Triple Cytotoxic Therapy for Advanced Ovarian Cancer: A Failed Application, Not a Failed Strategy
Authors: Paul J. Hoskins
Journal: Journal of Clinical Oncology (2009)

Recommended standard therapies for the initial treatment of advanced ovarian cancer are carboplatin and paclitaxel, on the basis of equivalent efficacy but lesser toxicity compared with cisplatin and paclitaxel, carboplatin and docetaxel, or the initial use of a platin analog as a single agent with the subsequent use of a taxane. The good news is that such therapies have increased median overall survival to 3 years, compared with the 1-year survival achieved in the era before platinum. The bad news is that they are still not curative for the great majority. Long-term follow-up in the Gynecologic Oncology Group (GOG) 111 study and European Canadian Intergroup study (OV.10) demonstrated progression-free survival in only 18% of patients at 6 years. Efforts to improve these poor long-term outcomes have resulted in a variety of experimental strategies. One extensively tested approach has beent to add a third cytotoxic drug. Selection criteria for picking that third drug are mechanisms of resistance that are different from the platins or taxanes, and more importantly, evidence of some degree of non– cross-resistance in the clinical setting. Gemcitabine, topotecan, and liposomal doxorubicin have been used in this setting because of their known and reproducible single-agent activity in the cohort of platinum-resistant patients; epirubicin has been used because of the apparent superiority of anthracycline-containing platin-based regimens in meta-analyses. However, they have all been tested without apparent benefit in nine phase III studies. There was absolutely no statistically significant superiority or clinically useful benefit associated with the three drugs, compared with the control arms receiving carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg/m over 3 hours) every 3 weeks for six or more cycles (Table 1). In fact, when comparing hazard ratios for progression-free survival (PFS), the standard arms were often as superior as the three-drug arms. For example, the maximum degree of benefit achieved by adding a third drug in the large, well-conducted GOG 182 study was an increase in median PFS of 2 weeks (16 to 16.4 months) and a 2% absolute overall survival increase at 3 years (57% to 59%), with the triplets containing gemcitabine or liposomal doxorubicin. In contrast, in patients in the sequential doublet arms receiving topotecan or gemcitabine, there was a 3-week decrement in median PFS. It is essential for us to understand why the triple-drug strategy has failed, not only in ovarian cancer but also, for example, in lung cancer. The negative consequences resulting from abandoning the strategy on the basis of flawed analysis will be significant, and these consequences are already becoming apparent. The assumption has already been made that it was a failed strategy, not a failed design or incorrect choice of drugs. The pharmaceutical industry has moved away from developing new cytotoxics and is now concentrating on targeted therapies instead, with new product pipelines consisting almost exclusively of targeted therapies. Similarly, the cooperative groups have moved wholeheartedly toward testing targeted therapies, such as vascular endothelial growth factor inhibition in conjunction with carboplatin and paclitaxel in women newly diagnosed with ovarian cancer, and away from testing additional cytotoxics in first-line combinations. It is