Originally published as JCO Early Release 10.1200/JCO.2008.19.7160 on December 22 2008

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Complete Cytoreductive Surgery Plus Intraperitoneal Chemohyperthermia With Oxaliplatin for Peritoneal Carcinomatosis of Colorectal Origin

From the Department of Oncologic Surgery and the Health Economics Department, Institut Gustave Roussy, Villejuif; Department of Surgery, Institut Alexis-Vautrin, Vandoeuvre-lès-Nancy; Department of Oncologic Surgery, Institut René-Gauducheau, Nantes; Department of Surgical Oncology, Institut Claudius Regaud, Toulouse; Department of Surgical Oncology, Institut Francois Baclesse, Caen; and Department of Surgical Oncology, Institut Leon Bérard, Lyon, France.

Corresponding author: Dominique Elias, MD, PhD, Département de Chirurgie Carcinologique, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France; e-mail: elias{at}igr.fr.

	ABSTRACT

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Purpose To compare the long-term survival of patients with isolated and resectable peritoneal carcinomatosis (PC) in comparable groups of patients treated with systemic chemotherapy containing oxaliplatin or irinotecan or by cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC).

Patients and Methods All patients with gross PC from colorectal adenocarcinoma who had undergone cytoreductive surgery plus HIPEC from 1998 to 2003 were evaluated. The standard group was constituted by selecting patients with colorectal PC treated with palliative chemotherapy during the same period, but who had not benefited from HIPEC because the technique was unavailable in the center at that time.

Results Forty-eight patients were retrospectively included in the standard group and were compared with 48 patients who had undergone HIPEC and were evaluated prospectively. All characteristics were comparable except age and tumor differentiation. There was no difference in systemic chemotherapy, with a mean of 2.3 lines per patient. Median follow-up was 95.7 months in the standard group versus 63 months in the HIPEC group. Two-year and 5-year overall survival rates were 81% and 51% for the HIPEC group, respectively, and 65% and 13% for the standard group, respectively. Median survival was 23.9 months in the standard group versus 62.7 months in the HIPEC group (P < .05, log-rank test).

Conclusion Patients with isolated, resectable PC achieve a median survival of 24 months with modern chemotherapies, but only surgical cytoreduction plus HIPEC is able to prolong median survival to roughly 63 months, with a 5-year survival rate of 51%.

	INTRODUCTION

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For a long time, peritoneal carcinomatosis (PC) was considered a terminal condition, and patients were treated palliatively.¹ In a recent study of 3,019 colorectal cancer cases, the prevalence of PC was 11%.² The larger studies investigating the prognosis of isolated PC treated with chemotherapy included between 50 and 392 patients and showed median survival lasting from 5.2 to 12.6 months.^2–5 However, in the majority of these studies, and even in the only randomized trial, fluorouracil-based chemotherapy was administered without modern drugs like oxaliplatin or irinotecan. Consequently, we are still unaware of the current median survival of patients with PC after therapy with these modern drugs. In a recent review on patients with PC, Yan et al⁶ regretted the absence of published data focusing on the efficacy of modern systemic chemotherapy. In the therapeutic arsenal against PC, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) has been reported to obtain median survival lasting from 13 to 32 months.^7–10 Despite differences in study design in all of these reports, because of variations in the chemotherapy regimens, in the timing of chemotherapy, and in hyperthermia techniques, cytoreductive surgery plus HIPEC has become a standard treatment for limited PC. However, this therapeutic approach remains restricted to a few expert centers, and a large-scale application of this technique could prove extremely challenging. Finally, some may question the place of cytoreductive surgery and HIPEC in the era of new chemotherapy.

The aim of this case-control study was to compare the long-term survival of patients with isolated and resectable PC in comparable groups of patients treated with systemic chemotherapy including oxaliplatin or irinotecan or by cytoreductive surgery (CRS) plus HIPEC and systemic chemotherapy (SC).

