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Combined-Modality Treatment for Resectable Metastatic Colorectal Carcinoma to the Liver: Surgical Resection of Hepatic Metastases in Combination With Continuous Infusion of Chemotherapy—An Intergroup Study

From the Cancer Center of Queens, Queens Hospital Center, Queens, NY; Dana-Farber Cancer Institute, Boston, MA; Morristown Memorial Hospital, Morristown, NJ; Fox Chase Cancer Center and University of Pennsylvania, Philadelphia, PA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; and Royal Perth Hospital, Perth, Australia.

Address reprint requests to M. Margaret Kemeny, MD, Cancer Center of Queens, 82-68 164th St, N Building, Rm 634, Jamaica, NY 11432; email: kemenym{at}nychhc.org

	ABSTRACT

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PURPOSE: Despite technical improvements that have minimized the morbidity and mortality of hepatic surgery, the long-term outcome of resection of hepatic metastases of colorectal cancer remains poor, with the majority of patients experiencing treatment failure in the liver. Because arterial chemotherapy regimens targeted to the liver have demonstrated high response rates, an intergroup trial of adjuvant therapy for patients undergoing hepatic resection of liver metastases from colorectal cancer was initiated.

PATIENTS AND METHODS: Patients with one to three potentially resectable metastases were randomized preoperatively to receive no further therapy (control arm, 56 patients) or postoperative hepatic arterial floxuridine combined with intravenous continuous-infusion fluorouracil (chemotherapy arm, 53 patients). After exclusion of patients identified as ineligible for the planned treatment at the time of surgery, there were 45 control patients and 30 on the chemotherapy arm. The study was powered to evaluate improvement in time to recurrence and hepatic disease-free survival, not overall survival.

RESULTS: The 4-year recurrence-free rate was 25% for the control arm and 46% for the chemotherapy group (P = .04). The 4-year liver recurrence-free rate was 43% in the control group and 67% in the chemotherapy group (P = .03). The median survival of the 75 assessable patients was 49 months for the control arm and 63.7 months for the chemotherapy arm (P = .60). The median survival of all 109 patients was 47 months for the control arm compared with 34 months for the chemotherapy arm (P = .19)

CONCLUSION: These data demonstrate that adjuvant intra-arterial and intravenous chemotherapy was beneficial in prolonging time to recurrence and pre-venting hepatic recurrence after hepatic resection of colorectal cancer.

	INTRODUCTION

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COLORECTAL CANCER IS diagnosed annually in more than 130,000 Americans, of whom more than 40,000 will develop liver metastases. In the 1970s and 1980s, advancing surgical expertise led to the adoption of hepatic resection for patients with multiple hepatic metastases (< four) from colorectal primary tumors. The 5-year survival after liver resection in these patients¹ is approximately 30%. For the 70% of patients who develop recurrences, more than half of them have recurrence in the liver.¹

Treatment of unresectable colorectal hepatic metastases with systemic chemotherapy (fluorouracil [5-FU] and leucovorin) results in a response rate² of 25% to 30%. More recent regimens have increased the response rates^3,4 to 36% to 40%. Hepatic arterial (HA) infusion chemotherapy in previously untreated patients yields response rates^5-11 of 50% to 70%.

In the past, the administration of adjuvant chemotherapy to patients after hepatectomy did not improve survival.¹² With the development of effective systemic chemotherapy as an adjunct to treatment of primary colon cancer, there was increased interest in administration of adjuvant therapy after hepatectomy. A randomized trial using adjuvant HA infusion after liver resection suggested improved liver control, but the number of patients was small.¹¹ On the basis of these data, we designed a randomized trial to compare hepatic resection alone with hepatic resection followed by a regimen comprising both HA and systemic fluoropyrimidines. The principle end point was to detect a 100% improvement in median time to recurrence. The goal was to accrue 109 patients over 3.5 years, but accrual was slower than expected, partly because of the complexity of the treatment. Because the question was of high priority, the study was continued until its accrual goals were met.

	PATIENTS AND METHODS

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This study was a randomized trial conducted from August 1990 to January 1997 by the Eastern Cooperative Oncology Group (ECOG), with participation from the Southwest Oncology Group.

Eligibility Criteria
Patients eligible for this study had histologically documented colorectal cancer with one to three hepatic metastases demonstrated by computed tomography (CT) and no evidence of metastases at other sites. The only staging studies required were a chest x-ray and a CT scan of the abdomen. They were required to have a performance status of 0 to 2, according to ECOG criteria. Patients were required to have adequate marrow (WBC count > 2,000, platelets > 100,000, and hematocrit > 30%) and liver (bilirubin < 2 mg/dL) function drawn within 14 days of randomization. Patients were permitted to have been treated with previous systemic, but not intra-arterial, chemotherapy and could not have had hepatic irradiation. Those with a past history of any other malignancy, except for squamous cell carcinoma of the skin and cervical cancer in situ, were ineligible. Patients were required to provide written informed consent.

