Gynecologic Oncology Group Protocol GOG-0258

1. Gynecologic Oncology GroupProtocol GOG-0258 Louise E. Francis, B.S., CMD

2. Gynecologic Oncology Group(GOG) • The only National Cancer Institute funded cooperative groupin the US currently conducting trials 0n gynecologic cancers • Has been conducting practice changing researchfor 40+ years • Design, conduct and monitor phase II & III trials involving cancers of the endometrium, uterine sarcomas and gestational trophoblastic neoplasia • Most gynecologic oncologists participate

3. Background • Historically for Stage III Endometrial Cancer, patients underwent surgery followed by radiation therapy (good local control) • Systemic failure beyond treatment fields is an issue • Chemotherapy for advanced endometrial cancer yielding good systemic control, but poor local control. • The experimental arm of protocol GOG-0258 examines chemotherapy given concomitantly with radiation therapy. • It is a randomized Phase III Protocol Study

4. GOG-0258 Objectives • Primary Objective: To compare whether Cisplatin and volume directed radiation therapy, followed by carboplatin and paclitaxel for 4 cycles vs carboplatin and paclitaxel for 6 cycles better reduces the rate of recurrence or death in Stage III-IVa endometrial cancer patients. • Secondary Objective: To assess acute and late treatment effects on Quality Of Life of patients before, during and after protocol treatment.

5. Protocol Criteria • Inclusion: • Surgical Stage III or IVa Endometrial Cancer • Hysterectomy and Salpingoophrectomyan optional lymph node (LN) sampling • Informed Consent and Release of Information • 18+ years of age • Adequate organ function • Compliance to tests and observations prior to, during and after protocol treatment completion.

6. Protocol Criteria • Exclusion: • Carcinosarcoma or liver metastasis • Recurrent or Stage IVb Endometrial Cancer • Post surgical residual disease > 2cm at single site • Previous pelvic XRT or chemotherapy • Serious or uncontrolled illness • Life expectancy less than 3 months • History of myocardial infarction, unstable angina or arrhythmia within 3 months prior to starting protocol

7. Randomization Image taken from : www.ctsu.org/public/data/protocols/GOG/GOG-0258

8. Protocol Discontinuation • Discontinuation: • Ideally it is hoped that all enrolled patients will be able to complete protocol treatments. However, discontinuation may occur for the following reasons: • Patient choose to withdraw for any reason • Delay of treatment over 3 consecutive weeks because of toxicity • Lack of compliance on patient’s behalf

9. GOG-0258 Arm 1 • Initial XRT given for 28 days (Cisplatin Day 1 & Day 28) • Whole Pelvis Dose: 45 Gy in 25 fractions at 1.8Gy per day • Boost of 10-15 Gy in 5-8 fractions may be given at radiation oncologist’s discretion. • Carboplatin/Paclitaxel for 4 cycles to follow XRT within 8 weeks of chemoradiation completion • Boost of 10-15Gy may be 3D conformal, IMRT, HDR or LDR depending on location of disease

10. GOG-0258 Arm 2 • This arm of protocol involves chemotherapy only and represents the current standard of treatment for surgical Stage III and IVa endometrial cancer • Chemothrapeutic agents Carboplatin plus Paclitaxel, are given every 21 days for 6 cycles • Patients are observed carefully during this period for protocol related toxicity issues that may lead patient to withdrawal from protocol

11. Simulation • Localization images taken on conventional or CT simulator • Patient should ingest diluted contrast for small bowel delineation and vaginal swab for vaginal apex delineation • IV contrast helpful for lymph node delineation • CT scan slice thickness should be < 3mm and scan should extend from L3-L4 level to below the perineum • For IMRT: • Radiopaque marker seeds inserted into vaginal apex • Vac-lokor Alpha Cradle Immobilization

12. Treatment Plan • All radiation treatments must use 6-25 MV photons • 3-D Conventional (4 Field Box): • AP/PA Field Borders: • Superior- L5-S1 interspace • Inferior- Mid portion of obtorator foramen • Lateral- > 1cm widest portion of true pelvis • Rt /Lt Lateral Field Borders: • Same superior and inferior borders as AP/PA • Anterior- At least 1.5 cm anterior to L5 • Posterior- Bisect 3rd sacral vertebral body (3 cm margin on vaginal stump)

13. Treatment Plan • Institutions utilizing IMRT treatments must be credentialed by the Radiologic Physics Center (RPC) at M.D. Anderson Cancer Center prior to entering a patient on protocol • Credentialing involves irradiation of a standardized phantom from the RPC. The irradiated treatment plan must be electronically submitted to the Image-Guided Therapy Center for evaluation. The institution must await approval prior to proceeding with an IMRT plan

14. Treatment Plan • Intensity Modulated Radiation Therapy (IMRT): • In the event that IMRT is used for treatment, physicians must refer to the RTOG Gynecologic Atlas for volume specification when contouring. • CTV must be contoured to include the vaginal apex with margin, pelvic lymph nodes and inguino femoral nodes if vaginal involvement is present • PTV is 7 mm- 1 cm expansion of CTV in all directions

15. Treatment Plan • Critical Structures: Bladder, Rectum, Small Bowel and Femoral Heads • Constraints: • Small Bowel: <30% to receive > 40Gy, Dmax < 46 Gy • Rectum: < 60% to receive > 40Gy, Dmax < 55 Gy • Bladder: < 50% to receive >45Gy, Dmax < 60 Gy • Femoral Heads: 50% to receive > 40Gy, Dmax < 50 Gy No more than 1% of tissue outside of PTV will receive 110% o prescribed dose

16. Expected Toxicities • Radiation Therapy: • Gastrointestinal symptoms may include nausea and vomiting. This more likely occur when Para-Aortic lymph nodes are treated • Increased bowel activity with diarrhea can be expected after the two weeks of pelvic irradiation. • Hematological toxicity of a mild nature will be seen with a decline in WBC and platelet count

17. Expected Toxicities • Chemotherapy: • Hematologic –myelosupression • Gastrointestinal - nausea, vomiting, diarrhea, neutorpenia, colitis, ishemic colitis and mucositis • Pulmonary – pneumonitis • Heart – MI, arrhythmia, tachycardia and bradycardia • Neurolgic- Sensory (taste),peripheral neuropathy, seizures, mood swings and encephopathy • Liver – hepatic failure • Blood Pressure- Hypotension or hypertension

18. Quality of Life Assessment • Quality of life assessments will occur prior to, during and following treatment to asses physical and functional well being. • They will occur in the following order • Baseline: 14 days prior to treatment start • 6 weeks from start of protocol • 18 weeks from start of protocol • 70 weeks from start of protocol

19. Conclusion….. • Clinical trials help to define future treatment regimens • Patient and physician participation are vital to the success of all clinical trials • To date, GOG-0258 has 298 of the 804 patients needed. It is due to close in December 2013 • Thank You…..

20. References… • Mahtani, R. Treatment of Stage IV Endometrial Cancer. Cancer4Caring Web site. http://www.caring4cancer.com/go/endometrial/treatments/treatment-of-stage-iv-endometrial-cancer.htm.Updated August 15, 2010. Accessed October 25, 2011. • Endometrial Cancer. National Cancer Institute Web site. http://www.cancer.gov/cancertopics/types/endometrial. .Accessed October 23, 2011. • CTSU Protocols. Cancer Trials Support Unit Web site. https://www.ctsu.org/public/prot_search.aspx?browse=cancer_type&DiseaseId=7.Accessed October 28, 2011. • Protocol GOG-0258. Gynecologic Oncology Group Web site. http://www.gog.org/index.html.Accessed October 15, 2011.