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Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy With Mitomycin C for Peritoneal Carcinomatosis from Nonappendiceal Colorectal Carcinoma

From Wake Forest University Baptist Medical Center (PS, JH, JL, KRG, EAL) and Kucera Pharmaceutical Company (RAF), Winston-Salem, NC; and Creighton University Cancer Center (BWL), Omaha, Nebraska.

Correspondence: Address correspondence and reprint requests to: Perry Shen, MD, Surgical Oncology Service, Wake Forest University Medical Center, Medical Center Blvd., Winston-Salem, NC 27157; Fax: 336-716-9758; E-mail: pshen{at}wfubmc.edu

	ABSTRACT

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Background: Cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy (IPHC) are efficacious in patients with disseminated mucinous tumors of the appendix. We reviewed our experience using this approach for nonappendiceal colorectal cancer (NACC).

Methods: We performed a retrospective chart review of a prospective database for patients undergoing CS and IPHC with mitomycin C for peritoneal carcinomatosis from colorectal primary lesions between December 1991 and April 2002.

Results: There were 77 patients, with a median age of 54 years. Peritoneal carcinomatosis was synchronous and metachronous in 27% and 73% patients, respectively. Seventy-five percent of patients (n = 58) had received chemotherapy prior to IPHC. Complete resection of all gross disease was accomplished in 37 patients (48%). The mean carcinoembryonic antigen level decreased from a preoperative value of 31.2 to a postoperative value of 6.9 (P < .0001). Overall survival (OS) at 1, 3, and 5 years was 56%, 25%, and 17%, respectively. With a median follow-up of 15 months, the median OS was 16 months. Perioperative morbidity and mortality were 30% and 12%, respectively. Hematologic toxicity occurred in 15 patients (19%). Cox regression analysis identified poor performance status (P = .018), bowel obstruction (P = .001), malignant ascites (P = .001), and incomplete resection of gross disease (P = .011) as independent predictors of decreased survival. Patients with complete resection of all gross disease had a 5-year OS of 34%, with a median OS of 28 months.

Conclusions: CS and IPHC with mitomycin C can improve outcomes for select patients with peritoneal spread from NACC. One third of patients who undergo complete resection of gross disease have long-term survival.

Key Words: Chemotherapy • Colorectal cancer • Hyperthermia • Peritoneal carcinomatosis • Surgery

	INTRODUCTION

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The treatment of patients with peritoneal carcinomatosis (PC) from gastrointestinal malignancies is in evolution. PC is the most common cause of death in patients resected for intra-abdominal carcinomas.¹ A multicenter study prospectively following 370 patients with PC of nongynecologic origin revealed a mean and median overall survival (OS) of 6.0 and 3.1 months, respectively.²

Surgical resection alone has been demonstrated to be ineffective for the treatment of PC, with median survivals of 1, 1, .7, and 6 months for PC from gastric, small bowel, pancreas, and colorectal cancer treated in this fashion.³ Attempts at controlling PC with either external beam radiation therapy or brachytherapy have failed to demonstrate efficacy.⁴ The use of systemic chemotherapy for PC has not been shown to be efficacious, as many patients present with PC after systemic chemotherapy fails.⁵

Intraperitoneal administration of chemotherapy has the benefit of delivering higher concentrations of cytotoxic drug locally to the site of the tumor while minimizing systemic toxicity, in comparison with intravenous administration. Pharmacokinetic studies have demonstrated a 107-fold increase in the concentration of mitomycin C (MMC) in the intraperitoneal perfusate versus plasma concentrations when administered systemically.⁵ Recent studies have reported on the combination of cytoreductive surgery and intraoperative intraperitoneal chemotherapy^6–12 administered under hyperthermic conditions (40°C to 43°C). The administration of intraperitoneal chemotherapy at the time of surgery allows a potentially more even distribution of drug, without the potential of catheter-related complications and postoperative adhesions. Hyperthermia has been shown to potentiate the cytotoxicity of drugs such as MMC and cisplatin.^13,14 These interactions are enhanced under hypoxic conditions, which is not true for most agents given after surgical resection.

