Optimal management of recurrent ovarian cancer remains an area of uncertainty. Unlike many other solid tumors with few salvage agents to choose from, a variety of regimens have demonstrated at least modest efficacy. How is an oncologist to develop an optimal treatment plan given the available options? In this issue of ONCOLOGY, Foley and colleagues present a comprehensive review of systemic therapies available to treat patients with recurrent ovarian cancer. They include a discussion of standard options, new chemotherapeutics, and biologic agents. Despite a thorough cataloging of available regimens, the authors rightly note that the process of deciding which agent to use in a particular patient remains highly individualized. In fact, most patients receive several (if not all) available salvage chemotherapy regimens in a variety of sequences. Unfortunately, we still do not have clear-cut data-driven pathways to guide treatment choices once recurrent disease develops.
One factor that clearly aids treatment planning in patients with recurrent ovarian cancer is determining the primary progression-free interval (PFI). As described in the review by Foley et al, patients can be divided into those who are platinum-sensitive (PFI > 6 months) vs platinum-resistant (PFI ≤ 6 months). Outside of clinical trials, patients with platinum-sensitive disease should generally be treated with platinum-based regimens, whereas patients with platinum-resistant disease should be treated with nonplatinum agents. One important component of managing patients with platinum-sensitive disease not addressed by the current review is the role of secondary cytoreductive surgery in this setting. A number of retrospective analyses suggest a potential survival advantage of secondary cytoreduction in selected patients with platinum-sensitive disease.[1-3] In this setting, secondary cytoreduction is most effective in patients with a prolonged PFI (preferably > 12 months) and limited sites of disease, and when a complete gross resection of all visible disease can be achieved.
It is hoped that two ongoing prospective randomized trials will shed further light on the role of secondary cytoreduction in this setting. In addition to evaluating whether the addition of bevacizumab to carboplatin and paclitaxel improves overall survival (OS) in patients with platinum-sensitive disease, the Gynecologic Oncology Group (GOG) trial 213 randomizes patients deemed to be favorable surgical candidates to secondary cytoreduction followed by one of the chemotherapy arms vs chemotherapy alone without debulking surgery. The Arbeitsgemeinschaft Gynkologische Onkologie (AGO) DESKTOP OVAR III trial (The Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer) employs a randomization scheme similar to that of the surgical arm of GOG 213, but without asking a chemotherapy question. Both studies utilize OS as a primary endpoint and are therefore well suited to ascertain the role of secondary cytoreduction in recurrent ovarian cancer if accrual can be completed successfully. In the absence of randomized trial data, secondary cytoreduction should be considered a reasonable option in selected patients with a prolonged PFI and a high likelihood of achieving a complete gross cytoreduction as determined by an experienced gynecologic oncologic surgeon.
We would also highlight the value of enrolling patients with recurrent ovarian cancer in clinical trials. As demonstrated in the current review, a large number of agents are either in use or are under development. This is especially the case for targeted therapies that can be used in combination with conventional chemotherapy without greatly increasing toxicity. Results of the OCEANS trial suggest an improvement in PFI with the addition of bevacizumab (Avastin) to carboplatin and gemcitabine. Trials evaluating the utility of bevacizumab in combination with other agents are ongoing.
Targeted therapies have also demonstrated efficacy when used in subsets of patients with specific genomic mutations. Clinical trials assessing the utility of poly ADP-ribose polymerase (PARP) inhibitors in BRCA-mutation carriers are likely the first of many such therapies to demonstrate efficacy in selected patients with recurrent ovarian cancer. With a greater understanding of the genomic changes present in serous ovarian cancer that will be identified through large-scale sequencing projects such as The Cancer Genome Atlas (TCGA), the opportunity to target new pathways for therapy will expand further in the future. Such changes have the potential to greatly alter treatment regimens in patients with recurrent ovarian cancer. Finally, it is important to help patients with recurrent ovarian cancer recognize and acknowledge when further therapy is likely to be futile. For some patients this might occur very early in their disease course, while for others it may be after many years of treatment. Such patients may hold out unreasonable hope that one of the agents on the long list of potentially active drugs will provide a miracle cure. Patients with a declining performance status and those with progressive organ dysfunction who have failed to respond to two or more treatment regimens are unlikely to benefit from more cytotoxic therapy. To continue cytotoxic therapy in this setting can not only negatively impact quality of life but can even hasten death.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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