Indications for the role of HIPEC in EOC and the optimal drug regimen(s) are controversial (22-24). Zivanovic et al., in a phase I trial, demonstrated both feasibility and an acceptable toxicity profile of HIPEC utilizing cisplatin 100 mg/m2 following optimal tumor cytoreduction in the primary setting. The authors propose this dose as the recommend phase II dose in future studies (27). In our study, when comparing toxicity profiles between mitomycin C and platinum-containing agents, the rates of toxicities are similar except for the rate of transient renal dysfunction; this may be due to the difference in patient populations as the majority of our patients had at least one prior platinum based chemotherapy regimen. It is important to note that in the case of some toxicities, anemia in particular, it is difficult to determine whether the toxicity is solely a side effect of the chemotherapy agent or is related to the surgical procedure itself. Importantly, recommended adjuvant therapy was received in all but two patients and only one did not receive this therapy due to prolonged surgical recovery. This study adds to the growing body of literature demonstrating the safety and feasibility of HIPEC in the treatment of EOC. The use of platinum-based HIPEC regimens is of particular interest because most EOCs are platinum sensitive. Median time to progression is 7 months for the platinum group and 9 months for the mitomycin C group, but this difference is not statistically significant. This result is limited by the small sample size and variability in indications for HIPEC in our study.
Overall, the toxicity profile in our study is comparable to those reported in the literature. In a systemic review by Chua et al., cytoreductive surgery plus HIPEC for various indications estimated the mortality rate attributable to HIPEC therapy to be 0-5.8% with an estimated rate of major morbidities from 12-52%. The rate of hematologic morbidity in this study was 0-28% and the rate of renal failure was 0-7% (28). A recent study by Cripe et al. investigated the short-term morbidity and mortality of 32 patients undergoing HIPEC for EOC in the interval, consolidative, and recurrent setting. The majority of patients in this study received platinum-based chemotherapy. The rate of major morbidity was 65.6%, with anemia being the most common. There were no perioperative deaths in their cohort. When anemia was excluded as a complication, the rate of major morbidity was noted to be 25% (29). These studies in conjunction with previously published literature further support a reasonable side-effect profile for HIPEC in patients with EOC with an overall low risk of perioperative mortality.
A major challenge in incorporating HIPEC into the treatment for EOC is determining the most efficacious treatment regimen with the best toxicity profile. A number of different agents have been used in HIPEC protocols. Platinum-based therapy is an obvious choice because the majority of EOCs are platinum sensitive tumors. Argenta et al. published a pilot study of HIPEC with carboplatin 1,000 mg/m2 for platinum-sensitive recurrent disease which demonstrated both feasibility and safety (30). Deraco et al. conducted a phase II trial of HIPEC with cisplatin and doxorubicin in the front-line setting. The authors demonstrated a 5-year OS of 60.7% and PFS of median of 30 months or 15.2% without significant toxicity (22). This is one of the largest phase II studies exploring both efficacy and toxicity of HIPEC in EOC published to date. Oxaliplatin has also been evaluated as a potentially effective agent with a similar side effect profile to the other platinum-based regimens (24). Studies comparing carboplatin to cisplatin in EOC have demonstrated equivalence in the IV setting and there are data to suggest similar tumor penetration of both agents when administered into the peritoneal cavity (3,31). Additional prospective investigations of platinum-based regimens as HIPEC agents will help elucidate drug effectiveness, as well as better define the IP side-effect profile. Other cytotoxics that have been used in HIPEC include taxanes, doxorubicin, and mitomycin C. Both taxanes and doxorubicin are active agents in the treatment of EOC while mitomycin C derives from HIPEC regimens for gastrointestinal malignancies. At our institution, treatment with a platinum-containing agent is preferred for patients with platinum-sensitive EOC; however, it is more toxic than mitomycin C, particularly with regard to renal dysfunction. In patients who are known to be platinum-resistant or in whom performance status, medical comorbidities, or end-organ disease prohibit the use of a platinum-containing agent, mitomycin C is preferred.
Prospective data demonstrating an improvement in progression free and OS in EOC patients receiving HIPEC are lacking. Several retrospective trials have suggested a survival benefit with the addition of HIPEC to the treatment regimens of patients with recurrent EOC (32,33). Safra et al. performed a retrospective case-control study of patients treated for recurrent EOC with cytoreduction plus HIPEC versus IV chemotherapy alone. Although OS endpoints in this study have not yet been reached, the results suggest a significant improvement in PFS for the cytoreduction plus HIPEC cohort compared to chemotherapy alone (15 vs. 6 months, P=0.001) (32). In another retrospective case-controlled study by Le Brun et al., patients with first recurrence, platinum-sensitive EOC treated with either cytoreduction plus HIPEC or with a regimen that did not include HIPEC. The 4-year OS rate in the HIPEC group was 75.6% while it was only 19.4% in the non-HIPEC group (P=0.013) (33). Both studies have the benefit of having included a group of patients with a single indication for HIPEC, but, the associated selection biases cannot be completely accounted for in these retrospective studies. Unfortunately, in our study similar to much of the current literature, the patient cohort is very heterogeneous both in terms of indication for HIPEC and of treatment regimen used and thus survival endpoints could not be reported because of the small sample size. Chiva et al. estimated the weighted average of OS in trials of HIPEC following cytoreduction in the front-line and recurrent settings to be 37.6 and 36.5 months, respectively. The authors note that these results are comparable to those results noted with standard therapies and propose pursuing prospective trials of HIPEC in EOC (17).
Our study reports a series of patients treated with HIPEC for EOC at a single institution. The strength of this study is that all patients were treated with the same technique, limiting inter-institutional variability and the associated biases. Also, our study is one of the few utilizing mitomycin C in HIPEC following cytoreductive surgery for EOC patients. However, the study is limited by the inherent bias of a retrospective study with a small sample size. It is possible that mild complications of surgery may not be adequately reported in the medical record; thus, missed in this analysis. Determining the extent of cytoreduction performed retrospectively is difficult and at times not reported in the operative report. Additionally, this study lacks an assessment of patient quality of life measures, which is particularly important in patients undergoing therapy for recurrent disease. The variable indications for surgery as well as the variable chemotherapy regimens significantly impact the ability to compare outcomes data within this patient population, thus making it difficult to draw any conclusions about how HIPEC impacts outcomes for patients with EOC.