First-line randomized trials: revisiting the Ptolemaic universe

Epithelial ovarian cancer is initially a chemosensitive neoplasm, with overall response rates to systemic platinum-based therapy exceeding 80% in conjunction with cytoreductive surgery. However, long-term survival remains poor due to eventual tumor recurrence and emergence of drug resistance. While platinum (cisplatin or carboplatin) and taxanes remain at the core of primary treatment, there has been increased interest in the evaluation of doublet and triplet combinations with diverse cytotoxic agents, including docetaxel, topotecan, gemcitabine, and PEG-liposomal doxorubicin. This has been prompted by single-agent activity in the setting of recurrent platinum-resistant disease and encouraging data from nonrandomized phase I-II trials. As a result, beginning in 1998, the international cooperative groups collaborated on a series of phase III trials to improve long-term outcomes through the development of new platinum-based combinations. More than 10,000 women have been randomized on these trials, and preliminary data from several studies have been reported. Although final data are pending, there is not currently any evidence to recommend adopting a new two- or three-drug combination, and carboplatin with paclitaxel remains the standard regimen of choice. Rapid developments in molecular-targeted therapy are challenging our paradigm for future clinical trials, and our priorities need to be carefully considered.