A report from Sugarbaker and colleagues¹⁵ at the Washington Cancer Institute described the use of cytoreductive surgery (CS) and intraoperative and perioperative intraperitoneal chemotherapy with 5-fluorouracil and MMC for 385 patients with PC from appendiceal malignancy. Patients with complete cytoreduction and pathology demonstrating adenomucinosis and adenocarcinoma had 5-year OS rates of 86% and 50%, respectively. Piso et al.¹⁶ also reported their experience with intraoperative hyperthermic intraperitoneal cisplatin after peritonectomy procedures for PC from appendiceal carcinoma. They reported a mean OS time of 39 months, with a 4-year OS rate of 75%. Patients with complete versus incomplete cytoreduction had a 4-year OS rate of 92% and 40%, respectively (P = .02). Another study report, by Zoetmulder and associates,¹⁷ described their experience with IPHC with MMC for pseudomyxoma peritonei in 46 patients. The actuarial survival rate at 3 years was 81%. These published results for over 400 patients provide strong evidence for the use of an aggressive multimodality approach to this rare disease process, especially when standard surgical therapy results in only a 10-year OS of 10% to 30%.¹⁸ In addition, we recently reviewed our experience with 109 patients treated with PC from various histologies and found that an appendiceal primary was an independent predictor of improved survival.¹⁹

Data regarding the use of CS and IPHC for other types of histologies have not been as extensively studied. Specifically, the treatment of PC from nonappendiceal colorectal carcinoma (NACC) with CS and IPHC with administration of MMC has been examined in only a limited fashion. Both Loggie et al.²⁰ and Sugarbaker et al.²¹ have reported a significant difference in outcome for patients with appendiceal versus colorectal primaries.

Other trials have suggested a benefit of CS and IPHC for PC from colorectal cancer, including one prospective randomized trial.^22,23 However, these trials included appendiceal cancers in their study populations, making it difficult to determine the true effect of this approach. We reviewed our experience with CS and IPHC using MMC for PC from NACC to examine their demographics, clinical outcome, predictors of survival, factors contributing to postoperative morbidity/mortality, and methods to improve patient selection.

	METHODS

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The study protocol was reviewed and approved by the Institutional Review Board of the Wake Forest University School of Medicine. Eligible patients were enrolled in the protocol from December 1991 through April 2002. All patients with PC from NACC primaries were enrolled in the study cohort. The Eastern Cooperative Oncology Group (ECOG) performance status was recorded for all patients enrolled in the protocol.²⁴

Cytoreductive Surgery
All patients enrolled in the study protocol were operated on by one of three surgeons (BWL, EAL, PS), each with significant experience with CS. CS consisted of the removal of all gross tumors with involved organs, peritoneum, or tissue that was deemed technically feasible and safe for the patient. Any tumor adherent or invasive to vital structures that could not be removed was cytoreduced with the Cavitron Ultrasonic Surgical Aspirator device. Peritonectomy was performed as indicated. The resection status of patients was estimated following CS with use of the following classification: R₀, complete removal of all visible tumor and negative cytology or negative microscopic margins; R₁, complete removal of all visible tumor and positive cytology or microscopic margins; R_2a, minimal residual tumor, nodule(s) .5 cm; R_2b, gross residual tumor, nodule >.5 cm but 2 cm; and R_2c, extensive disease remaining, nodules >2 cm.

Intraperitoneal Hyperthermic Chemotherapy
Patients were cooled to a core temperature of about 34°C to 35°C by passive measures (i.e., not warming airway gases or intravenous solutions and cooling the room). After CS was completed, peritoneal perfusion inflow and outflow catheters were placed percutaneously into the abdominal cavity. Temperature probes were placed on the inflow and outflow catheters. The abdominal skin incision was closed temporarily with a running suture to prevent leakage of peritoneal perfusate. A perfusion circuit was established with approximately 3 L of Ringer’s lactate. Flow rates of approximately 600 to 900 mL/min were maintained with a roller pump managed by the pump technician. The circuit continued through a single roller pump, through a heat exchanger (SCI-MED, No. A-714; Gish Biomedical, Irvine, Ca), and then to the patient.