	PATIENTS AND METHODS

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CRS + HIPEC + SC Group
All patients with gross PC from colorectal adenocarcinoma who had undergone cytoreductive surgery plus HIPEC at the Gustave Roussy Institute (Villejuif, France) from January 1998 to December 2003 were prospectively included. These patients were selected preoperatively according to the following criteria: ¹ no huge and symptomatic PC, ² no extra-abdominal malignancy, ³ a good general status and younger than 66 years old, and ⁴ no disease progression after 2 to 3 months of neoadjuvant chemotherapy. To classify the extension of the PC, the abdominopelvic cavity was divided into five regions that included the four abdominal quadrants plus the pelvis.⁹ Before CRS, the distribution of PC was noted: one or two regions invaded defined limited PC, whereas three or more regions defined extended PC. CRS was always complete, with no residual peritoneal disease exceeding 1 mm in diameter. Peritonectomy procedures have been described in previous studies.^11,12 HIPEC was administered intraperitoneally with oxaliplatin 460 mg/m² in 2 L/m² of dextrose at a temperature of 43°C (two in-flow drains at 45°C and two out-flow drains at > 42°C) over 30 minutes after attaining the minimal temperature of 42°C throughout the abdominal cavity (5 to 10 minutes were required to warm the liquid from 37°C to 42°C), with a flow rate of 2 L/min.¹³ Before the beginning of HIPEC, and during CRS, patients had received intravenous fluorouracil 400 mg/m² and leucovorin 20 mg/m² to potentiate oxaliplatin activity.¹⁴ Because fluorouracil cannot be mixed with oxaliplatin inside the peritoneal cavity (because of pH incompatibility), it was administered intravenously to bathe the tumor and healthy tissue before HIPEC.¹⁵

Standard Group
We performed a retrospective study on highly selected patients with colorectal PC treated with palliative chemotherapy during the same period in five French comprehensive anticancer centers. This control group of comparable patients had received standard chemotherapy combined or not with palliative surgery. These patients had not benefited from HIPEC because the technique was unavailable in these five centers and because patients could not be referred to the reference center because of its limited treatment capacity. Patients were highly selected to ensure comparability with the CRS + HIPEC + SC group. The selection process was divided into two steps. During the first step, surgeon investigators from each anticancer center selected from their records all patients with colorectal PC diagnosed between January 1998 and December 2003 who had been treated with palliative chemotherapy and who met eligibility criteria. Eligibility criteria included those defined as good prognostic factors for HIPEC in the literature:^{1 1} a good general status (WHO performance status of 1 to 2), ² age younger than 65 years, ³ no extra-abdominal extension, ⁴ no evidence of bowel obstruction, ⁵ no tumor larger than 2 cm at computed tomography, and ⁶ no rapid progression of PC under SC. During the second step, the principal investigator (D.E.) double-checked the medical records of the potentially eligible patients provided by the centers by recontacting the investigators to ensure that the eligibility criteria had been applied homogeneously. During double-checking, the investigator was blinded to the detailed characteristics of the patients in the CRS + HIPEC + SC group.

Follow-Up and Statistics
Patients in the CRS + HIPEC + SC group were recorded prospectively in a specific database. Patients in the standard group were recorded retrospectively. Follow-up was every 3 months, with a rectal examination and carcinoembryonic antigen measurements. A computed tomography scan of the abdomen and thorax and abdominal ultrasonography were performed alternately every 6 months. No patient was excluded from survival analyses (including postoperative deaths). The ² test or Fisher's exact test, when appropriate, was used for univariate comparisons. Survival curves were calculated with the Kaplan-Meier method¹⁶ and compared with the log-rank test. Survival was measured from the diagnosis of PC until death or the last follow-up. Although the retrospective group was selected after thorough scrutiny of medical records, we still had to control for any residual selection bias. We performed a Cox regression analysis to predict the impact of patient characteristics on survival and to test the need to include significant variables in a sensitivity analysis. Differences were considered significant at P = .05.

	RESULTS

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Constitution of the Standard Group
Seventy-five patients were proposed by the five comprehensive anticancer centers, and after double-checking for eligible criteria, only 48 patients were included in the standard group. The fact that there was exactly the same number in both groups was purely coincidental.

