Therapy for recurrent ovarian cancer is not curative, and presumed overall survival benefits of standard strategies are uncertain and often based on low-level evidence. Treatment toxicity and patient quality of life should be considered at all points during disease management.
Oliva Foley and coauthors have done a nice job summarizing the current state of the art of treating recurrent epithelial ovarian cancer (EOC). About 75% of EOC patients whose disease is not cured by primary therapy will have disease that recurs more than 6 months after completion of primary chemotherapy (termed “platinum-sensitive”), and more than half of these recurrences will happen more than 12 months after completion of primary chemotherapy. In this scenario, further systemic therapy is likely to achieve meaningful treatment response and symptom palliation. Nonetheless, as appropriately emphasized in the article, therapy for recurrent ovarian cancer is not curative, and presumed overall survival (OS) benefits of standard strategies are uncertain and often based on low-level evidence. Treatment toxicity and patient quality of life should be considered at all points during disease management.
In their article, Foley et al describe areas of uncertainty, including the controversy over the timing of initiation of second-line therapy: should an asymptomatic patient with a rising CA-125 level be treated, since it is rather certain that her tumor has recurred even in the absence of radiologic abnormalities? If not, should patients’ CA-125 levels be monitored at all? The “watchful waiting” period between rise of CA-125 and institution of therapy is a time of high anxiety for patients and physicians, as the optimal timing for institution of therapy is unclear. Although the recent Medical Research Council (MRC)/ European Organisation for Research and Treatment of Cancer (EORTC) randomized trial showed no improvement in survival and a worse quality of life with early institution of chemotherapy, the practice of CA-125 monitoring for patients in first complete remission remains widespread in the United States. Physicians at academic centers remain optimistic that new agents will improve outcomes, and instituting therapy prior to symptomatic recurrence may allow more chances for use of novel therapeutics. In addition, resection of recurrent disease, which was not part of the paradigm in the MRC/EORTC trial, may be more beneficial and successful in asymptomatic patients who may have lower-volume or isolated disease. In a representative retrospective review, Chi et al reported that patients whose residual disease at the end of secondary cytoreductive surgery was less than 0.5 cm had a median survival of 56 months, compared with 27 months for those with larger volumes of residual disease. Whether this represents “causation” or “correlation” is being explored by two ongoing randomized trials in which women with platinum-sensitive recurrent ovarian cancer are randomized to undergo or not undergo secondary cytoreduction. The Gynecologic Oncology Group (GOG) study 213 is currently recruiting in the US, and the Arbeitsgemeinschaft Gynkologische Onkologie (AGO) DESKTOP III trial is active in Europe.
The article also nicely describes uncertainties surrounding the timing and use of bevacizumab (Avastin). The authors suggest that since the OCEANS study in women with platinum-sensitive recurrent disease showed that the addition of bevacizumab to carboplatin/gemcitabine chemotherapy increased toxicity with no improvement in OS (despite an improvement in response rate and progression-free survival), combination therapy without bevacizumab could generally be appropriate, with single-agent bevacizumab being reserved for subsequent use. The progression-free survival (PFS) advantage seen with bevacizumab comes with the use of maintenance therapy, which does not provide a period completely off treatment. The calculus is different for women with platinum-resistant disease, as many are or soon become symptomatic from their disease, and response rates to therapy are dismal. Here the improvement in response rate and PFS preliminarily reported by the AURELIA trial for the addition of bevacizumab to cytotoxic therapy in women with platinum-resistant disease might translate into important symptom palliation even if there is not an OS benefit.
