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© 2003 American Society for Clinical Oncology Randomized Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Versus Systemic Chemotherapy and Palliative Surgery in Patients With Peritoneal Carcinomatosis of Colorectal Cancer
From the Departments of Surgery, Biometrics, and Gastroenterology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. Address reprint requests to Vic J. Verwaal, MD, Department of Surgery, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: v.verwaal{at}nki.nl.
Purpose: To confirm the findings from uncontrolled studies that aggressive cytoreduction in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is superior to standard treatment in patients with peritoneal carcinomatosis of colorectal cancer origin. Patients and Methods: Between February 1998 and August 2001, 105 patients were randomly assigned to receive either standard treatment consisting of systemic chemotherapy (fluorouracil-leucovorin) with or without palliative surgery, or experimental therapy consisting of aggressive cytoreduction with HIPEC, followed by the same systemic chemotherapy regime. The primary end point was survival. Results: After a median follow-up period of 21.6 months, the median survival was 12.6 months in the standard therapy arm and 22.3 months in the experimental therapy arm (log-rank test, P = .032). The treatment-related mortality in the aggressive therapy group was 8%. Most complications from HIPEC were related to bowel leakage. Subgroup analysis of the HIPEC group showed that patients with 0 to 5 of the 7 regions of the abdominal cavity involved by tumor at the time of the cytoreduction had a significantly better survival than patients with 6 or 7 affected regions (log-rank test, P < .0001). If the cytoreduction was macroscopically complete (R-1), the median survival was also significantly better than in patients with limited (R-2a), or extensive residual disease (R-2b; log-rank test, P < .0001). Conclusion: Cytoreduction followed by HIPEC improves survival in patients with peritoneal carcinomatosis of colorectal origin. However, patients with involvement of six or more regions of the abdominal cavity, or grossly incomplete cytoreduction, had still a grave prognosis.
PERITONEAL CARCINOMATOSIS (PC) of colorectal origin is common and is the second-most frequent cause of death in colorectal cancer after metastatic disease to the liver. In an estimated 25% of patients, no other tumor locations can be found, even when a detailed diagnostic work-up is performed.1–3 Sugarbaker4,5 has suggested that PC of colorectal origin should probably not be equated with generalized disease, but can be a first step of dissemination, not unlike the situation with liver metastases of colorectal origin. Based on this concept, attempts have been made to achieve long-term survival in patients with PC by combining surgery and intraperitoneal chemotherapy to eradicate microscopic residual disease. Advances in surgical techniques and improved anesthesiology have made it possible to remove most or all macroscopic tumor in PC.6 In theory, intraperitoneal chemotherapy could eradicate limited residual tumor, and should have an optimal chance to succeed if it would immediately follow surgery (to avoid regrowth of tumor cells), and if exposure of the peritoneal surface at risk could be guaranteed. To achieve these goals, peritoneal lavage, as part of the surgical procedure, has been developed.7 Others and our group have shown that peritoneal lavage containing mitomycin C (MMC) results in a drug exposure to the peritoneal surface that is 20 times higher than elsewhere in the body.8,9 This degree of pharmacokinetic advantage is thought to result in optimal circumstances for tumor cell kill. In addition, enhancement of MMC cytotoxicity at temperatures higher than 39°C has been demonstrated in animals and in vitro models.10,11 The addition of intraperitoneal hyperthermia has been shown to be technically feasible in the surgical setting.12,13 This approach of aggressive cytoreduction in combination with intraperitoneal chemotherapy, often employing MMC and hyperthermia, has been studied in 11 phase II studies on patients with PC of colorectal origin.12,14–23 The results of these studies show a strikingly long median survival and, more importantly, a 20% to 30% long-term (5-year) survival rate, reminiscent of that of surgery for isolated liver metastases. It has been advocated that these favorable results justify such an aggressive treatment, particularly since long-term survival is hardly ever seen after systemic chemotherapy alone. It remains to be shown that these encouraging results of uncontrolled studies are not the result of patient selection. The need for a controlled study was recently re-emphasized in an editorial in the Journal of Clinical Oncology by Sugarbaker,24 who originally pioneered the approach. This need is particularly urgent because HIPEC is associated with significant morbidity and treatment-related mortality. In this article, we report the results of a randomized single-institution phase III study, and present data that may aid in better selection of patients for aggressive treatment of peritoneal carcinomatosis.
