Comparison of Two Kinds of Intraperitoneal Chemotherapy Following Complete Cytoreductive Surgery of Colorectal Peritoneal Carcinomatosis Dominique Elias, MD, PhD, Emmanuel Benizri, MD, Daniela DiPietrantonio, MD, Paola Menegon, MD, David Malka, MD, PhD, and Bruno Raynard, MD
De´partement de Chirurgie Oncologique, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805, Villejuif, Cedex, France
Background: Recently, the combination of complete cytoreductive surgery followed immediately by intraperitoneal chemotherapy achieved cure in some patients suffering from peritoneal carcinomatosis (PC). It is now well established that the prognostic impact of the completeness of cytoreduction is high. However, two different modes of intraperitoneal chemotherapy are proposed: early postoperative intraperitoneal chemotherapy (EPIC), which lasts for 5 days and is normothermic, and peroperative intraperitoneal chemohyperthermia (IPCH). To date, the results of these procedures have never been compared. 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 43C, 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.
high.1 4 In addition to cytoreductive surgery treating macroscopically detectable disease, intraperitoneal chemotherapy was logically proposed, early after surgery, to treat residual disease measuring less than 1 mm.5,6 This combined modality has already proved its superiority over standard treatment in patients with colorectal PC, in a randomized study.7 However, intraperitoneal chemotherapy modalities are numerous. Historically, intraperitoneal chemotherapy with
The prognostic impact of maximal cytoreductive surgery in the treatment of peritoneal carcinomatosis (PC) from ovarian cancer or from colorectal cancer is Received February 5, 2006; accepted March 11, 2006; published online November 10, 2006. Address correspondence and reprint requests to: Dominique Elias, MD, PhD; E-mail: [email protected] Published by Springer Science+Business Media, Inc. 2006 The Society of Surgical Oncology, Inc.
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normothermia was proposed ﬁrst. It was started just after the end of surgery, was simple to perform and could be used for a long period of time. In practice, it was carried out continuously for 5 days with longacting and non heat-potentiating compounds, such as 5-ﬂuorouracil [5-FU],8 and was termed ‘‘early postoperative intraperitoneal chemotherapy’’ (EPIC). Later, intraperitoneal chemohyperthermia (IPCH) was proposed which required the use of a speciﬁc heating device. The physiological repercussions of hyperthermia prohibited long-duration treatment. Moreover, IPCH was performed intraoperatively over a short period (30 to 90 min) and with different drugs, resulting in a different procedure. No randomized study has compared these two procedures. Some teams use both procedures, based on the same logic, but with their respective modalities. It should be possible to use either EPIC or IPCH indifferently unless one procedure is better than the other. To determine whether one procedure has an edge over the other, we compared the effects of EPIC and those of IPCH in a similar population of patients with colorectal PC.
MATERIAL AND METHODS Selection of Patients Group 1 Between January 1999 and June 2002, 23 patients underwent complete cytoreductive surgery followed by IPCH for colorectal PC. They were included in a prospective phase II trial approved by both our institutional review board and an independent ethics committee. Also they gave their written informed consent to participate in the study. Eligibility criteria were as follows: PC of colorectal origin, a good general status and age under 70, no extra-abdominal disease, no evidence of bowel obstruction, no abundant ascites and no bulky clinical or radiological PC. These 23 patients were retrospectively selected among the 29 patients in this trial based on the following criteria: (1) a complete resection of all visible and detectable disease, (2) no more than two liver metastases (resected at the same time), and (3) a minimal follow-up of more than 30 months since IPCH. The six other patients also underwent complete cytoreduction but were excluded because they had more than 2 LM or follow-up was shorter than 30 months. Group 2 Twenty-three patients with the same disease and the same criteria used to select patients in group 1 Ann. Surg. Oncol. Vol. 14, No. 2, 2007
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 SugarbakerÕs 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 44C
COMPARISON OF TWO KINDS OF INTRAPERITONEAL CHEMOTHERAPY
throughout the cavity. The perfusion lasted for 30 min after attaining the optimal temperature (42 44C). 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.
RESULTS Similarity of the two groups As reported in Table 1, 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.
Postoperative course 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 FisherÕs 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.
Mortality and morbidity were not signiﬁcantly higher in the EPIC group than in the IPCH group (Table 2). 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.
Survival rates and recurrences The median follow-up for the two groups was 113 months (range: 70 188). Overall survival of the two groups is reported in Fig. 1. 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. Ann. Surg. Oncol. Vol. 14, No. 2, 2007
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TABLE 1. Preoperative, intra-operative and pathologic characteristics
Number of patients Age (mean ± SD) Sex (m/f) Colon/rectum Completeness of cytoreduction Peritoneal score (mean ± SD) Number of resected organs (mean) Digestive anastomosis (mean ± SD) Operative time (mean ± SD) (min) Blood loss (mean ± SD) (ml) Positive lymph nodes Associated liver metastases*
DISCUSSION To date, there is no randomized study comparing EPIC with IPCH as curative treatment of residual disease measuring less than 1 mm after complete cytoreductive surgery of PC which is why we conducted this retrospective comparative study. We were very careful when selecting patients suﬀering from colorectal PC who were matched for general status, disease extent and completeness of surgical cytoreduction. The main diﬀerence between the two groups was the peritoneal treatment (EPIC or IPCH) and also the date of treatment, but the surgical procedures were not modiﬁed with time. EPIC was used before IPCH, but we took pains to exclude the patients treated between 1992 and 1994 to avoid any bias due to the learning curve. The main conclusion of this comparison is that mortality and morbidity (mainly due to anastomotic ﬁstulas) were more common with EPIC, and that the Ann. Surg. Oncol. Vol. 14, No. 2, 2007
FIG. 1. Overall survival rates after EPIC and after IPCH.
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
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TABLE 3. Recurrences
Total Peritoneal carcinomatosis Extraperitoneal Liver Lung Spleen Multiple
Peritoneal recurrence rates
18/23 13/23 12/23 4/23 2/23 0/23 6/23
18/23 6/23 13/23 4/23 4/23 1/23 4/23
NS 0.0361 NS
p = 0.03
0,60 0,50 0,40
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
0,30 0,20 0,10 0,00 0
Months FIG. 2. Peritoneal recurrence rates after EPIC and after IPCH.
(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, Ann. Surg. Oncol. Vol. 14, No. 2, 2007
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(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.
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