Abstract IA25: Personalizing treatment for women with rare epithelial ovarian cancers (EOC): Lessons learned

Prior to the mid-2000s, all epithelial ovarian cancer subtypes were treated identically worldwide. In 2005, the Gynecologic Oncology Group (GOG) established the Rare Tumor Committee. Over the past almost 15 years, GOG (subsequently merged into NRG Oncology) has been a leader in the development of clinical trials for rare gynecologic tumors, and a number of lessons have been learned. Initially the Rare Tumor Committee was faced with the challenge of determining on which rare gynecologic cancers it should focus. Lesson 1: There is no universal definition of a rare cancer. Ultimately, the group decided to concentrate on trials of rare EOC. Prior to this point, there were essentially no prospective data on these histotypes. Lesson 2: The study of rare EOC was energized by a number of converging factors. Refinement of histopathologic criteria, advances in the molecular biology, and publication of hypothesis-generating observational studies all played a major role in moving the field forward. Lesson 3: Significant challenges and barriers to conducting clinical trials of rare cancers exist and need to be fully understood. These include small numbers of cases, long accrual times, few interested investigators, less attention by the scientific community, low funding priority, low priority by pharma, fewer patient advocates, and lack of standard bioinformatics methods and trial designs. Lesson 4: In designing rare EOC clinical trials, one must balance scientific value with feasibility. Over time and with trial and error, it became obvious that accrual to clinical trials for recurrent clear-cell and low-grade serous ovarian cancers was completely feasible, but the unexpected extreme rarity of mucinous ovarian cancer led to a failed international trial. Lesson 5: Trials for rare EOC in the front-line or salvage setting may have different implications for feasibility. Front-line trials for clear-cell ovarian cancer, both randomized and nonrandomized, have been feasible. Front-line randomized trials for mucinous ovarian cancers do not appear to be feasible. A new clinical trial for front-line treatment of low-grade serous ovarian cancer has recently been activated; feasibility is as yet unknown. Lesson 6: Accurate pathologic diagnosis is essential to quality rare EOC clinical trials. In some instances, prospective digital pathology review was used as an eligibility criterion to optimize efficiency. Lesson 7: Characterization of the molecular signatures of rare EOC and availability of targeted agents significantly facilitated the development of innovative clinical trials. We now have excellent information regarding the common molecular aberrations in clear-cell carcinoma, low-grade serous carcinoma, and mucinous carcinoma. Lesson 8: Strategies for clinical trial design for rare EOC should include consideration of certain principles. These principles include determination of feasibility of phase II versus randomized phase II versus phase III designs; clinical trials that seek large benefits in selected populations with small sample size; tolerating a higher degree of uncertainty; relaxation of type I and type II errors; adaptive and Bayesian trial designs; rigorous use of early stopping rules; use of surrogate endpoints (response, PFS, or DFS, etc.); full exploitation of modern imaging techniques; strong translational research endpoints; and, in absence of known effective standard treatment, use of randomized phase II design to compare two or more experimental treatments. Finally, Lesson 9: Organizational aspects may be critical in the conduct of rare EOC trials. Key ingredients for successful conduct of rare tumor trials may include national or international networks involving centers of excellence; use of cancer registries to identify, screen, and recruit patients; utilization of retrospective or observational studies for hypothesis-generating data; quality tumor repositories; understanding differences in regulatory and funding issues across the world; and regular consultations between regulatory bodies, pharmaceutical companies, patient advocates, and investigators. All of these lessons will hopefully assist future investigators in the development of clinical trials for rare EOC. Citation Format: David M. Gershenson. Personalizing treatment for women with rare epithelial ovarian cancers (EOC): Lessons learned [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA25.