Patient Selection and Study Design Patients with histologically proven peritoneal metastases of colorectal adenocarcinoma (CRC) or positive cytology of ascites, who were diagnosed either at first presentation or at recurrence of CRC, were eligible. No signs of distant metastases (liver, lung) on computed tomography (CT) scan of abdomen and chest x-ray were allowed. Patients had to be younger than 71 years and fit for major surgery (normal bone marrow indices, and normal renal and liver functions). Initially, patients who had received fluorouracil (FU) within 12 months before random assignment were excluded. In the first year of the study, an amendment to the protocol was made to allow inclusion of these patients. Patients were randomly allocated to either standard treatment or to the experimental treatment. The randomization was performed centrally by computer, and stratified for presentation (primary or recurrence) and site (appendix, colon, or rectum). The medical ethical committee of the Netherlands Cancer Institute approved the study, and written informed consent was obtained from all patients.
Standard Treatment
Experimental Treatment The objective of cytoreduction was to leave no macroscopic tumor behind, or at least to have limited residual tumor (<2.5 mm in thickness). To achieve this, the stripping of the parietal peritoneum was carried out as described by Sugarbaker et al.26 Infiltrated viscera were resected if this was compatible with retaining function. Most often this concerned the rectum, parts of small bowel and colon, the gall bladder, parts of the stomach, and the spleen. The greater omentum was routinely removed. Reconstruction of gastrointestinal continuity was postponed until after the lavage, to prevent entrapment of tumor cells in suture lines. At completion of cytoreduction, the absence of residual tumor was recorded as R-1. If the largest residual tumor was smaller than 2.5 mm, it was regarded as an R-2a resection. In cases of residual tumor larger than 2.5 mm, cytoreductive surgery was scored as R-2b. The total length of the operation, and blood loss were also recorded. Hyperthermic intraperitoneal chemotherapy (HIPEC). To increase the volume of the abdominal cavity and to prevent spillage of lavage fluid, the skin of the laparotomy wound was pulled up against a retractor. A plastic sheet covered the laparotomy opening to reduce heat loss and to avoid drug spilling. A central aperture was made to allow manipulation to achieve optimal drug and heat distribution. The perfusion circuit consisted of a centrally placed inflow catheter, outflow catheters, placement in the pelvis below left and right diaphragm, a roller pump, and a heat exchanger. Temperature probes were attached to inflow and outflow catheters. Perfusion was started with a minimum of 3 L of isotonic dialysis fluid, at 1 to 2 L/min, and an inflow temperature of 41°C to 42°C. As soon as the temperature in the abdomen was stable above 40°C, MMC was added to the perfusate at a dose of 17.5 mg/m2 followed by 8.8 mg/m2 every 30 minutes. The total dose was limited to 70 mg at maximum. If the core temperature exceeded 39°C, the inflow temperature was reduced. After 90 minutes, the perfusion fluid was drained from the abdomen, and bowel continuity was restored. A temporary colostomy was made in most cases if the rectum was resected. A draining gastrostomy and transgastric jejunal feeding tube were inserted. The outflow catheters were used for postoperative drainage of the abdomen cavity.
Postoperative Care Jejunal tube feeding was begun on day 1. Parenteral nutrition was given until jejunal feeding could cover all nutritional needs. Oral fluid and food intake was resumed as soon as the gastrostomy production dropped below 500 mL per 24 hours.
Adjuvant Chemotherapy
Toxicity/Complications
Follow-Up
Statistical Analysis To improve patient selection in the future, additional exploratory analyses were performed to identify potential prognostic factors. Presentation (primary v recurrence), site (appendix v colon v rectum), number of regions involved (<5 regions v >5 regions), and completeness of cytoreduction (R-1 v R-2a v R-2b) were included in a Cox proportional hazards regression model in order to obtain hazard ratios and 95% confidence intervals. All P values are two-sided.