Constant temperature monitoring was performed with temperature probes placed on both the inflow and outflow catheters. Once inflow temperatures exceeded a temperature of 38.5°C, 30 mg of MMC was added to the perfusate, and at 60 minutes an additional 10 mg of MMC was added to the perfusate to keep MMC perfusate concentrations >5 µg/mL. A maximum inflow temperature of 40.5°C was achieved during the perfusion, with outflow at the pelvis of 39.5°C. The abdomen was gently massaged throughout the perfusion to improve drug distribution to all peritoneal surfaces. The total perfusion time after the initial addition of MMC was 120 minutes. In certain patients (elderly, those with extensive prior chemotherapy, those with inanition or poor performance status, and those having extensive peritoneal stripping during surgery), reductions in the dose of MMC (to 30 mg total) and/or the perfusion time (60–90 minutes) were made because of concerns about potential toxicity. The peritoneum was washed out with 3 L of lactated Ringer solution, and the abdomen was reopened for removal of perfusion catheters.

In 2000, a new perfusion device (ViaCirq, Pittsburgh, PA) was introduced that allowed the perfusate to be heated to higher temperatures. Subsequent sessions of IPHC were conducted with a maximum inflow temperature of 43°C and a minimum outflow temperature of 40.5°C.

Perioperative Evaluation
Perioperative morbidity in the database was classified into four main groups: bowel leak, respiratory failure, infection, and sepsis. Bowel leak was defined by any occurrence of an anastomotic leak or bowel perforation, respiratory failure was defined by any extended period of mechanical respiration beyond the first 24 hours after surgery or any incidence of reintubation (regardless of cause), and infection was defined as any infection of the wound, abdomen, catheter, blood, or lung. Sepsis was defined as a worsening clinical condition requiring management in the intensive care unit. Other complications not covered by these four categories were also included in the database. These included deep venous thrombosis, ileus, pneumonia, renal failure, and pleural effusion.

Clinical Follow-Up
Clinical follow-up occurred at 1 month, 3 months, and then every 3 months thereafter for up to 1 year. After 1 year, follow-up was at 3-month intervals or less frequently if the patient continued to remain without evidence of disease. Abdominal and pelvic CT scans were obtained at 3, 6, and 12 months postoperatively or when clinically indicated. Some patients received systemic chemotherapy after referral back to their medical oncologists.

Statistical Analysis
OS was calculated from the date of CS and IPHC to the last recorded date of follow-up or recorded date of death. All data were collected prospectively. Kaplan-Meier analysis was performed on all pertinent clinicopathologic variables to determine estimates of survival over time. Group comparisons of OS were done with the log-rank test. Cox’s proportional hazards regression model was used to perform multivariate analysis of clinicopathologic factors to determine independent predictors of OS. Fisher’s exact test was used to correlate type of surgical procedure with postoperative morbidity. A P value <.05 was considered significant for the purposes of this manuscript.

	RESULTS

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Patients
A total of 77 patients with PC from NACC were enrolled in the protocol. Table 1 lists demographic characteristics and baseline data. The median age was 54 years. The primary sites were 74 in the colon and 3 in the rectum. All patients had a histologic diagnosis of adenocarcinoma. PC was synchronous and metachronous in 27% and 73% of patients, respectively. In those with metachronous presentation, median disease-free interval between primary diagnosis and peritoneal disease was 14 months (range, 3 to 85 months). More than three quarters of patients had undergone prior surgery or chemotherapy. About one third of patients presented with either bowel obstruction or malignant ascites. Complete resection of all gross disease was accomplished in 37 patients (48%). Table 2 correlates resection status with type of surgical procedure performed. Pre-IPHC cytology was not performed or the results were not available in approximately one quarter of patients.

View larger version (14K): [in this window] [in a new window]   FIG. 1. Overall survival as related to performance status (Eastern Cooperative Oncology Group).

View larger version (15K): [in this window] [in a new window]   FIG. 2. Overall survival as related to resection status.

View larger version (13K): [in this window] [in a new window]   FIG. 3. Overall survival as related to bowel obstruction.

View larger version (13K): [in this window] [in a new window]   FIG. 4. Overall survival as related to malignant ascites.

Fifteen subjects (19%) developed hematologic toxicity requiring growth factor support or platelet transfusion. Thirty-three patients (43%) required a blood transfusion, with a median of 2 units (range, 1–17) transfused. The median operative time and length of hospital stay for CS and IPHC were 9 hours (range, 5–16) and 10 days (range, 5–150), respectively.

Chi-square analysis and Fisher’s exact test were used to correlate the occurrence of a perioperative complication (bowel leak, infection, respiratory failure, sepsis) with the performance of either a bowel resection (n = 49) or bowel anastomosis (n = 42). Patients with resection but no anastomosis had ostomies created. There was no correlation of either bowel resection or anastomosis with perioperative complications as a group. However, when complications were individually analyzed against bowel resection and anastomosis, there was a significant correlation of sepsis with bowel anastomosis (P = .0032) (see Table 5).