Most recurrent ovarian cancers will be high-grade serous tumors. Patients with recurrent tumors of clear cell, mucinous, or low-grade serous histology should be considered separately, as these histologic subtypes respond very poorly to standard cytotoxic chemotherapy, whether or not the tumor is technically “platinum-sensitive.” Gershenson et al reported a response rate of 3.8% for 108 chemotherapy regimens administered to 58 patients with low-grade serous tumors. A review of 51 patients with recurrent clear-cell ovarian carcinoma treated at MD Anderson showed that only 9% of those with platinum-sensitive disease responded to therapy and none of those with platinum-resistant disease responded. Mucinous tumors are even more chemotherapy-resistant. Anti-angiogenic therapy such as bevacizumab is worth exploring in all these histologic subsets, and has been reported to produce responses in two women with recurrent low-grade tumors. Patients should, where possible, be referred for trials specific to the different histologic subtypes, such as studies targeting KRAS and BRAF mutations in low-grade tumors or mutations of PIK3CA in clear-cell cancers. Increased HER2 copy number has been reported in mucinous tumors and might provide a target for future study.[7,8]
Molecular targeting of recurrent high-grade serous cancers has been challenging, and genomic analyses to date have generally failed to reveal high-frequency “druggable targets.” This is further complicated by the genomic instability and intratumoral heterogeneity of the disease. Intratumoral hetereogeneity is not news: older work using in vitro chemoresistance assays demonstrated areas of both low drug resistance and extreme drug resistance in 11.3% of recurrent ovarian cancers. Attempts to direct therapies to the obvious target of homologous recombination defects (which appear in about half of ovarian tumors; about 13% of high-grade serous disease is attributable to germline mutations in BRCA1 or BRCA2) have been less successful than hoped. While single-agent therapy with PARP inhibitors (which target homologous recombination defects) have produced response rates of 50% in women with platinum-sensitive disease, cancers in women with a germline BRCA1 or BRCA2 mutation have been shown to develop secondary genetic mutations that restore the reading frame of the BRCA protein, and the addition of PARP inhibitors to chemotherapy in women with recurrent disease has so far failed to improve survival. Front-line trials with PARP inhibitors are being planned, and may yield better results. However, there is reason to be optimistic about the future of therapy for patients with recurrent ovarian cancer. Inhibition of Wee-1 may target the universal p53 aberrations observed in high-grade serous cancers, and Wee-1 inhibitors are being developed. Objective responses to a variety of immune therapies have been observed, such as an antibody against cytotoxic T lymphocyte protein 4 (CTLA 4) (see reference 66 from Vaughn et al) or BMS-936559, and antiprogrammed death ligand-1 (PDL-1) monoclonal antibody and immune therapies are a promising area for development. Aberrant DNA methylation is a frequent epigenetic event in ovarian cancer, and the use of chemotherapy plus epigenetic modulators such as demethylating agents or histone deacetylase inhibitors is being studied. The ability to analyze complex genomic data is rapidly increasing, and ovarian cancer is fairly readily biopsiable. More than ever, patients with recurrent disease should consider participation in high quality research trials.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Rustin GJ, van der Burg ME, Griffin CL, et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet. 2010;376:1155-63.
2. Chi DS, McCaughty K, Diaz JP, et al. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer. 2006;106:1933-9.
3. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039-45.
4. Gershenson DM, Sun CC, Bodurka D, et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol. 2009;114:48-52.
5. Crotzer DR, Sun CC, Coleman RL, et al. Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary. Gynecol Oncol. 2007;105:404-8.
6. Bidus MA, Webb JC, Seidman JD, et al. Sustained response to bevacizumab in refractory well-differentiated ovarian neoplasms. Gynecol Oncol. 2006;102:5-7.
7. Huang RY, Chen GB, Matsumura N, et al. Histotype-specific copy-number alterations in ovarian cancer. BMC Med Genomics. 2012;5:47.
8. Anglesio MS, Kommoss S, Tolcher MC, et al. Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas. J Pathol. 2013;229:111-20.
9. Vaughan S, Coward JI, Bast RC, Jr, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nature Rev Cancer. 2011;11:719-25.
10. McAlpine JN, Eisenkop SM, Spirtos NM. Tumor heterogeneity in ovarian cancer as demonstrated by in vitro chemoresistance assays. Gynecol Oncol. 2008;110:360-4.
11. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609-15.
12. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12:852-61.
13. Norquist B, Wurz KA, Pennil CC, et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011;29:3008-15.
14. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382-92.
15. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-65.