Recurrent Epithelial Ovarian Cancer: An Update on Treatment
Emerging therapies in the management of ovarian cancer have resulted in a shift in paradigm, including in the appropriate time to institute therapy, and in the selection of therapy. This review focuses on chemotherapy and emerging biologic agents that present a therapeutic option for patients with recurrent ovarian cancer.
An estimated 85% of patients with epithelial ovarian cancer who achieve a full remission following first-line therapy will develop recurrent disease. Although each subsequent line of therapy is characterized by shorter disease-free intervals, median survival for these patients ranges from 12 months to 24 months. Emerging therapies in the management of ovarian cancer have resulted in a shift in paradigm, including in the appropriate time to institute therapy, and in the selection of therapy. This review focuses on chemotherapy and emerging biologic agents that present a therapeutic option for patients with recurrent ovarian cancer.
Introduction
An estimated 75% of women with ovarian cancer present with advanced-stage (III or IV) disease. For patients with low residual disease (all lesions < 1 cm in size following surgical debulking), the risk for recurrence after completion of primary therapy is 60% to 70%; however, for women with large-volume residual disease, the risk is estimated at 80% to 85%.[1]
We conducted a systematic review using the MEDLINE database, PubMed, EMBASE, and the Cochrane Library. The search was restricted to English-language articles published from 1979 through July 2012. Priority was given to articles reporting original research, in particular randomized controlled trials, although review articles and commentaries also were consulted. Recent abstracts of research presented at symposia and scientific conferences were also considered.
The selection of therapy for women with recurrent disease is in large part determined by response to first-line therapy. Specifically, recurrent ovarian cancer has been dichotomized to either platinum-sensitive (progression-free interval [PFI] > 6 months) or platinum-resistant (PFI ≤ 6 months) disease, with PFI predicting the expected response rate (RR) and duration of response.[2-5] Irrespective of treatment selected, recurrent ovarian cancer remains incurable. The goals of therapy should focus on palliation of cancer-related symptoms, prolongation of life, and optimization of quality of life. This review will focus on the medical treatment, specifically chemotherapy options, available for women with recurrent ovarian cancer.
Role of Timing in the Treatment of Recurrent Ovarian Cancer
Recurrent ovarian cancer can be heralded by onset of new symptoms, radiologic evidence of recurrent disease, or a rising CA-125 level in an asymptomatic patient. CA-125 elevation may precede radiologic detection or onset of symptoms by several months.[6,7] Although formal definitions of ovarian cancer recurrence and progression have been described, based on both clinical and CA-125 criteria, many patients present with either an asymptomatic, radiologic recurrence or an asymptomatic rise in CA-125 level without a radiographic correlate.[7,8]
Given that recurrent disease is incurable, the goals of therapy outlined earlier should guide decisions about initiation of subsequent therapy.[9] In patients with symptomatic recurrence, immediate institution of treatment may be justified and warranted to palliate cancer-related symptoms. For asymptomatic recurrences (rising CA-125 level, for example), timing of therapy is much more controversial. Those who advocate institution of immediate treatment argue that treating small-volume disease is more likely to succeed in achieving a complete response following early intervention.[10-12] Advocates for delaying treatment emphasize that the goal of therapy is palliation, so that medical intervention should be deferred until symptom onset, given the lack of data to show that early treatment improves survival.[13]
The controversy surrounding the appropriate timing of institution of therapy was addressed in a prospective study of 1,442 women with ovarian cancer. The trial was conducted among patients in full clinical remission, with a normal CA-125 level following completion of primary surgical treatment and platinum-based systemic therapy.[14] Both investigators and patients were blinded. Serum CA-125 levels were checked every 3 months. Women whose CA-125 rose to a level twice above the upper limit of normal and remained asymptomatic (n = 527) were randomized to either immediate treatment or treatment when clinical or symptomatic recurrence occurred. Women randomized to immediate therapy initiated chemotherapy a median of 5 months earlier than those who initiated therapy with the onset of symptoms. Survival and remission duration were comparable between the two arms at 57-month follow-up. However, quality of life was worse for the women undergoing immediate treatment. The investigators concluded that early institution of second-line therapy did not benefit patients, advocating for treatment to be delayed until symptoms develop or patients have signs of recurrent disease.