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Original Article |
Département de Chirurgie Oncologique, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805, Villejuif, Cedex, France
Correspondence: Address correspondence and reprint requests to: Dominique Elias, MD, PhD; E-mail: elias{at}igr.fr
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIAL AND METHODSRESULTSDISCUSSIONREFERENCES |
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Aim of the study: To compare the complications and therapeutic results of EPIC and IPCH after complete cytoreductive surgery of colorectal PC.
Materials and methods: Twenty-three consecutive patients with colorectal PC were selected based on the completeness of cytoreductive surgery and sufficient follow-up. They received IPCH with oxaliplatin (460 mg/m2) in 2 l/m2 of dextrose, for 30 min at an intraperitoneal temperature of 43°C, using the coliseum technique. We retrospectively carefully selected another 23 patients, for comparison purposes, suffering from the same disease, with characteristics as similar as possible, but treated earlier with EPIC (mitomycin C 10 mg/m2 at day 0 and 5-FU 650 mg/m2 from days 1 to 4), in 1 l/m2 of ringer lactate. Data concerning these two groups were verified prospectively, but this study was a comparative historical analysis.
Results: The two groups were statistically comparable, except for the duration of surgery which was 68 min longer for the IPCH group. Mortality and morbidity were not significantly different, even if two deaths occurred in the EPIC group, and none in the IPCH group. However, the rate of digestive fistulas was higher (P = 0.02) in the EPIC group (26%) than in the IPCH group (0%). Overall survival (OS) was higher in the IPCH group, (54% at 5 years vs. 28% for EPIC), but not significantly (P = 0.22). Peritoneal carcinomatosis recurred much (P = 0.03) more frequently in the EPIC group (57%) than in the IPCH-group (26%).
Conclusion: This study provides strong arguments indicating that IPCH with oxaliplatin is better tolerated than EPIC with mitomycin C and 5-FU, and is twice as efficient in curing residual peritoneal carcinomatosis measuring less than 1 mm.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIAL AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIAL AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIAL AND METHODSRESULTSDISCUSSIONREFERENCES |
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Group 2
Twenty-three patients with the same disease and the same criteria used to select patients in group 1 retrospectively, were treated with EPIC during a prospective trial which took place between May 1994 and December 2000. They were carefully selected retrospectively among the 37 patients in that trial so that the group was as similar as possible to the patients in group 1. Similarity criteria used for selection were as follows: age, sex, primary, peritoneal scoring, number of resected organs and digestive anastomosis, blood loss and metastases (in liver and in lymph nodes).
Results concerning these two different trials have already been published8,9 in part. There was no peritoneal pseudomyxoma whose origin was appendiceal in the two groups.
Treatment Modalities
Surgery
At laparotomy, we confirmed the diagnosis of PC by frozen section and scored the extent of PC according to Sugarbaker’s peritoneal index.10 This index is calculated for each patient by allocating a score from 0 to 3 to each of the 13 areas of the peritoneal cavity (0 = no disease, 1 = tumor seeding <5 mm, 2 = tumor seeding from 5 mm to 5 cm and 3 = tumor seeding >5 cm or diffuse). This index theoretically ranges from 1 to 39. Macroscopically, detectable disease had to be completely resected before patient inclusion in the trial.
Resection of PC obeyed principles described elsewhere.11 Intestinal anastomoses were delayed until after IPCH in order to treat bowel margins, but were performed before EPIC in the other group.
Intraperitoneal chemohyperthermia (IPCH)
We performed IPCH with a continuous closed circuit using four 36-French drains (two inlets and two outlets) connected to two pumps. We used one heating unit and two heat exchangers to eliminate any Y connector that would reduce flow rates and heat homogeneity.12 IPCH was performed with the abdomen open and the skin pulled upwards (having demonstrated in our institution that this technique was the only one capable of achieving temperature homogeneity and complete spatial diffusion of the peritoneal instillation in the whole peritoneal cavity).12 The flow rate was 1 1/min for each pump. Four thermal probes inside the peritoneal cavity ensured continuous temperature feedback, and we monitored the whole procedure and recorded the thermal data on a computer. During IPCH, the intra-abdominal temperature was maintained between 42 and 44°C throughout the cavity. The perfusion lasted for 30 min after attaining the optimal temperature (42–44°C). Usually, less than 5 min was necessary to reach a high homogeneous temperature, leading to a total peritoneal infusion duration of approximately 35 min. We then completely evacuated the infusion. The total oxaliplatin (LOHP) dose was delivered as a bolus mixed with 5% dextrose at the beginning of the procedure. The total quantity of peritoneal liquid used was based, as was the case for LOHP, on the body surface area: 2 l/m2. The LOHP dose was 460 mg/m2, as recommended in our previous study on humans.13 Determination of the instillation volume and the LOHP dose based on the measurement of the body surface area (in m2) resulted in a similar intraperitoneal concentration of the drug in each patient. One hour before IPCH, leucovorin (LV) 20 mg/m2 and 5-fluorouracil (5-FU) 400 mg/m2 were delivered i.v. because 5-FU potentiates the action of LOHP and because 5-FU cannot be mixed with LOHP in the peritoneal cavity due to pH incompatibility.13 Thus, following this systemic infusion, tumor and healthy tissue were soaked with 5-FU before starting IPCH.
