIA: Tumor invades the serosa of the corpus uteri and/or adnexae 3 IIIB: Vaginal and/or parametrial invovlement 3 IIIC: Metastases to pelvic and/or para-aortic lymph nodes 3 IIIC1: Positive pelvic nodes IIIC2: Positive para-aortic lymph nodes with or without positive pelvic lymph nodes Tumor invades bladder and/or bowel mucosa, and/or distant metastases IVA: Tumor invasion of bladder and/or bowel mucosa IVB: Distant metastases, including intra-abdominal metastases and/or inguinal lymph nodes 1 Either G1, G2, or G3 2 Endocervical glandular invovlement only should be considered as Stage I and no longer as Stage II 3 Positive cytology has to be reported separately without changing the stage APPENDIX C: Systemic Therapy Multi-agent chemotherapy Paclitaxel and Carboplatin Docetaxel and Carboplatin Ifosfamide and paclitaxel (carcinosarcoma) Cisplatin and Ifosfamide (carcinosarcoma) Cisplatin and Gemcitabine Single Agents Cisplatin Carboplatin Doxorubicin Liposomal Doxorubicin Paclitaxel Hormonal Agents Topotecan Bevacizumab Temsirolmus Docetaxel Ifosfamide (carcinosarcoma)

8 SUGGESTED READINGS Creutzberg C.L., van Putten W.L., Koper P.C.; et al. (2000). Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet. 355(9213): Homesley H.D., Filiaci V., Gibbons S.K.; et al. (2009). A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol. 112(3): Jhingran A, Ramondetta LM, Bodurka DC, et al. (2013). A prospective phase II study of chemoradiation followed by adjuvant chemotherapy for FIGO stage I-IIIA (1988) uterine papillary serous carcinoma of the endometrium. Gynecol Onc; 129(2): doi: /j.ygyno Keys H.M., Roberts J. A., Brunetto V.L; et al. (2004). A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol. Oncol. 92(3): National Comprehensive Cancer Network. (2013). Uterine Neoplasms Guidelines. Retrieved December 11, 2013 from Nout, Lancet (full citation to be added) Pecorelli S. (2009). Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 105(2):103-4.

9 DEVELOPMENT CREDITS This practice consensus algorithm is based on majority expert opinion of the Endometrial cancer work group Faculty at the University of Texas MD Anderson Cancer Center. It was developed using a multidisciplinary approach that included input from the following medical, radiation and surgical oncologists. Ŧ Patricia Eifel, MD Charles F. Levenback, MD Michael W. Bevers, MD Ŧ Anuja Jhingran, MD Diane C. Bodurka, MD Karen H. Lu, MD Thomas W. Burke, MD Pedro T. Ramirez, MD Robert L. Coleman, MD Lois M. Ramondetta, MD Kathleen M. Schmeler, MD Anil K. Sood, MD, Pamela T. Soliman, MD Shannon N. Westin, MD David M. Gershenson, MD Ŧ Ann Klopp, MD Michael M. Frumovitz, MD Alpa M. Nick, MD Jennifer K. Burzawa, MD Jubilee Brown, MD Ŧ Nicole Fleming, MD Larissa Meyer, MD Ŧ Core Development Team