In the late 1980s and early 1990s, paclitaxel became the next major advance in treating advanced epithelial ovarian cancer. Several phase II trials demonstrated significant activity in patients with platinum-refractory disease.56-58 In 1990, the GOG initiated the first phase III trial, comparing six cycles of cisplatin plus paclitaxel with the control regimen of cisplatin plus cyclophosphamide in suboptimally debulked disease.59 The paclitaxel regimen demonstrated significant improvements in overall response, clinical complete remission, median progression-free survival, and overall survival. Beyond 5 years, treatment with paclitaxel was still associated with a 34% reduction in the risk of death. The OV-10 trial, initiated by a collaborative group of European and Canadian investigators, substantiated the GOG findings.60 A subsequent GOG trial, which randomized patients to paclitaxel only, or cisplatin only, or cisplatin/paclitaxel, somewhat challenged the superiority of cisplatin/paclitaxel by reporting similar median overall survivals (26 to 30 months) among the three groups, and no difference in first progression or death between cisplatin and cisplatin-pacli-taxel.61 However, nearly 50% of patients in each arm of the study were treated with crossover salvage therapy before radiographic disease progression. This crossover treatment may have clouded survival differences among the three arms. Additional contradictory data come from the ICON-3 trial. The authors of ICON-3 concluded that combination paclitaxel-carboplatin demonstrated no advantage over single-agent carboplatin or combined cytoxan-adriamycin-cisplatin.62 This trial has been widely criticized for its design and methodology, and in North America the taxane-platinum combination remains the standard chemotherapy for advanced epithelial ovarian cancer.
Initially, paclitaxel infusions were given over 24 hours because of the concern for severe allergic reactions. Dose ranges for paclitaxel are 135 to 175 mg/m2 when the drug is given every 3 to 4 weeks. Eisenhauer and colleagues63 demonstrated that response rates were similar for 3-hour and 24-hour infusions; however, 3-hour pacli-taxel infusions appear to be associated with more neurotoxicity and less myelosup-pression than 24-hour infusions. Currently, in the United States the most common administration is 3-hour infusions followed by carboplatin in the outpatient setting. Although this administration is more convenient for patients, paclitaxel-associated neuropathy can be a significant chronic problem for some patients.
A newer taxane, docetaxel, may offer less toxicity than paclitaxel. In the SCOTROC study, 1077 women were randomized to docetaxel-carboplatin versus paclitaxel-carboplatin.64 Patients in the docetaxel arm reported less neurotoxicity, less muscle and joint pain, and less musculoskeletal weakness. However, docetaxel was associated with more gastrointestinal toxicity and neutropenia. Docetaxel is currently being studied in advanced epithelial ovarian cancer at several U.S. centers, and the results of these trials are pending.
NCCN guidelines list carboplatin-paclitaxel as the preferred regimen in advanced disease, but carboplatin-docetaxel is an alternative (see Fig. 8-8).
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