Early intraperitoneal chemotherapy (EPIC)
After maximal cytoreductive surgery, the patient underwent irrigation of the peritoneal cavity as soon as the abdominal incision was closed watertight. In the operative room, a peritoneal infusion with mitomycin C (10 mg/m2) in 1 l/m2 of fluid was given at day 0. Then 5-FU (650 mg/m2) in 1 l/m2 of fluid was infused for the next four days.14 These drugs remained in place for 23 h prior to drainage lasting 1 h before reinfusion. Overall, this early postoperative bathing of the abdominal cavity lasted for 5 days.
Statistics
Patients were recorded prospectively in a specific database, but the two groups were retrospectively selected and analyzed. Follow-up included a rectal examination and CEA measurements every 3 months. A CT-scan of the abdomen and thorax, and abdominal ultrasonography were performed alternately every 6 months. The exact status of each patient was clear on the date of the analysis of the series (February 2005). The chi-square test or Fisher’s exact test, when appropriate, were used for univariate comparisons. Survival curves were calculated with the Kaplan–Meier method and compared with the log rank test. Differences were considered significant at P = 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIAL AND METHODSRESULTSDISCUSSIONREFERENCES |
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, the characteristics of the groups were statistically identical except for the mean duration of the operative time which was 68 min longer in the IPCH group ; this being due to the procedure itself. The extent of PC, mainly the mean number of resected organs (n = 4), as measured with the peritoneal index, was similar in both groups, and eight patients in each group had associated liver metastases (
2). The definition of a resected organ was the resection of one part of the digestive tract, of the uterus and/or ovary, of the spleen and/or pancreas, and of one part the bladder and/or ureter. The resection of the whole colon was considered as one resection because one digestive anastomosis was required to restore the continuity of the digestive tract, but the resection of two distant segments of the colon was counted as two resected organs because two digestive anastomoses were required.
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). However, two patients died in the EPIC group (mortality: 8.7%; due to peritonitis) and none in the IPCH group (mortality: 0%). Overall, morbidity (mainly lung or urinary infections) was similar whether due to surgical complications or medical complications (Table 2), but the rate of digestive fistulas was significantly (P = 0.02) higher in the EPIC group (26%) than in the IPCH group (0%), and so was the rate of surgical reintervention: 26% in the EPIC group and 4% in the IPCH group (P = 0.09). No severe hematological toxicity occurred in either group.
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. It was higher, albeit not significantly (P = 0.22) in the IPCH group (54% at 5 years vs. 28% for EPIC). Recurrence occurred in 18 patients (78%) in the EPIC group and in 18 patients in the IPCH group (Table 3). Peritoneal carcinomatosis recurred significantly (P = 0.03) more frequently in the EPIC group (57%) than in the IPCH group (26%), as reported in Fig. 2.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIAL AND METHODSRESULTSDISCUSSIONREFERENCES |
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The main conclusion of this comparison is that mortality and morbidity (mainly due to anastomotic fistulas) were more common with EPIC, and that the peritoneal recurrence rate was at least twice as high with EPIC. There was also a clear trend towards better overall survival with IPCH. The recurrence rate was similar after EPIC or IPCH, but recurrences were more easily controlled in the IPCH group. In other words, IPCH appears to be better tolerated and more efficient than EPIC.
Clearly, this study could be challenged on the grounds that it is not randomized, there are minor differences in patient characteristics between the two groups, the treatment period was not the same, and also the chemotherapeutic agents were different. Notably, we can regret that systemic pre- and postoperative chemotherapy which most of the patients received (data not shown) did not contain oxaliplatin or irinotecan in the EPIC group. However, it is now clearly established that the gain in median survival with the adjunction of these two new drugs is only 3 months in these patients, and this improvement cannot by itself explain the difference in the survival rate observed between the two groups. Notwithstanding, this study has the merit of answering continual questions, namely, is hyperthermia really necessary and could agents other than mitomycin C be used ? In other words, is a sophisticated treatment necessary or can a simpler one be used ? The question is important given that IPCH requires meticulous programming, whereas EPIC can be easily performed off-the-cuff during the postoperative course.