	DISCUSSION

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In 1995 Sugarbaker et al.²¹ published their experience using perioperative intraperitoneal 5-fluorouracil and MMC without hyperthermia for patients with PC secondary to appendiceal and colorectal cancer. The 3-year OS rates for the appendiceal and colorectal PC patients were 70% and 30%, respectively (P = .0001). In 2000, Loggie et al.²⁰ published a report from our institution examining the outcomes for patients with disseminated peritoneal cancer of gastrointestinal origin. The median OS of patients with colorectal primaries was 15 months. The median OS for appendiceal primaries had not been reached. A study in France by Elias and associates²² used both early intraperitoneal and hyperthermic intraoperative intraperitoneal chemotherapy with a combination of agents: 5-fluorouracil, MMC, and cisplatin. The results of two separate trials were combined in one report.²² The study cohort was patients with PC arising from colorectal adenocarcinomas, of which 14% were mucinous cancers of the appendix. All patients in this study had an R0/1 resection with all gross disease removed. The 5-year OS was 27%, with a median OS of 36 months. These results are comparable to those for our subset of patients with a similar type of resection status.

A prospective study on the natural history of PC from colorectal cancer demonstrated a median OS of 5 months.² This subset of patients did not include pseudomyxoma peritonei. The median OS of patients in our study was 16 months, with a 5-year OS of 17%. Three quarters of the patients had already undergone systemic chemotherapy for metastatic disease that failed. Univariate predictors of survival were performance status, resection status, bowel obstruction status, malignant ascites status, liver metastases status, and pre-IPHC cytology status. The best outcomes were for patients undergoing an R0 resection, which yielded a 5-year OS of 55%, with a median OS that has not yet been reached.

On multivariate Cox regression analysis, only four factors remained independent predictors of OS: ECOG performance status of 0/1, R0/1 resection status, absence of bowel obstruction, and absence of malignant ascites. Two of these factors—performance status and bowel obstruction—appear to favor patients who will best tolerate the significant physiological stress induced by the multimodality application of not only extensive CS but also IPHC. The other two factors—resection status and ascites—appear to identify patients with more limited disease that best responds to CS and IPHC from an oncologic perspective. Three of these four factors can be determined preoperatively and help to optimize patient selection. The fourth factor, resection status, is a variable that is most accurately determined intraoperatively. The use of a peritoneal carcinomatosis index has been reported to be predictive of resectability in patients with PC.¹⁵ However, because this index can be determined only at the time of laparotomy, it does not help prevent unnecessary surgery.

Complications after CS and IPHC can be due to the extensive surgery or the intraperitoneal chemotherapy or the combination of both. Major peritonectomy procedures were not performed when cytoreduction with the Cavitron Ultrasonic Surgical Aspirator was possible. The most significant detrimental effect is on the hematologic, pulmonary, and gastrointestinal organ systems.²⁵ The perioperative morbidity and mortality in our study cohort were 30% and 12%, respectively. Although the morbidity compares favorably with that in other published series, the mortality is substantial for any surgical procedure, especially one that is performed with palliative intent. However, we counted all deaths related to CS and IPHC, not limiting the number to deaths occurring only within 30 days of the procedure.

Respiratory failure accounted for 44% of the perioperative deaths. MMC has been reported to cause adult respiratory distress syndrome in patients exposed to FIO₂ concentrations greater than 50% perioperatively.²⁶ This complication usually manifests after multiple doses in patients given the drug systemically with other chemotherapy combinations. The marrow toxicity that can occur with MMC usually occurs 4–8 weeks after systemic administration,²⁶ but the two patients who developed fatal myelosuppression had evidence of hematologic toxicity within 72 hours of IPHC. Previous studies have shown that platelet counts begin to decline after the procedure and typically return to normal values within 1–2 weeks.^27,28 The differences in timing of nadir counts between IPHC and intravenous bolus MMC may be due to kinetic differences from the two administration schedules.

