The Scottish Randomised Trial in Ovarian Cancer (SCOTROC)-1 established that the substitution of paclitaxel (175 mg/m²) with docetaxel (75 mg/m²) was not inferior in terms of survival or clinical response and was associated with less neurotoxicity, at the expense of increased grade 3/4 neutropenia [11]. Carboplatin in combination with docetaxel may be an acceptable alternative to carboplatin/paclitaxel for some patients where neurotoxicity is a particular concern.

Several phase III trials have addressed the addition of a third cytotoxic agent to carboplatin/paclitaxel [12–14]. The GOG0182-ICON5 was a randomized, phase III trial containing five arms which incorporated gemcitabine, liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel [14]. The addition of a third cytotoxic agent has not been shown to improve long-term clinical outcomes and is associated with increased hematological toxicity.

The standard of care is a three-weekly schedule of carboplatin and paclitaxel. However, it has suggested that a dose-fractionated schedule may enhance antitumor activity leading to improved survival. A Japanese study JGOG3016 set out to address this. The study compared six cycles of dose dense weekly paclitaxel (80 mg/m², given IV over 1 h) in addition to 3-weekly carboplatin (AUC6) against 3-weekly carboplatin (AUC 6) and paclitaxel (180 mg/m² IV over 3 h) in patients with advanced ovarian cancer [15]. Despite higher rates of myelosuppression, delays and dose modifications in the dose dense group, at the median follow up period of 76.8 months, the median PFS (28.2 months vs. 17.5 months, P = 0.004) and median OS (100.5 months vs. 62.2 months, P = 0.039) was longer in the dose dense group compared to the conventional group [16]. The outcome of this study could lead to change in standard of care and confirmation of the findings of the JGOG study in different study populations is required. Results of the MITO-7 study comparing 3-weekly carboplatin (AUC6) and paclitaxel (175 mg/m²) against weekly carboplatin (AUC2) and weekly paclitaxel (80 mg/m²) did not demonstrate a significant benefit in PFS with weekly administration compared to standard carboplatin/paclitaxel every 3 weeks, but was associated with better QoL and toxicity [17]. The ongoing ICON-8 trial is a randomized, phase III, three arm, study evaluating dose fractionation schedules (3 weekly carboplatin/paclitaxel vs 3 weekly carboplatin/weekly paclitaxel vs weekly carboplatin/paclitaxel) following immediate surgery or as part of delayed primary surgery.

Despite surgery and first-line chemotherapy, at least 65 % of women who achieve a complete response will eventually relapse, at which stage the condition is deemed incurable. Maintenance chemotherapy after initial therapy has been explored as a possible strategy to prevent or delay relapse. In the phase III SWOG 9701/GOG 178 study, patients with advanced ovarian cancer who had achieved complete clinical response were randomly assigned to receive 3 or 12 additional cycles of 4-weekly paclitaxel. Based on an interim analysis which reported a significant improvement in PFS of 7 months (21 vs 28 months) in the 12 cycle arm, the study was stopped prematurely [18]. However, no OS advantage was demonstrated [19]. Potential reasons for a lack of OS benefit include the effect of subsequent therapies, crossover of patients from 3 cycles to 12 cycles and reduced sample size due to the closure of the study. The Italian Cooperative Group After-6 phase III trial evaluated six cycles of 3-weekly paclitaxel as maintenance therapy compared with observation. No significant difference in PFS (34 vs 30 months) or OS (2 year survival rate: 87 % vs 90 %) between the paclitaxel and observation arms was seen following an interim futility analysis and the study closed early [20]. The ongoing GOG-0212 study is evaluating paclitaxel or polyglutamate paclitaxel or observation in women with stage III/IV ovarian cancer who achieve a complete clinical response to primary platinum/paclitaxel chemotherapy.

