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ORIGINAL ARTICLES |
From the Departments of Surgery, Medical Oncology, and Statistics, Gustave Roussy Institute, Villejuif, France (DE, LS, EB, MP, OB, PL); and the Paoli-Calmette Institute, Marseille, France (J-RD).
Correspondence: Address correspondence and reprint requests to: Dominique Elias, MD, PhD, Service de Chirurgie Carcinologique, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France; Fax: 33-1-42-11-52-56; E-mail: elias{at}igr.fr
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ABSTRACT |
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Methods: Between 1996 and 2000, we conducted a two-center prospective randomized trial comparing EPIC plus systemic chemotherapy with systemic chemotherapy alone, both after complete cytoreductive surgery of colorectal PC. Only 35 patients could be included among the 90 who were theoretically required, mainly because of patient dissatisfaction with the inclusion criteria. For this reason, the trial was stopped prematurely.
Results: Analysis of these 35 patients showed that complete resection of PC resulted in a 2-year survival rate of 60%—far above the classic 10% survival rate among patients with colorectal PC treated with systemic chemotherapy and symptomatic surgery. In this small series, EPIC did not demonstrate any advantage for survival.
Conclusions: This supports the use of complete cytoreductive surgery in selected patients and calls for a prospective randomized trial comparing adjuvant systemic chemotherapy with intraperitoneal chemohyperthermia after complete resection.
Key Words: Colorectal • Peritoneal carcinomatosis • Cytoreductive surgery • Intraperitoneal chemotherapy • Randomized trial
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INTRODUCTION |
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METHODS |
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Eligibility criteria were PC of colorectal origin, a good general status (Eastern Cooperative Oncology Group status 1–2), age younger than 65 years, no extra-abdominal extension, no evidence of bowel obstruction, no important ascites, and no bulky clinical or radiological PC. PC arising from appendix adenocarcinomas could also be included because this prognosis is similar to that with PC of colorectal origin.5 The presence of one or two liver metastases, easily resectable, was not a contraindication.6 All patients had already received intravenous 5-fluorouracil (5-FU)– and leucovorin-based chemotherapy for at least 3 months. Some of them were also treated with oxaliplatin or irinotecan. Any patient presenting a rapid progression of PC under systemic chemotherapy was excluded. The preoperative work-up included a clinical rectal examination, a computed tomographic scan of the thorax and abdomen, a complete colonoscopy, and carcinoembryonic antigen measurements. No positron emission tomography imaging was performed. The primary tumor had always been previously resected.
After signing written, informed consent, all patients underwent surgery. They were included in the study only after complete resection of the PC and of other intra-abdominal tumor sites (including liver metastases). They were then randomized into two arms: EPIC followed by adjuvant systemic chemotherapy (5-FU and leucovorin bimonthly for 6 months, starting within 1 month after EPIC) or similar adjuvant systemic chemotherapy without EPIC. In cases of recurrent cancer disease, oxaliplatin- and/or irinotecan-based regimens were administered. EPIC was performed according to Sugarbaker’s schedule (mitomycin C on postoperative day 1 and 5-FU on postoperative days 2–5 given in a 2-L solution during 23 h/24).7
Our working hypothesis was that the 10% 2-year survival rate generally reported in the literature for patients with PC1,2 could be increased to 40% (4-fold) by the complete cytoreductive surgery and EPIC treatment. To reach these figures, 90 patients had to be randomized in the study (
risk = .05; ß risk = .10; 1-sided test).
Patients were recorded prospectively in a specific database. The 
2 test or Fisher’s exact test, when appropriate, was 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 = .05.
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RESULTS |
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DISCUSSION |
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This trial was initially designed to appreciate the efficacy of EPIC after complete resection of PC, but only 35 patients were enrolled in 4 years, and the study was closed before it reached the required 90 patients. In fact, the most logical randomized trial to perform would have been to compare the standard treatment for PC—that is, systemic chemotherapy (any type)—with a combined treatment with maximal cytoreductive surgery followed by EPIC. In 1995, we began a first bicentric trial with this design, but it was rapidly abandoned because of important patient dissatisfaction with inclusion criteria in six of the first seven eligible patients. These patients, most of whom had already received multiple lines of systemic chemotherapy, were coming to our institution with the specific intent to undergo the combined treatment. They were very disappointed to hear that EPIC was given in our institution only on a randomized trial basis. It was clear during the discussion that these patients were fully aware of the futility of the control arm of the study. Despite a strong scientific rationale for this approved clinical research, patients considered the trial unethical and detrimental to their right to choose their treatment. At last, they did give their consent to be in the study, hoping to be randomized to combined treatment. After randomization, the patients who were randomized to the non-EPIC group immediately asked to be taken out of the study. We therefore had to modify the design of the trial. During the same period, Zoetmulder’s group from The Netherlands, probably in a different sociomedical environment, succeeded in realizing a randomized study comparing standard systemic chemotherapy with more or less complete cytoreductive surgery combined with intraperitoneal chemohyperthermia (IPCH) with mitomycin C.8 This first and probably unique randomized study demonstrated the superiority of the combined treatment with IPCH.