A randomized trial proved that combining cytoreductive surgery (not always maximal) with IPCH was more efficient than the standard treatment in curing colorectal PC in selected patients.7 It was performed with the classic anticancer drug, mitomycin C. In addition, it is well established that the prognostic impact of the completeness of cytoreduction of PC is very high.1–4 However, to date no randomized trial has been conducted comparing the efficacy of EPIC versus that of IPCH, after complete cytoreductive surgery. Awaiting the results of this hypothetic future trial, a number of experimental and clinical data indicate that early local chemotherapy inside the peritoneal cavity can be useful.5,6 EPIC and IPCH are two different ways of performing this local chemotherapy, and both have various advantages and disadvantages.
The EPIC has the great advantage of being easy to perform, and thus could be used everywhere. Furthermore, it makes it possible to use long-acting drugs, like 5-FU. However, it lasts only for 5 days, does not add the effects of hyperthermia, does not allow the whole surface of the abdominal cavity to be attained or bathed (as is the case when dying is used during procedures with a closed abdominal cavity).12 In addition, digestive sutures float in a liquid with chemotherapy for 5 days with this procedure whose quality control is poor. We think that this "floating period", which hampers the process whereby digestive sutures are rapidly reinforced by physiologic postoperative adhesions, probably explains the occurrence of digestive fistulas in 26% of the patients (vs. none in the IPCH group, with the same number of digestive anastomoses).
The IPCH has the main advantage of adding the effect of hyperthermia to chemotherapy,6 it is rapid, all risky surfaces are bathed within an open abdominal cavity using the Coliseum technique,12 and digestive sutures are prevented from floating in liquid for a long time. Quality control of this procedure is easy to implement. Its disadvantages are that a special and costly apparatus is required for hyperthermia, "minute-drugs" (drugs acting immediately on cancer cells, independently of the phase of the cell cycle) which are potentiated with hyperthermia must be used, and the duration of the operative time is longer.
An important question that needs to be addressed is whether the results obtained with EPIC are different from those obtained with IPCH. If not, these two kinds of local chemotherapy could be used indifferently. The present study only partially answers this question. Partially, because it is not a randomized study, because the number of patients is low, and because it is not only a perfusion technique but also the drugs were different. However, EPIC clearly appeared to be more risky (in terms of mortality and morbidity), and less efficient than IPCH in curing residual peritoneal disease measuring <1 mm. The recurrence rate of PC was twofold lower with IPCH than with EPIC (26 vs. 56%, P = 0.03). These clinical results confirm the experimental results regarding the following three points: (1) IPCH bathes the abdominal cavity more completely than EPIC, (2) hyperthermia potentiates the effect of chemotherapy, (3) digestive sutures floating in liquid for a long period of time are more risky.
Is the initiation of a randomized study comparing IPCH to EPIC after complete cytoreductive surgery currently feasible? In our opinion, the answer is no. A trial worth initiating should compare IPCH versus no IPCH, in a selected group of patients in whom complete cytoreductive surgery has been achieved, (both groups receiving the best systemic chemotherapy of the moment in a similar manner). Moreover, it could be ethically questionable to compare EPIC with IPCH in the future, given the body of experimental and clinical data in favor of IPCH compared with EPIC.
In conclusion, our study provides strong arguments indicating that IPCH (with oxaliplatin) is less dangerous than EPIC (with mitomycin and 5-FU) and twice as efficient in curing residual peritoneal carcinomatosis measuring <1 mm. However, it does allow us to determine whether these improvements are due to the technique, to the chemotherapy agent, or to both.
Received for publication February 5, 2006. Accepted for publication March 11, 2006.
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This article has been cited by other articles:
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  D. Elias, J. H. Lefevre, J. Chevalier, A. Brouquet, F. Marchal, J.-M. Classe, G. Ferron, J.-M. Guilloit, P. Meeus, D. Goere, et al. Complete Cytoreductive Surgery Plus Intraperitoneal Chemohyperthermia With Oxaliplatin for Peritoneal Carcinomatosis of Colorectal Origin J. Clin. Oncol., February 10, 2009; 27(5): 681 - 685. [Abstract] [Full Text] [PDF]
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 B. L. van Leeuwen, W. Graf, L. Pahlman, and H. Mahteme Swedish Experience with Peritonectomy and HIPEC. HIPEC in Peritoneal Carcinomatosis Ann. Surg. Oncol., March 1, 2008; 15(3): 745 - 753. [Abstract] [Full Text] [PDF]
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T. D. Yan and P. H Sugarbaker An Evolving Role of Perioperative Intraperitoneal Chemotherapy After Cytoreductive Surgery for Colorectal Peritoneal Carcinomatosis Ann. Surg. Oncol., July 1, 2007; 14(7): 2171 - 2172. [Full Text] [PDF]
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