In patients undergoing primary surgery, the optimal time to initiate chemotherapy is an important issue. While it can be argued that chemotherapy should be initiated as soon as possible to prevent metastatic re-growth, patients who have been optimally debulked may have required invasive surgery including liver and/or bowel resection, as well as diaphragmatic stripping. In an analysis of prospective phase III trials, the median time to chemotherapy was 19 days (range 1–56) and a delayed start to chemotherapy was associated with decreased OS (p = 0.038) in optimally debulked patients whereas in patients with residual disease, a longer time to initiate chemotherapy had no effect on OS (p = 0.452) [26]. This analysis provides evidence to support an earlier start to initiate chemotherapy in optimally debulked patients.

Intra-peritoneal (IP) chemotherapy is another strategy that has been investigated in an attempt to improve outcomes in ovarian cancer. The rationale behind its use stems from the concept that advanced ovarian cancer predominantly affects peritoneal surfaces. Delivering cytotoxic agents directly to the peritoneum therefore increases dose intensity while preventing systemic toxicity.

Three randomized trials provided evidence for a survival advantage with IP chemotherapy compared to IV administration in women with optimally debulked (to <0.5 cm) stage III epithelial ovarian cancer [27–29]. The GOG 104 study compared six cycles of three-weekly IV cyclophosphamide (600 mg/m²) combined with either IV or IP cisplatin (100 mg/m²) [27]. The IP arm had a significantly longer median survival, (49 vs. 41 months, P = 0.02) but at the expense of more frequent moderate to severe abdominal pain. The GOG 114 trial incorporated a taxane into the treatment arms and provided further support for IP chemotherapy [29]. Six cycles of IV paclitaxel (135 mg/m²) and cisplatin (75 mg/m²) every 3 weeks was compared with IV carboplatin (AUC 9) every 28 days for two cycles followed by six cycles of IV paclitaxel (135 mg/m²) and IP cisplatin (100 mg/m²) every 3 weeks in patients with stage III optimally debulked ovarian cancer. Median PFS was longer in the IP arm (28 months vs. 22 months, P = 0.01) and median OS was increased in this arm (63 months vs. 52 months, P = 0.05) but again patients in the IP arm experienced increased toxicity and 18 % of patients received less than two courses of IP chemotherapy as a consequence. In GOG 172, 415 patients with optimally debulked stage III ovarian cancer were randomized to receive 63 weekly cycles of IV paclitaxel (135 mg/m ² over 24 h) followed by either IV cisplatin (75 mg/m²) on day 2 or IP cisplatin (100 mg/m²) on day 2 plus IP cisplatin (60 mg/m²) on day 8 [28]. The median survival data was impressive and again in favor of the IP arm (65.6 months vs. 49.7 months, P = 0.03). Despite the results of all three trials appearing to support the role of IP chemotherapy, it has not become routine clinical practice internationally. This is in part largely due to the increased toxicity (abdominal discomfort, infection, bowel injury, catheter-related problems, fatigue, hematological, gastrointestinal and neurological events) in the IP arms. It has been argued that the favorable outcome in GOG 114 [29] may be influenced by the increased amount of chemotherapy delivered in the IP arm (eight cycles). Furthermore, in GOG 172, the control arm did not receive the current standard of care i.e., IV carboplatin and paclitaxel and the dose and schedule of cisplatin and paclitaxel was different in the two arms of the study [28]. Therefore the higher dose of chemotherapy in the IP arm may have played a significant part in the survival benefit seen rather than the mode of delivery itself. Finally, the analysis was not a true intention-to-treat analysis and therefore it is feasible for minor imbalances in the number of excluded patients impacting on the statistical significance.

Combined data from the GOG114 and GOG172 demonstrated a significant improvement in median OS with IP administration, compared with IV administration (61.8 vs 51.4 months; P = 0.048) [30]. A subset analysis of 393 patients within the GOG172 study suggested that the survival advantage of IP chemotherapy was limited to a subset of patients with low BRCA1 expression as measured by immumohistochemistry (84 months IP vs 47 months IV; p = 0.0002) and that low BRCA1 expression was an independent prognostic factor for better survival in women randomized to IP therapy (hazard ratio (HR) = 0.67 p = 0.032) [31].