Several randomized trials have addressed whether the use of a platinum in combination is superior to single agents (see Table 7). A platinum-plus-paclitaxel combination yielded a superior outcome, in terms of response rates, PFS, and OS, in comparison to carboplatin as a single agent or other platinum-containing combinations as controls in an analysis of data analyzing jointly the results of three trials performed by the Medical Research Council/Arbeitsgemeinschaft Gynaekologische Onkologie (MRC/AGO) and ICON investigators (known as ICON4). Platinum plus paclitaxel was compared with several control regimens, though 71% used carboplatin as a single agent in the control, and 80% used carboplatin plus paclitaxel. Prolonged PFS (HR = 0.76; 95% CI, 0.66-0.89; P = .004) and overall survival (HR = 0.82; 95% CI, 0.69-0.97; P = .023) were improved in the platinum-plus-paclitaxel arm.[Level of evidence: 1iiA] The AGO had previously compared the combination of epirubicin plus carboplatin to carboplatin alone and had not found significant differences in outcome.
Another trial by European and Canadian groups compared gemcitabine plus carboplatin to carboplatin. The PFS of 8.6 months with the combination was significantly superior to 5.8 months for the carboplatin alone (HR = .72; 95% CI, 0.58-0.90; P = .003). The study was not powered to detect significant differences in OS, and the median survival for both arms was 18 months (HR = 0.96; CI, 0.75-1.23; P = .73).
Carboplatin plus paclitaxel has been considered the standard regimen for platinum-sensitive recurrence in the absence of residual neurotoxicity. The GOG-0213 trial is comparing this regimen to the experimental arm that adds bevacizumab to carboplatin plus paclitaxel.
In a phase III trial, carboplatin plus PLD (CD) was compared to carboplatin plus paclitaxel (CP) in patients with platinum-sensitive recurrence (>6 months). The primary endpoint was PFS with a median PFS for the CD arm of 11.3 months versus 9.4 months for the CP arm (HR = .823; 95% CI, 0.72-0.94; P = .005).[Level of evidence: 1iiDiii] The CP arm was associated with increased severe neutropenia, alopecia, neuropathy, and allergic reaction; the CD arm was associated with increased severe thrombocytopenia, nausea, and hand-foot syndrome. Although OS data have not been reported, given its toxicity profile and noninferiority to the standard regimen, CD is an important option for patients with platinum-sensitive recurrence.
Platinum-Refractory or Platinum-Resistant Recurrence
Clinical recurrences that take place within 6 months of completion of a platinum-containing regimen are considered platinum-refractory or platinum-resistant recurrences. Anthracyclines (particularly when formulated as PLD), taxanes, topotecan, and gemcitabine are used as single agents for these recurrences based on activity and their favorable therapeutic indices relative to agents listed in Table 8. The long list underscores the marginal benefit, if any, generally conveyed by these agents. Patients with platinum-resistant disease should be encouraged to enter clinical trials.