We have previously reported that there is a direct relationship between hematologic toxicity and MMC concentrations in plasma.²⁹ The AUCs of MMC in plasma after a 2-hour IPHC perfusion are similar to that observed after an intravenous bolus of MMC. The dosing rationale for MMC during IPHC was to achieve a peritoneal concentration of 5–10 µg/mL in a fixed volume of perfusate, versus the standard practice of dosing by body surface area. Several recent reviews in the oncology literature question whether dosing by body surface area is any better than fixed dosing.^30–32 Given the tremendous pharmacokinetic variations between patients, dosing differences by body surface area may not be significant when the real sources of variability are the organs (or enzymes, etc.) responsible for drug elimination (renal function for renally eliminated drugs and hepatic function for hepatically cleared drugs).

Three of the patients died of either bowel leak or perforation, which appears more plausible given the often extensive nature of the surgery and evidence from animal models that intraperitoneal chemotherapy with MMC has an adverse effect on anastomotic bowel healing.³³ It is interesting that only one of these deaths was due to an anastomotic leak, whereas the other two patients who died developed bowel perforations at a site other than the anastomosis. The two patients with perforations presented with bowel obstruction, whereas the patient with an anastomotic leak had obstructive jaundice. Cox regression analysis has clearly identified bowel obstruction as an independent predictor of decreased OS, and we no longer perform IPHC in such patients. When we conducted a Fisher’s exact test to correlate the presence of a bowel resection or anastomosis with complications, we found that the presence of a bowel anastomosis was significantly correlated with sepsis. However, on Cox regression analysis (Table 4), the hazard ratio for bowel anastomosis was .9. It appears the creation of a bowel anastomosis may increase the risk of perioperative complications but not perioperative mortality. Although we do not believe bowel anastomosis during IPHC is contraindicated, we believe its association with perioperative complications should be considered in light of the patient’s overall status, especially when the creation of a stoma is another option.

When perioperative mortality among patients with the independent predictors of OS was assessed, the death rate was 4%. This conclusion should not be surprising, because these are the patients who presented in the best physiological condition with grossly resectable disease. Our experience with these 77 patients reflects an aggressive approach for patients with advanced cancer who have few meaningful therapeutic options. Some of these patients presented in poor health due to their malignant disease, and the perioperative mortality reflects the tremendous stress this multimodality approach places on the patient. However, our data clearly demonstrate that for select patients with PC from NACC, the application of CS and IPHC with MMC can extend survival. Other reports from our institution have shown that quality of life, a vital parameter for the evaluation of palliative interventions, is also preserved for the majority of patients, both in the short term and in the long term.^34,35

One criticism of the use of CS and IPHC is the lack of randomized, controlled trials confirming its efficacy in comparison with supportive care, surgery alone, or systemic chemotherapy. A recent prospective trial in Europe randomized 104 patients with PC from colorectal adenocarcinoma to CS and IPHC with MMC, followed by systemic therapy with 5-fluorouracil/leucovorin, in comparison with CS and systemic 5-fluorouracil/leucovorin alone. With a mean follow-up of 24 months, the 2-year OS was 43% in the IPHC arm (median OS, 21 months) and 16% in the standard therapy arm (median OS, 10 months) (P = .0145).²³ Previous studies of untreated patients with metastatic colorectal cancer have revealed median OS of 14–19 months with the use of new systemic chemotherapeutic agents such as irinotecan and oxaliplatin.^36–38 Our study revealed that patients undergoing R0/1 resection had a median OS of 28 months. In addition, our study provides information on which clinicopathologic factors predict improved outcome from this procedure.

Future research directions may include the use of molecular markers to determine which patients will derive the most benefit. Just as the preoperative carcinoembryonic antigen level was seen to significantly decrease after CS and IPHC, investigations with other surrogate markers may yield more prognostic information. We previously reported that the presence of a polymorphism that causes reduced activity of quinone oxidoreductase 1 (NQO1) is associated with a decrease in survival for patients undergoing CS and IPHC for PC.³⁹ NQO1 is important in the activation of MMC. Such a mutation found in tumor tissue of patients with PC may identify those who should be treated with agents other than MMC or undergo alternative treatments. Multicenter trials are needed to confirm these findings and improve perioperative and long-term outcome.

	FOOTNOTES

 
Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy with mitomycin C for nonappendiceal colorectal carcinoma offer effective palliation for select patients. Malignant ascites, bowel obstruction, poor performance status, and incomplete resection are independent predictors of decreased overall survival.

Received for publication May 8, 2003. Accepted for publication October 8, 2003.

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