Among these 48 patients, 36 patients (75%) had undergone a laparotomy, which confirmed the PC. The operative reports gave a clear description of peritoneal seeding, which seemed to be resectable. In 12 patients, no laparotomy had been performed, and the diagnosis had been based on a transcutaneous biopsy in four patients and on a modification of the rectal examination (appearance of a tumor nodule in Douglas' pouch) and/or imaging in eight patients, associated with an increased blood carcinoembryonic antigen level.

Comparison of the Two Groups
Patient characteristics are detailed in Table 1. All characteristics were comparable, except age and tumor differentiation. Patients in the CRS + HIPEC + SC group were significantly younger. The Cox regression model applied to our data showed that the survival benefit was not sensitive to age nor to tumor differentiation. There was no difference in SC, either in the type of agents used or in the number of lines administered in each group (102 v 110; P = .52). In the CRS + HIPEC + SC group, all patients had received neoadjuvant therapy; intraperitoneal chemotherapy consisted of oxaliplatin for 30 patients and oxaliplatin combined with irinotecan for the remaining 18 patients. In the standard group, the 48 patients had received a first line of chemotherapy, 33 patients had received a second line, 17 patients had received a third line, and 12 patients had received a fourth line (Tables 2 and 3), resulting in a mean of 2.3 lines of chemotherapy per patient.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival of group receiving cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic treatment versus those receiving standard treatment.

	DISCUSSION

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Regarding SC, a recent review of PC identified four clinical studies dedicated to this classic approach.¹ Patients were treated with fluorouracil and leucovorin in all of the studies. Although modern SC regimens have improved response rates and yielded better survival results for patients with colorectal metastases in general, there is an absence of data on the outcomes of the subset of patients with isolated and limited PC treated with modern SC.

Two questions needed to be addressed: ¹ What is the prognosis of PC treated with new drugs, such as oxaliplatin and irinotecan, that are known to be more efficient? ² Does HIPEC yield better outcomes when compared with these recent chemotherapy regimens? The aim of this retrospective comparative study was to answer these two questions.

Regarding the effect of several lines of chemotherapy on PC, we observed an overall survival duration of almost 2 years. To our knowledge, such high median survival has never been reported with SC for patients with colorectal PC in the literature. This is the highest median survival that can currently be obtained with systemic treatment and without recent targeted therapies. This result compares favorably with the median survival of 7 months reported by Jayne et al² in a series of 392 patients with colorectal PC. Nevertheless, this study included all forms of PC, whereas our series selected resectable PC without extraperitoneal disease. In addition, our median survival is longer than the 12.8 months achieved in the 50 patients considered eligible for the randomized study of HIPEC conducted by the Amsterdam group.³ These 50 patients were randomly assigned in the control group and were treated with intravenous fluorouracil and leucovorin as first-line chemotherapy and with irinotecan in second-line chemotherapy. All of them were selected patients and were eligible for this randomized study.

Even with this better outcome for patients treated with chemotherapy alone, CRS associated with HIPEC remains a better treatment for isolated PC. A significant improvement was observed in median survival and in the survival rates at 2, 3, and 5 years. To our knowledge, this is the first study to assess the efficacy of cytoreduction plus HIPEC versus modern chemotherapy. One of the main criticisms of previous studies on HIPEC is therefore no longer applicable.⁶

One major limitation is the question of confidence in survival results based on a nonrandomized study. Our study was not randomized because it would have been unethical to do so. HIPEC was proposed as the last recourse for cure of PC. The procedure has been performed for more than 10 years at the Gustave Roussy Institute, even though its efficacy had not been proven in a randomized trial until 2003.³

The usual main argument against HIPEC is the stringent selection of patients. It is commonly thought that the survival rate with standard chemotherapy in these selected patients with PC should probably be close to that obtained with HIPEC. In this study, we stringently selected eight to 10 patients in each cancer center treated with standard treatment but who had not undergone HIPEC.¹⁸ Patient characteristics were similar, except for age and tumor differentiation. However, when a Cox regression model was applied to our data, it showed that the survival benefit was not sensitive to age and tumor differentiation. We also did not have total proof that the peritoneal disease was completely resectable in the standard group, even if there were strong arguments in favor of such an opinion mainly based on a precise description of the extent of the peritoneal disease during laparotomy in 36 of the 48 patients in the standard group. That their median survival was 24.8 months with systemic chemotherapy is indirect proof that these patients were highly selected.