Between January 1998 and August 2001, 105 patients were randomly assigned in this study—51 to standard therapy and 54 patients to experimental therapy. Two patients proved ineligible—one patient with pseudomyxoma peritonei in the standard arm and one with peritoneal mesothelioma in the experimental arm. Figure 1  shows the trial profile. All patients, including the ineligible ones, were included in the intention-to-treat analysis. The patient group included 58 men and 47 women, with a median age of 54 years (range, 28 to 70 years). Fifty-eight patients had PC at their primary presentation, and 47 patients had the disease at recurrence. The primary sites were appendix in 18 patients, colon in 75, and rectum in 12. The patient and tumor characteristics were well balanced within both arms, except for a nonsignificant overrepresentation of males in the "HIPEC" arm (63% v 47%; P = .11). Tumor size and differentiation grade were equally distributed in both arms. The majority of the patients (95.8% standard arm; 98.0% HIPEC arm) had large tumors (T3 and T4). All patients with small tumors (3.1%; T1 and T 2) were patients with PC at recurrence of CRC. (Table 1).
Standard Arm Seven patients never started systemic chemotherapy: five patients withdrew their consent; two patients had severe progressive disease before they could start, and deteriorated rapidly. Thirty-eight patients started with FU-leucovorin, of whom 21 received treatment for at least 5.4 months (median, 5.8 months; range, 5.4 to 6.7); 12 stopped because of progression of disease; two stopped because of toxicity; and three were still on treatment. Six patients started with irinotecan, of whom two completed treatment.
Experimental Arm
An average of 1.8 visceral resections were performed per patient. Most often, parts of small bowel (45 patients) and rectum (25 patients) were resected. Twenty-four patients needed a colostomy. The median number of bowel anastomoses was two (range, zero to seven anastomoses). In 18 patients, no macroscopic residual disease was left behind (R-1); in 21, the residual deposits were smaller than 2.5 mm (R-2a); and in 10 cases, residual deposits were
Grade 3 and 4 toxicity, as well as complications, are shown in Table 2
Fourteen patients never started adjuvant chemotherapy after cytoreduction followed by HIPEC. This was because of early progression (eight patients) or refusal (three patients). All 33 patients who started chemotherapy received FU-leucovorin. Nineteen completed 6 months of therapy, four stopped early because of disease progression, two stopped because of toxicity, and one withdrew consent. At the time of closing the database, seven patients were still receiving the treatment.
Survival
This study was designed to answer the question of whether the addition of aggressive cytoreduction and HIPEC with MMC improves survival in patients with PC of colorectal origin. In this analysis, the results of all 105 randomly assigned patients are reported. The median follow-up at the time of analysis was 21.6 months, which is more than twice the median survival in the standard arm. At the time of this writing, an event (either recurrence or death) had occurred in 61% of the patients—almost two-thirds of what had been experienced in the standard arm. Follow-up, therefore, is long enough to demonstrate any impact of this new therapy on survival. The analysis was carried out according to the intention-to-treat principle, irrespective of the actual treatment received. Protocol violations, including ineligibility of enrolled patients and treatment alterations, should have a negative impact on the experimental arm. Nevertheless, Kaplan-Meier survival analysis showed a statistically significant survival benefit for the experimental therapy. The effect is of a remarkable size. The median duration of survival almost doubled, while the 2-year survival was even more than twice as high. The difference between the patient groups withstands selection bias, as in the control arm, life expectancy exceeded 6 months known from literature.27,28 Nevertheless, these relative good results suggest positive selection before random assignment.
