Systemic multiagent chemotherapy is the standard treatment for metastatic epithelial ovarian cancer (193–217). After the introduction of cisplatin in the latter half of the 1970s, platinum-based combination chemotherapy became the most frequently used treatment regimen in the United States. Paclitaxel became available in the 1980s, and this drug was incorporated into the combination chemotherapy in the 1990s (192–196). Comparative trials of paclitaxel, cisplatin, and carboplatin are summarized below.
In a meta-analysis performed on studies of patients with advanced-stage disease, those patients given cisplatin-containing combination chemotherapy were compared with those treated with regimens that did not include cisplatin (197). Survival differences between the groups were seen from 2 to 5 years, with the cisplatin group having a slight survival advantage, but this difference disappeared by 8 years.
A major advance in the treatment of advanced-stage disease was the incorporation of paclitaxel into the chemotherapeutic regimens in the late 1990s. A series of randomized, prospective clinical trials with paclitaxel-containing arms defined carboplatin and paclitaxel as the standard treatment protocol in advanced epithelial ovarian cancer, although there are data to support intraperitoneal chemotherapy in selected patients (194,195,201,202).
Reporting the GOG data (Protocol 111), McGuire et al. showed that the combination of cisplatin (75 mg/m2) and paclitaxel (135 mg/m2) was superior to cisplatin (75 mg/m2) and cyclophosphamide (600 mg/m2), each given for six cycles (194). In suboptimally resected patients, the paclitaxel-containing arm produced a 36% reduction in mortality. These data were verified in a trial conducted jointly by the EORTC, the Nordic Ovarian Cancer Study Group (NOCOVA), and the National Cancer Institute of Canada (NCIC), in which patients with both optimal and suboptimal disease were treated (195). In this study, the paclitaxel-containing arm produced a significant improvement in both progression-free interval and overall survival in both optimal and suboptimal groups. Based on these two studies, paclitaxel is included in the primary treatment of all women with advanced-stage epithelial ovarian cancer, unless there are contraindications to paclitaxel, such as preexisting peripheral neuropathy.
A three-arm comparison of paclitaxel (T) versus cisplatin (P) versus PT in suboptimal stage III and IV patients (Protocol 132) showed equivalency in the three groups, but crossover from one drug to the other was permitted (196). The study showed that the combination regimen was better tolerated than the sequential administration of the agents in suboptimally resected patients.
The second-generation platinum analogue, carboplatin, was developed to have less toxicity than its parent compound, cisplatin. In early trials, carboplatin had lower overall toxicity (204). Fewer gastrointestinal side effects, especially nausea and vomiting, were observed than with cisplatin, and there was less nephrotoxicity, neurotoxicity, and ototoxicity. Carboplatin is associated with a higher degree of myelosuppression (206).
The dose of carboplatin is calculated by using the area under the curve (AUC) and the glomerular filtration rate (GFR) according to the Calvert formula (207). The target AUC is 5 to 6 for previously untreated patients with ovarian cancer.