Finally, a potential selection bias in our study may stem from the way patients were identified. Patients in the CRS + HIPEC + SC group were identified through the HIPEC procedure item, whereas patients in the standard group were identified through their diagnosis of PC. The fact that patients in the CRS + HIPEC + SC groups were selected through the HIPEC item signifies that these patients were still alive at the time of the HIPEC procedure. The median interval between the diagnosis of PC and HIPEC was 9 months. This median interval could have led to an overestimation of survival in this group.¹⁹ We checked that each patient in the CRS + HIPEC + SC group was matched with a standard patient on the following criterion: the time interval from the diagnosis until death for a standard patient was at least equal to the interval from the diagnosis to HIPEC for the patient in the CRS + HIPEC + SC group. Any potential bias should therefore be minimized.

In conclusion, patients with isolated, resectable PC have a median survival of 24 months with modern chemotherapies, but only CRS plus HIPEC is able to prolong median survival to 63 months, with a 5-year survival rate of 51%.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Dominique Elias, Jérémie H. Lefevre, Julia Bonastre

Administrative support: Dominique Elias, Julie Chevalier, Frédéric Marchal, Jean-Marc Classe, Gwenaël Ferron, Jean-Marc Guilloit, Pierre Meeus, Julia Bonastre

Provision of study materials or patients: Dominique Elias, Jérémie H. Lefevre, Julie Chevalier, Frédéric Marchal, Jean-Marc Classe, Gwenaël Ferron, Jean-Marc Guilloit, Pierre Meeus, Diane Goéré, Julia Bonastre

Collection and assembly of data: Dominique Elias, Jérémie H. Lefevre, Julie Chevalier, Antoine Brouquet, Diane Goéré, Julia Bonastre

Data analysis and interpretation: Dominique Elias, Jérémie H. Lefevre, Julie Chevalier, Antoine Brouquet, Diane Goéré, Julia Bonastre

Manuscript writing: Dominique Elias, Jérémie H. Lefevre, Julie Chevalier, Antoine Brouquet, Julia Bonastre

Final approval of manuscript: Dominique Elias, Jérémie H. Lefevre, Julie Chevalier, Julia Bonastre

	Acknowledgment

 
We thank Lorna Saint Ange for editing.

	NOTES

 
Supported in part with French Government funding from the program "Technological support to expensive innovations."

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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3. Verwaal VJ, van Ruth S, de Bree E, et al: Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 21:3737–3743, 2003.[Abstract/Free Full Text]

4. Sadeghi B, Arvieux C, Glehen O, et al: Peritoneal carcinomatosis from non-gynecologic malignancies: Results of the EVOCAPE 1 multicentric prospective study. Cancer 88:358–363, 2000.[CrossRef][Medline]

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11. Elias D, Ouellet JF: Intraperitoneal Chemohyperthermia: Rationale, technique, indications, and results. Surg Oncol Clin N Am 10:915–933, 2001.[Medline]

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14. Bécouarn Y, Ychou M, Ducreux M, et al: Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients: Digestive Group of French Federations of Cancer Centers. J Clin Oncol 16:2739–2744, 1998.[Abstract]

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17. Elias D, Delperro JR, Sideris L, et al: Treatment of peritoneal carcinomatosis from colorectal cancer: Impact of complete cytoreductive surgery and difficulties in conducting randomized trials. Ann Surg Oncol 11:518–521, 2004.[CrossRef][Medline]

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Submitted August 18, 2008; accepted September 22, 2008.

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