This trial was accepted more easily by the patients because there was an attempt at complete surgical resection of the carcinomatosis for all patients and because the information sheet clearly explained that it was currently not known whether EPIC was better than systemic chemotherapy. Patients were also advised that EPIC could generate significant morbidity. There were adequate numbers of eligible patients; however, most patients refused to participate in this trial and asked to be included in phase I and II trials involving IPCH. In retrospect, this is not surprising because during this same time period, the rationale for IPCH gained considerable prominence in the literature. This large number of eligible colorectal carcinomatosis patients allowed us to perform three consecutive phase I and II studies concerning the techniques and pharmacokinetics of IPCH.9–11 Inclusion criteria in these three phase I and II studies initially excluded patients with colorectal carcinomatosis who were eligible for the ongoing phase III randomized EPIC study. However, referring physicians and patients had heard about the probable benefits of hyperthermia, and most patients subsequently refused to be randomized in the EPIC study. They persistently asked to be included in an IPCH trial. We thus had to modify the IPCH trial inclusion criteria to include patients with colorectal carcinoma who had previously refused to participate in the randomized EPIC study.
When we first designed this study, we thought that we would observe approximately a 10% 2-year survival rate in the control group. We thus hypothesized obtaining a 4-fold increase in 2-year survival (from 10% to 40%) in the EPIC group. From a statistical point of view, 90 patients were needed to obtain a significant 4-fold increase in 2-year survival. However, two points contributed to the relative failure of our trial: First, with only 35 patients enrolled, only a 7-fold increase in the 2-year survival of the EPIC group over the control group (from 10% to 70%) would have allowed reaching statistical significance. Second, the 2-year survival in the control group was not 10%, as expected, but was 60%. This difference was mainly caused by the complete cytoreductive surgery that our included patients underwent. Thus, even if statistically negative, this trial taught us that the sole complete surgical resection of PC, when feasible, resulted in an unexpected 60% 2-year survival rate. This is a new message.
Three secondary lessons emanate from this trial. First, in our study, complete surgical resection seemed to be more potent than EPIC in increasing overall survival. Complete cytoreductive surgery for colorectal carcinomatosis should thus be re-evaluated in the era of new, more efficient intravenous polychemotherapy regimens.12–15 Second, the survival curves obtained in the two groups of this trial were similar despite more advanced cases and higher postoperative mortality rates in the EPIC group. EPIC might have had a therapeutic advantage that did not appear in our study because of the small number of patients. Finally, in 2003, IPCH was considered more efficient than EPIC for the treatment of inframillimetric or microscopic PC residues. It should thus be preferred to EPIC in future trials.4,7,16
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CONCLUSION |
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FOOTNOTES |
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Received for publication September 9, 2003. Accepted for publication December 29, 2003.
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This article has been cited by other articles:
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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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T. D. Yan, J. Sim, and D. L. Morris Selection of Patients with Colorectal Peritoneal Carcinomatosis for Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy Ann. Surg. Oncol., June 1, 2007; 14(6): 1807 - 1817. [Abstract] [Full Text] [PDF]
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D. Elias, D. Goere, F. Blot, V. Billard, M. Pocard, N. Kohneh-Shahri, and B. Raynard Optimization of Hyperthermic Intraperitoneal Chemotherapy With Oxaliplatin Plus Irinotecan at 43{degrees}C After Compete Cytoreductive Surgery: Mortality and Morbidity in 106 Consecutive Patients Ann. Surg. Oncol., June 1, 2007; 14(6): 1818 - 1824. [Abstract] [Full Text] [PDF]
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D. Elias, E. Benizri, D. DiPietrantonio, P. Menegon, D. Malka, and B. Raynard Comparison of Two Kinds of Intraperitoneal Chemotherapy Following Complete Cytoreductive Surgery of Colorectal Peritoneal Carcinomatosis Ann. Surg. Oncol., February 1, 2007; 14(2): 509 - 514. [Abstract] [Full Text] [PDF]
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J.-H. Cheong, J. Y. Shen, C. S. Song, W. J. Hyung, J. G. Shen, S. H. Choi, and S. H. Noh Early Postoperative Intraperitoneal Chemotherapy Following Cytoreductive Surgery in Patients with Very Advanced Gastric Cancer Ann. Surg. Oncol., January 1, 2007; 14(1): 61 - 68. [Abstract] [Full Text] [PDF]
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 T. D. Yan, D. Black, R. Savady, and P. H. Sugarbaker Systematic Review on the Efficacy of Cytoreductive Surgery Combined With Perioperative Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis From Colorectal Carcinoma J. Clin. Oncol., August 20, 2006; 24(24): 4011 - 4019. [Abstract] [Full Text] [PDF]
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D. Elias, G. Liberale, D. Vernerey, M. Pocard, M. Ducreux, V. Boige, D. Malka, J.-P. Pignon, and P. Lasser Hepatic and Extrahepatic Colorectal Metastases: When Resectable, Their Localization Does Not Matter, But Their Total Number Has a Prognostic Effect Ann. Surg. Oncol., November 1, 2005; 12(11): 900 - 909. [Abstract] [Full Text] [PDF]
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