Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer
- Willemien J. van Driel, M.D., Ph.D.,
- Simone N. Koole, M.D.,
- Karolina Sikorska, Ph.D.,
- Jules H. Schagen van Leeuwen, M.D., Ph.D.,
- Henk W.R. Schreuder, M.D., Ph.D.,
- Ralph H.M. Hermans, M.D., Ph.D.,
- Ignace H.J.T. de Hingh, M.D., Ph.D.,
- Jacobus van der Velden, M.D., Ph.D.,
- Henriëtte J. Arts, M.D., Ph.D.,
- Leon F.A.G. Massuger, M.D., Ph.D.,
- Arend G.J. Aalbers, M.D.,
- Victor J. Verwaal, M.D., Ph.D.,
- Jacobien M. Kieffer, Ph.D.,
- Koen K. Van de Vijver, M.D., Ph.D.,
- Harm van Tinteren, Ph.D.,
- Neil K. Aaronson, Ph.D.,
- and Gabe S. Sonke, M.D., Ph.D.
Treatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.
In a multicenter, open-label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measuring 10 mm or less in diameter remain (optimal cytoreduction) was deemed to be feasible. Three additional cycles of carboplatin and paclitaxel were administered postoperatively. The primary end point was recurrence-free survival. Overall survival and the side-effect profile were key secondary end points.
In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P=0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P=0.76).
Among patients with stage III epithelial ovarian cancer, the addition of HIPEC to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects. (Funded by the Dutch Cancer Society; ClinicalTrials.gov number, NCT00426257; EudraCT number, 2006-003466-34.)
Ovarian Cancer Treatment — Are We Getting Warmer?
- David R. Spriggs, M.D.,
- and Oliver Zivanovic, M.D.
Regional chemotherapy theoretically results in a decreased rate of systemic toxic effects and a high pharmacologic advantage in tumors that are confined to a single organ or body cavity.1However, only in the case of ovarian cancer has such chemotherapy (intraperitoneal chemotherapy) been accepted as part of the standard of care.2 Hyperthermia, at temperatures of up to 42.0°C (107.6°F), has also been considered to be a potential strategy for enhancing the chemotherapeutic effect but has not been widely accepted as part of routine cancer care. Previous uncontrolled trials in which hyperthermia was used in combination with intraperitoneal chemotherapy showed improved efficacy, but the findings were limited by the intrinsic biases of patient selection and institutional expertise. The results of the randomized trial by van Driel et al., reported in this issue of the Journal,3 represent the most convincing information to date that a single administration of hyperthermic intraperitoneal chemotherapy (HIPEC) delivered at the end of a surgical resection of ovarian cancer may provide a meaningful advantage for a defined group of patients with cancer.
Some of the outcomes of the trial by van Driel et al. are certainly encouraging, but questions remain about how best to apply this technique to routine care. The treatment is apparently reasonably safe; the patients who underwent interval cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) and those who underwent the surgery without HIPEC (surgery group) had a similar side-effect profile and a similar rate of grade 3 or 4 adverse events. There was not a significant delay in the reinitiation of routine chemotherapy after surgery with HIPEC was performed. The median recurrence-free survival, which was the primary end point of the trial, was 10.7 months in the surgery group as compared with 14.2 months in the surgery-plus-HIPEC group (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; stratified P=0.003). At the time of the analysis of survival, 44% of the patients across the two groups were alive, with a median overall survival that was longer in the surgery-plus-HIPEC group than in the surgery group by nearly a year (45.7 vs. 33.9 months; hazard ratio for death, 0.67; 95% CI, 0.48 to 0.94; stratified P=0.02). The recurrence-free survival and overall survival are consistent with those among patients who received neoadjuvant chemotherapy followed by interval debulking surgery in a previous trial.4
However, many questions remain about the treatment evaluated in the current trial. What part of the HIPEC treatment was responsible for the apparent benefit? Do the results reflect simply a dose effect of cisplatin? In small clinical trials of high-dose cisplatin with thiosulfate rescue treatment that were conducted in the 1980s and 1990s, the toxic effects of the chemotherapy were controllable, but improvement in outcomes was limited. Could the beneficial effects seen in the current trial be a result of the use of the intraperitoneal route of administration? Intraperitoneal chemotherapy has shown benefit in most trials of primary treatment of ovarian cancer, but the intraperitoneal route has not been explored carefully in the context of interval debulking surgery. Is hyperthermia necessary for the incremental effectiveness of the chemotherapy? In preclinical trials, hyperthermia has been shown to increase the cytotoxic effect of cisplatin and of some (but not all) other chemotherapeutic agents by increasing the tumor penetration, promoting DNA cross-linking, impairing DNA repair, and promoting apoptosis.5 Does the early intraoperative administration of intraperitoneal therapy offer advantages over routine postoperative chemotherapy? The answers to these questions are not known.
Beyond the mechanistic questions, the overall role of HIPEC in the treatment of ovarian cancer is still uncertain and will depend on additional information regarding clinical outcomes. What is the incremental cost of this intervention? The extra time needed in the operating room, the longer duration of hospitalization, and the increased use of diverting colostomies or ileostomies will all increase the overall cost of treatment. The assessment of a cost–benefit ratio warrants serious consideration. Can the results observed in this trial be expected to be reproduced at centers at which surgeons do not have as much experience in administering HIPEC as those involved in the current trial, and how much of the favorable side-effect profile depended on highly experienced surgeons? Clinical experience is an important driver of outcomes in the case of any highly technical procedure. Most important, who should be considered for HIPEC? The authors enrolled only patients who underwent interval cytoreductive surgery after receiving three cycles of neoadjuvant chemotherapy for the primary treatment of ovarian cancer. Although the survival outcomes among the patients who underwent cytoreductive surgery with HIPEC were better than those among the patients who underwent surgery alone, neither group had results that came close to the published results for progression-free survival (approximately 2 years) seen in patients who undergo optimal cytoreduction (i.e., surgery after which one or more residual tumors measuring 10 mm or less in diameter remain) at the initial surgery.2 Well-designed clinical trials may eventually identify other subgroups of patients with ovarian cancer who are undergoing therapeutic interventions that differ from those of the population eligible for this trial and might benefit from intraoperative administration of HIPEC, but the results of the current trial cannot yet be extrapolated to any other conditions or clinical settings.
In conclusion, this randomized trial is a very important first step but should not drive changes in practice yet. Primary cytoreductive surgery for certain patients with ovarian cancer remains the preferred approach over neoadjuvant treatment, and administration of HIPEC at the time of interval cytoreductive surgery does not change that. New confirmatory clinical investigations of HIPEC are needed to clarify some of the unanswered questions before HIPEC can become a common treatment strategy. These considerations will be important for clinical trial investigators as they focus on the positive effect of HIPEC as an intervention as compared with the effects of promising new agent combinations or immunotherapy treatments.
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