Evaluating New Regimens in Recurrent Ovarian Cancer: How Much Evidence Is Good Enough?

Recurrent ovarian cancer remains a difficult disease to treat. Drugs used in the recurrent disease setting include platinum compounds, taxanes, pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, pemetrexed, and etoposide. Investigational agents with activity include bevacizumab, AZD2171, poly ADP ribose polymerase inhibitors, and epothilones. After a trial of three to four such drugs in the recurrent disease setting, patients usually do not derive a clinically meaningful response to additional agents as a result of mechanisms of cross-resistance that are still poorly understood. Each of us can recount exceptions to this rule, especially in the setting of germline BRCA1 or BRCA2 mutation, but they are not common. The algorithm for chemotherapy selection in the recurrent disease setting is fairly straightforward. Patients who experience disease progression through first-line, platinum-based therapy (platinumrefractory) or those who experience relapse within 6 months of receiving prior platinum therapy (platinum-resistant) are typically treated with a non–platinum-based regimen, such as single-agent PLD, gemcitabine, weekly paclitaxel, or topotecan, yielding responses in the range of 10% to 15% that last a median of approximately 4 months. Such patients represent a heterogeneous group, with patients with platinum-refractory disease being unlikely to experience an objective response to currently available agents and patients with platinum-resistant disease experiencing the occasional good response that provides meaningful palliation (and sometimes even experiencing another response to platinum rechallenge). Patients who experience relapse after a platinum-free interval (PFI) of greater than 6 months (platinum-sensitive) typically receive a platinum-based regimen, often in combination with a drug like paclitaxel, gemcitabine, or, more recently, PLD, yielding responses in the range of 30% to 40% or higher, especially for those with a PFI of greater than 24 months. Unlike platinum-resistant relapse, where single agents are preferred outside of a clinical trial setting, patients with platinum-sensitive disease seem to experience an overall survival (OS) benefit through the use of the combination of paclitaxel and platinum. This conclusion is based on the results of the International Collaborative Ovarian Neoplasm-4 trial (ICON4), involving 802 patients with platinum-sensitive recurrence who received either single-agent platinum or a combination of paclitaxel and platinum. Thus far, this is the only trial to demonstrate a statistically significant improvement in OS in favor of combination chemotherapy for recurrent ovarian cancer (7% absolute improvement at 2 years; P .023). ICON4 was well conducted but has some methodologic limitations, including the fact that approximately 40% of patients randomly assigned to the control (single-agent) arm never received a taxane at any point in their disease course, including first-line therapy. In addition, the majorityofpatients inthecontrolarmdidnotreceivepaclitaxelondisease progression, raising the possibility that the sequential use of platinum followed by paclitaxel on disease progression might have conferred the same survival advantage, but with less toxicity. Of note, the OS benefit observed with combination paclitaxel and platinum in ICON4 was restricted to thosepatientswhosePFIwasgreater than12months,although manypractitionersseemtoextrapolatethesedatatoanypatientforwhom platinum is considered appropriate, such as those with a PFI of between 6 and 12 months. Regardless of these issues, ICON4 has justifiably broadenedthegoalof treatingplatinum-sensitiverelapse fromoneof symptom control to one of also improving survival. For all the good that ICON4 has done, it seems that this study has unintentionally created a precedent whereby it has become fashionable to acceptloosercriteriaasevidenceofbenefitforcombinationtherapyinthis disease setting. For example, a subsequent study performed by the Arbeitsgemeinschaft Gynaekologische Onkologie compared single-agent carboplatin with the combination of carboplatin and gemcitabine in 356 patients with platinum-sensitive relapse. This trial showed that the combination was associated with a 2.8-month improvement in PFS (P .0031), greater toxicity than single-agent carboplatin, no improvement inqualityof life(QOL),and,unlikeICON4,noimprovement inOS (the fact that the study was not powered to detect an OS advantage begs the question). Nevertheless, despite the absence of an OS or QOL advantage, the combination of carboplatin and gemcitabine was ultimately approved for use by the US Food and Drug Administration (FDA). In the post-ICON4 era, is it appropriate to decrease the rigor with which we evaluate subsequent combination trials in recurrent disease, and in particular, is it appropriate to make assumptions about the value of PFS as a surrogate for OS in this setting? These issues will be explored further as we discuss the results of an interesting combination published in this issue of Journal of Clinical Oncology by Monk et al. The report by Monk et al describes the results of a randomized phaseIIItrialcomparingPLDwithacombinationofPLDandtrabectedin in 672 patients with recurrent epithelial ovarian cancer. Trabectedin is derived from the marine tunicate Ecteinascidia turbinata and exerts its cytotoxiceffectsthroughbindingtotheminorgrooveofDNA,interfering with nucleotide excision repair, and causing lethal DNA strand breaks. This drug has single-agent activity in relapsed ovarian cancer in approximately the same range for platinum-sensitive patients as drugs like topotecan, PLD, and gemcitabine. In addition, there is in vitro evidence to JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 28 NUMBER 19 JULY 1 2010