Although the longest survivor is at present only 4 years after randomization, the Kaplan-Meier survival curve suggests a 5-year survival rate in the order of 20%, which is comparable to survival found in phase II studies. Together with the results of published phase II studies12,14–23 (Table 3
This effect was associated with considerable morbidity and mortality (8%), which is similar to that reported by others.21 Most of the serious complications seem to be related to the extent of surgery, and may be related to the extent of peritoneal involvement, rather than to the HIPEC procedure. The median blood loss of almost 4 L is high. The most extreme blood loss measurements were found in patients with six and seven regions involved. Characteristically, these patients would undergo a partial gastrectomy, splenectomy, resection of the tail of the pancreas, omentectomy, multiple small bowel resections, ileocecal resection, rectosigmoid resection, and uterus with adnex extirpation combined with multiple peritonectomy procedures, leaving an enormous intra-abdominal wound bed. Exhaustion of coagulations factors, though replaced with fresh frozen plasma and thrombocytes if measurably low, has probably contributed to the blood loss. It is noteworthy that in the first 6 months, the period in which the treatment-related deaths occurred, survival was identical in both treatment arms. This emphasizes one of the problems of this study—the inclusion of many patients with extensive peritoneal disease. This was due partly to our lack of understanding of the impact of extent of the disease on morbidity and survival, which meant that we did not exclude any patients based on the extent of the disease. Even if we had designed the study to exclude patients with extensive disease (six or seven regions), we would not have been very successful in predicting the extent of the disease based on preoperative findings. CT scans failed because typical PC is a like a coating that projects as a thin line on a cross-section. More modern positron emission tomography scans are based on tumor density per volume unit, which is low in these circumstances. The only trustworthy moment of predicting outcome occurs after exploration of the abdomen. The analysis of prognostic factors in the HIPEC arm shows that patients with cancer deposits in six or seven regions of the abdomen do poorly, both in respect to direct postoperative complications and long-term survival. Eighty percent of all incidences of grade 4 toxicity (postoperative complications included) and all treatment-related deaths were in this patient group. These are the same patients in whom we failed to obtain a complete cytoreduction. These patients have clearly not benefited from cytoreduction and HIPEC. Both Sugarbaker et al,26 and Elias and Ouellet29 have reported very similar findings. Patients in whom six or seven regions were affected by tumor also had poor survival (median, 5.4 months). Patients with a high tumor load could be spared unnecessary toxicity since there is little chance of improved survival. Such patients should be identified before surgery by standardization of explorations in every patient affected by PC. Many questions remain unanswered. The experimental arm of this study combined two treatment elements: aggressive cytoreduction and HIPEC. Whether the combination of these treatment modalities was required for the survival benefit is unclear. Complete or nearly complete resection seems to be a prerequisite for a favorable outcome. This is consistent with our understanding that intraperitoneal chemotherapy only leads to drug delivery advantages to the superficial layers below the peritoneal surface, and can therefore only be effective in minimal-residue disease. Nevertheless, it cannot be excluded that the observed effect was exclusively or mainly caused by the aggressive cytoreduction alone. In this study, a moderately dosed regimen of FU-leucovorin was used, as this is a convenient outpatient regimen with only minimal gastrointestinal toxicity or other toxicity.25 Recently, somewhat more aggressive schedules of combination chemotherapy have been introduced in advanced colorectal cancer, which may be associated with a small survival benefit.30,31 It is possible that the use of these contemporary chemotherapy schedules would have slightly prolonged survival in both treatment arms. However, it seems unlikely that it would have had any influence on the survival differences found in this study. The combination of cytoreduction and HIPEC with continuous FU-leucovorin, irinotecan, and/or oxaliplatin seems certainly promising for further outcome improvement. Questions concerning other aspects of HIPEC, for instance, the role of hyperthermia and the best choice of drug or dosage for intraperitoneal therapy, remain completely open. Other drugs such as oxaliplatin32 and floxuridine33 have been studied and may be incorporated alone or in novel combinations. In this study, the open coliseum technique is used. This open system presents the possibility to maintain optimal distribution by manual stirring. Recently, this system has been tested for safety by operating room personnel.34 In this study, MMC was found neither in the operating room air, nor in the urine of the surgeon or perfusionist, and is therefore safe. This study shows that the therapeutic nihilism that has dominated the care for patients with PC for such a long time may not be appropriate. Limited PC may represent a situation analogous to that of isolated liver metastases, in which long-term survival can be achieved in some patients by the surgical removal of macroscopic disease and by systemic treatment to deal with microscopic residual disease. With the appropriate patient selection and a determined locoregional treatment effort, PC of colorectal origin may even be a potentially curable disease in patients with limited peritoneal involvement.
The authors indicated no potential conflicts of interest.
Supported with grant OG98-041 from Ontwikkelings Geneeskunde.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2.5 mm (R-2b). 
) indicating the overall result corresponds with the 95% CI. HIPEC, hyperthermic intraperitoneal chemotherapy.
