What is the role of IP chemotherapy in women with optimally debulked advanced epithelial ovarian cancer (EOC)?

The natural history of ovarian cancer is transcoelomic spread and the disease is frequently confined to the peritoneal compartment at diagnosis and relapse. The benefit of administering chemotherapy directly into the peritoneal compartment is supported by pharmacokinetic data showing a multi-fold higher concentration of drug in the abdominal cavity. In 2006, the National Cancer Institute (NCI) published a meta-analysis of 8 randomised studies evaluating the benefit of IP chemotherapy. In the combined analysis of 6 of the 8 randomized studies, the hazard ratio (HR) for OS for IP versus IV therapy was 0.79 (95% confidence interval 0.70 0.89). The latest study by Armstronget al.comparing IP cisplatin and IP paclitaxel with the standard IV cisplatin and IV paclitaxel (GOG 172) was included. Although only 42% of patients on the IP chemotherapy arm completed all 6 cycles of therapy, on an intention-to-treat analysis, IP chemotherapy extended median OS by 16 months (66 versus 50 months) in a comparison with standard IV paclitaxel and IV cisplatin.19The most common toxicities were related to port catheter complications, increased nausea, vomiting and abdominal pain and higher haematologic, metabolic and neurotoxicity.

Consequently, the NCI issued a clinical announcement in January 2006 regarding their position on the preferred treatment for optimally debulked stage III ovarian cancer.20This stated that Based on the results of eight phase III clinical trials, the NCI is encouraging doctors to follow surgery with a combination of two-drug-delivery methods: IV and IP. The combined approach, though more toxic, extends OS for women with advanced ovarian cancer by about a year compared to IV drip alone.

The NCCN guideline18, in line with NCI, has recommended that stage II and III optimally debulked (<1cm) patients with ovarian cancer who are eligible for chemotherapy should be informed of the option of IP chemotherapy versus IV chemotherapy (or be considered for participation in a clinical trial). The guideline recommends for all women to be counseled about the benefit of IP chemotherapy prior to surgery.

In contrast, the 2011 NICE guidelines21were explicit in their recommendationagainstthe use of IP chemotherapy except in the context of a clinical trial. While the NICE guideline development group placed importance on the improvements in disease-free survival (DFS) and OS associated with IP chemotherapy, they also recognized that IP chemotherapy was more toxic, complex to administer and expensive. The ESMO 2013 guidelines has also highlighted that IP chemotherapy has not been adopted as a standard of care in the majority of institutions and countries due to its greater toxicity and the difficulty in delivering the entirety of the planned treatment.22The guidelines further recognize that much of the IV chemotherapy used in the control arms of reported IP chemotherapy trials are no longer considered current IV treatment standards.

In 2013, SIGN emphasized that IP chemotherapy may be considered as a first line therapy for eligible women with advanced ovarian cancer, provided that it is delivered in a centre with appropriate expertise and that the potential for toxicities is fully explained.17In contrast, the Australian 2009 GMCT guidelines indicate that IP chemotherapy is not recommended for patients who have significant intra-abdominal adhesions at the conclusion of their surgery as these adhesions may limit the distribution of the chemotherapy drug within the abdomen.23

Ongoing trials such as PETROC/OV21 (NCT00993655)24, JGOG 3109 (NCT01506856)25and GOG 252(NCT00951496)26are seeking to evaluate the benefit of IP chemotherapy against standard arms that incorporate weekly IV paclitaxel, bevacizumab and the use of IP carboplatin vis--vis cisplatin for the reduction of toxicity.

Cost-effectiveness Analyses

No cost-effectiveness analyses using local cost data and societal norms in Singapore have been performed. An analysis performed by the GOG based on an American perspective showed that compared to the IV paclitaxel and carboplatin regimen, the IP paclitaxel and cisplatin combination has an incremental cost-effectiveness ratio of USD $180,022 per quality-adjusted life year (QALY) saved (using a 7-year time horizon).27

Recommendations for IP Chemotherapy in Optimally Debulked Advanced EOC

The SCAN Workgroup has voted 5 to 3 in favour of the adoption of the 2013 ESMO guidelines.22The workgroup recognizes that there exists no local efficacy and toxicity data on IP chemotherapy. The workgroup agreed that the current evidence-based schedule for IP chemotherapy as described in GOG 172 is associated with excess toxicity, more complex to administer and also that there is a lack of experience and familiarity with the procedure locally. In Singapore, the most commonly used regimen is the JGOG dose-dense chemotherapy which has been shown to be superior to the standard 3 weekly IV paclitaxel and carboplatin regimen.13As such, the SCAN Workgroup has voted in support of the adoption of the 2013 ESMO guidelines22for local patients (Supplementary Table 1).