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Letter to the Editor |
Peritoneal Surface Malignancy Program, Washington Cancer Institute, 106 Irving St, NW, Suite 3900, Washington, DC 20010, USA
We read with interest the recent article by Elias et al. that compared hyperthermic intraperitoneal chemotherapy (HIPEC) with early postoperative intraperitoneal chemotherapy (EPIC) after complete cytoreductive surgery for colorectal peritoneal carcinomatosis.1 The authors demonstrated that there was a reduced peritoneal recurrence rate in the HIPEC group (6 of 23) as compared with the EPIC group (13 of 23), but this did not translate into a statistically significant difference in survival (P = .22). This absence of a difference in survival probably occurred because the total numbers of patients who had disease recurrence, including both peritoneal and systemic, were equal in the two comparative groups (18 of 23). But this said, the 5-year survival of 54% in the HIPEC group and 28% in the EPIC group did indicate that there was a trend of difference. The results are particularly promising when we consider that 38% of the total patients had synchronous liver metastases and 48% had positive lymph nodes resected at the time of cytoreductive surgery.
In 1996, Elias and co-workers attempted a randomized study comparing cytoreductive surgery and EPIC versus cytoreductive surgery without EPIC.2 The trial was terminated prematurely as a result of recruitment difficulties. According to the investigators, the patients’ reluctance to be randomized in the EPIC trial was related to promising results found in cytoreductive surgery with HIPEC at the time. In this incomplete trial, EPIC did not show any measurable effect; patients who had complete cytoreduction with or without EPIC demonstrated a 2-year survival of 60%. The authors concluded that complete cytoreduction was a prerequisite for long-term survival. Although these reports, including the present study, may be predictive of outcome, they only apply to the subset of patients who received complete cytoreduction as defined by Elias and colleagues. Therefore, the evidence is insufficient to conclude that the survival advantage is entirely due to the combined treatment; it may be caused by selection of patients whose cancer biology allowed complete cytoreduction.
Although this article might suggest a potential difference in efficacy of HIPEC and EPIC, we are concerned about the retrospective comparison between the two treatment regimens for several reasons. First, the only significant difference between the two comparators in this report was the incidence of peritoneal recurrence. How was the recurrence diagnosed? Did all or some of these patients undergo a second-look procedure? As we know, the detection of peritoneal disease by radiological modalities is limited.3,4
Second, the time frame for patient accrual for the two treatment regimens was separated by many years. EPIC was used from 1994 to 2000, and HI-PEC was used from 1999 to 2002.1 During this time, there was a marked improvement in the benefits of systemic chemotherapy agents. As indicated in the original reports of both treatment arms (data not shown in the present study), all patients in the HI-PEC group had received systemic neoadjuvant oxaliplatin- or irinotecan-based regimens for at least 3 months.5 Patients who experienced rapid progression of disease while receiving systemic chemotherapy were not eligible for combination treatment. In the EPIC group, 5-fluorouracil– and leucovorin-based chemotherapy was used.2 Not only was the neoadjuvant chemotherapy different, but also a more effective adjuvant treatment was available. Although no solid evidence documents the efficacy of modern systemic chemotherapy in colorectal peritoneal carcinomatosis, its potential benefits cannot be ignored.
Third, over a 10-year period, it is likely that there is an improvement in patient selection, increase in surgical expertise, and greater familiarity with the clinical management, which may not be reflected by comparing baseline characteristics between the HI-PEC and EPIC groups. Elias and colleagues undoubtedly have extensive experience over the last 10 years because they are a leading peritonectomy center in Europe.
Finally, we think that these two treatment regimens should not be regarded as competitive, but rather complementary. The fundamental goal of intraperitoneal chemotherapy administration is to maximize the total amount of drug delivered to the peritoneal tumor nodules while minimizing drug delivered to the systemic circulation. The cytotoxic effects on peritoneal cancer nodules are the result of direct physical contact with intraperitoneal chemotherapy followed by penetration by diffusion. These events are influenced by the drug concentration in the chemotherapy solution, the uniform distribution of chemotherapy solution and heat, the ability of the drug to penetrate the tumor, and the rate of elimination of the drug from the tumor nodules into the systemic circulation by capillary blood flow.6 In addition, both natural and acquired drug resistance are important considerations in long-term outcome.
The timing of administration of intraperitoneal chemotherapy is critically important in achieving the best therapeutic outcomes. We think that both the intraoperative time and the early postoperative time should be used to achieve maximal effects. Drugs selected for intraoperative use should be augmented by heat and can cause a cytotoxic effect within 60 to 90 minutes, independent of cell division. Heat is used because it has a direct cytotoxic effect on cancer cells, causes an augmentation of cell kill of some drugs, and increases the penetration of chemotherapy into cancer cells. In the early postoperative period, before the inevitable postoperative intra-abdominal adhesive process occurs, EPIC with cell cycle–specific drugs that are maintained in the peritoneal cavity for a long period of time may have additional value. Usually the EPIC is continued for 4 or 5 days and uses gravity distribution of the chemotherapy solution. Currently, the selection of complementary agents for HIPEC and EPIC is made on the basis of the pharmacologic properties of the drugs. There are no convincing data from clinical trials that suggest choosing one drug over another.
The challenge for the oncologists interested in peritoneal surface malignancy may not be the selection of HIPEC versus EPIC. Unfortunately, despite complete cytoreduction combined with HIPEC, EPIC, or both, patients’ disease still fails to respond to treatment for carcinomatosis. The challenge is to use the best combination treatment that will eradicate carcinomatosis as a mechanism of treatment failure for patients with gastrointestinal and gynecologic cancer. This goal will most likely require HIPEC, EPIC, long-term bidirectional chemotherapy with intraperitoneal and intravenous administration,7 and possibly also neoadjuvant treatment. At present, there is only a small benefit to cytoreductive surgery and intraperitoneal chemotherapy. Greater improvements in survival of these patients must be sought.
Received for publication January 6, 2007. Accepted for publication January 8, 2007.
REFERENCES
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