What is the optimal IV chemotherapy regimen for advanced epithelial ovarian cancer (EOC) following primary cytoreductive surgery?

Platinum-taxane Chemotherapy

As advanced EOC has a high risk of recurrence when treated with debulking surgery alone, chemotherapy following surgery is recommended. Platinum-paclitaxel has been the standard of care for the last 15 years, a consequence of 2 high quality landmark phase III randomised controlled trials (RCTs), the Gynecologic Oncology Group (GOG) 111 and EORTC-NCIC OV10. These trials demonstrated that cisplatin-paclitaxel combinations yield significant improvements in PFS and OS in women with advanced EOC following primary cytoreductive surgery as compared to cisplatin-cyclophosphamide chemotherapy.1,2

Cisplatin versus Carboplatin

The combination carboplatin-paclitaxel has demonstrated similar efficacy as cisplatin-paclitaxel but has advantages such as a more favourable toxicity profile and added convenience due to it being administered in an outpatient setting. These advantages have been demonstrated in 2 non-inferiority phase III RCTs.3,4

Carboplatin-paclitaxel has since become the worldwide standard of care in front-line treatment of EOC. The most commonly used schedule is carboplatin (AUC 5-6) in combination with paclitaxel (175mg/m2), both administered intravenously every 3 weeks. Typically, 6 cycles of chemotherapy are given. There is no evidence to suggest that improved outcomes will be obtained with more than 6 cycles of chemotherapy.

Paclitaxel Intolerance

For women who are allergic to or intolerant of paclitaxel, carboplatin-pegylated liposomal doxorubicin (PLD) can be considered as an alternative, based on a single phase III RCT, the MITO 2 study.5PLD (30mg/m2) in combination with carboplatin (AUC 5) given every 3 weeks yielded similar PFS and OS as the paclitaxel (175mg/m2) and carboplatin (AUC 5) combination.

Patients Unfit for Combination Chemotherapy

Women who are unfit for combination chemotherapy can be given single agent carboplatin, as indicated by the ICON 3 findings.6

Adding in a Third Cytotoxic Drug

To date, there have been at least 5 good quality phase III RCTs involving more than 6,000 patients that investigate the addition of a third cytotoxic drug to the standard platinum and paclitaxel combination, either as triplet therapy7,8,9,10or as sequential doublets.11Not only did the addition of a third drug not improve survival outcomes, it also enhanced toxicities, in particular haematological toxicities.

Chemotherapy Scheduling: Dose-dense Chemotherapy

The rationale for dose-dense chemotherapy comes from the Norton- Simon Hypothesis, which states that increasing the dose density of chemotherapy reduces the chance of emergence of resistant clones and improves efficacy by reducing the regrowth of tumour cells between treatment cycles.12

This concept was tested in a single large phase III RCT in Japan (NOVEL-JGOG 3062). In this trial, IV paclitaxel (80mg/m2) given weekly in combination with IV carboplatin (AUC 6) given every 3 weeks resulted in significant improvement in PFS and OS in women with advanced EOC as compared to those of the standard IV carboplatin and paclitaxel regimen.13Long-term follow-up results showed that at a median follow-up of 76.8 months, the median PFS was 28.2 months in the dose-dense arm (versus 17.5 months in the conventional group; HR 0.76, 95% CI 0.61-0.91; p=0.0037) and the median OS was 100.5 months (versus 62.2 months in the conventional group; HR 0.79, 95% CI 0.63-0.99; p=0.039). However, the dose-dense carboplatin-paclitaxel combination was associated with greater haematological toxicities leading to greater dose-delays and lower completion rates. Less than half of the patients completed treatment according to study protocol and 38% of patients stopped this regimen prematurely (versus 21% in the conventional group). Incidence of Grade 3 or 4 anaemia was significantly higher in the dose-dense arm (69% vs 44%; p<0.001). Dose-dense chemotherapy is also more inconvenient due to the weekly treatment schedule. The overall quality of life (QoL) did not differ significantly between the 2 treatment groups.14However, according to the taxane subscale, QoL was significantly lower in the dose-dense group, a consequence of the increased neurotoxicity (p=0.02).

A second dose-dense study, the MITO-7, was a recently published15phase III RCT that used a different chemotherapy schedule from the JGOG 3062. It administered IV carboplatin (AUC 2) in combination with paclitaxel (80mg/m2) weekly in the treatment of EOC following primary debulking surgery. Although the weekly regimen has a more favourable toxicity profile compared with the conventional 3-weekly chemotherapy, contrary to the JGOG 3062, there was no difference in PFS between the two treatment arms. The OS data was immature. The findings of two other dose-dense studies, the GOG 262 (NCT 00951496) and the ICON 8 (NCT 01654146), are yet to be published.

Cost-effectiveness Analyses for Dose-dense Chemotherapy

An actual cost data collection was not performed by the JGOG 3062. However, a cost-effectiveness analysis using the Markov economic decision model found that dose-dense paclitaxel administered weekly is a cost-effective treatment option for advanced ovarian cancer.16The incremental cost-effectiveness ratio was USD $4,859 per progression-free life-year saved for the dose-dense weekly regimen as compared to the conventional 3-weekly regimen.

Recommendations for Front-line IV Chemotherapy following Primary Cytoreductive Surgery

The SCAN Workgroup has voted 6 to 2 in favour of the adoption of the SIGN guidelines17for front-line IV chemotherapy following cytoreductive surgery (Table 1 and Supplementary Table 1) due to its comprehensive nature. The workgroup also recommends the discussion of dose-dense chemotherapy as a treatment option with patients.

There is unanimous agreement amongst the working group members that platinum-taxane is the standard of care for front-line chemotherapy and that the SIGN guidelines are the most comprehensive of all guidelines reviewed as it recommends

single agent carboplatin in patients who are unable to tolerate combination chemotherapy

carboplatin-pegylated liposomal doxorubicin in cases of taxane-intolerance

against the addition of a third cytotoxic agent to platinum-taxane.

The role of dose-dense chemotherapy was more contentious. Two working group members felt that based on the JGOG 3062 data13, there is sufficient evidence to support the use of dose-dense chemotherapy as a standard treatment. They therefore voted for the NCCN guidelines18(Table 1) which endorses this mode of treatment as a Category 1 treatment. Six working group members felt that although the JGOG 3062 is a potentially practice-changing study, there exists a possibility that the results may be a chance finding or could be due to pharmacogenomics differences between the Japanese and Caucasian populations. In the absence of confirmatory trial data and in view of the increased toxicities and increased hospital visits associated with dose-dense treatment, they opined that pending the results of other dose-dense studies, dose-dense chemotherapy can only be considered an option and not a standard of care. Hence, they endorsed the SIGN guidelines which recommend dose-dense chemotherapy as a treatment option to be discussed with patients.

The workgroup acknowledges that there is no local data regarding front-line IV chemotherapy for advanced EOC.