Randomization/Stratification
On determining eligibility, patients were randomized to receive postoperative HA chemotherapy (which required placement of an HA catheter) or not (no catheter placed). Because the participating institutions included several from Australia and because the study was conducted in two cooperative groups, preoperative randomization was used. As a result, a number of patients who were randomized were found not to meet the eligibility criteria at the time of surgery. These patients were considered off-study for purposes of treatment because many of them did not even have a hepatic resection and subsequently were managed at the discretion of the surgeon and medical oncologist. Patients were placed off-study intraoperatively for the following reasons: presence of more than three hepatic metastases, extrahepatic disease in any area (excluding local resectable colorectal recurrence), or absence of hepatic metastases; they were also placed off-study if the hepatic resection was not technically feasible. Patients were stratified at the time of randomization for prior systemic chemotherapy (yes/no) and synchronous versus metachronous (relative to colorectal primary tumor) appearance of the hepatic metastases.

Treatment
Patients with one to three hepatic metastases were randomized to resection alone or resection followed by continuous HA infusion of floxuridine (FUDR) and continuous systemic infusion of 5-FU. The surgical technique (wedge resection, segmentectomy, lobectomy, or trisegmentectomy) was at the discretion of the operating surgeon. The technique used as described in the operative report was reviewed by the principal investigator. Surgeons were told to remove the tumors with clear margins. Patients with metastasis involving more than 60% of the liver, those with tumor involving the porta hepatis or hepatic veins, or those with biopsy positive for carcinoma in the portal or celiac lymph nodes were taken off the study. For patients randomized to postoperative chemotherapy, the catheter of the subcutaneous device or of the implantable pump was placed into the gastroduodenal artery. Patients were required to have a hepatic angiogram before surgery to aid in pump placement. If there was a dual arterial supply, surgeons were advised to tie off one of the replicated arteries or to put in dual catheters. This was left up to the operating surgeon, with the caveat that the whole liver must be perfused. Catheter placement was checked intraoperatively by injection of fluorescein dye. Postoperatively, and before using the pump, verification of correct pump placement and of liver perfusion was performed by use of labeled technetium injected into the arterial catheter. Infusion of FUDR was initiated between 4 and 8 weeks after surgery. The schedule of administration was a 14-day infusion, followed by 14 days off (heparin/saline infusion through pump). The initial dose of FUDR was 0.1 mg/kg/d (0.05 mg/kg/d for patients who had had a lobectomy). If no toxicity greater than grade 2 resulted from this dose, the dose in the second and subsequent cycles was doubled, to a maximum of 0.2 mg/kg/d. The HA infusion was given for a maximum of four cycles. Systemic 5-FU was begun on the day after completion of the first HA infusion (day 15). The 5-FU dose was 200 mg/m²/d as a continuous 14-day infusion during the HA phase of treatment; after the fourth cycle of HA therapy, the intravenous treatment was continued for a further eight cycles (14 days on, 14 days off) at a dose of 300 mg/m²/d.

Dose Modifications
Patients were observed on treatment with hematologic and biochemical testing at regular intervals. The FUDR and 5-FU infusions were interrupted for any of the following: WBC count less than 3,000/mm³, platelet count less than 90,000/mm³, or hematocrit less than 25%; diarrhea more than six stools per day or the appearance of stomatitis with ulcers; the appearance of any new cerebellar dysfunction; a maculopapular rash; alkaline phosphatase or AST more than three times the upper limits of normal; and serum bilirubin more than two times the upper limits of normal, blood urea nitrogen more than 40 mg/dL, or creatinine more than 2.1 mg/dL. Patients with persistently increased alkaline phosphatase were evaluated for biliary sclerosis. If strictures were demonstrated on transhepatic cholangiography or on endoscopic retrograde cholangiopancreatography, no further FUDR was administered. The FUDR infusion was permanently discontinued in the event of two episodes of toxicity.

Measurement of Effect
Patients were observed during and after therapy with history and physical examination, chest x-rays, CT scanning of the abdomen and pelvis, and plasma carcinoembryonic antigen (CEA) every 3 months for the first 3 years. CT scan was performed yearly after that, all other tests continued every 3 months. Recurrence was diagnosed by the appearance of new lesions on a scan. A CEA more than 10 ng/dL prompted a repeat CT scan. Biopsy proof of recurrence was encouraged but not required.

Statistical Methods
Fisher’s exact test was used to compare groups with respect to categoric end points (eg, recurrence).¹³ Statistical significance was set at a level of .05, and the P values reported from Fisher’s exact test are two tailed.

Survival distributions for survival time, time to recurrence, time to liver recurrence, and disease-free survival were estimated with the Kaplan-Meier method and compared by use of the log-rank test.^14,15 Statistical significance was set at a level of .05, and all log-rank P values reported are two tailed. The 4-year survival rates (along with the corresponding SEs) were also estimated from the Kaplan-Meier distributions. A comparison of the 4-year survival rates by treatment was performed by use of a one-sided normal test. A logistic regression model was used to estimate the joint effect of prognostic factors on recurrence rates (overall and liver specific). Stepwise selection was used to determine more parsimonious models. Statistical significance was set at a significance level of .10 for multivariate analysis, and all P values reported are two tailed.¹⁶ Possible factors for inclusion in the model consisted of the stratification factors (prior chemotherapy and metastases synchronous with the primary tumor) and selected baseline patient characteristics (age group, sex, race, ECOG performance status, prior surgery, and prior radiotherapy).

	RESULTS

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One hundred nine patients were randomized preoperatively to receive postoperative chemotherapy (53 patients) or not (56 patients; control). The median follow-up time was 51 months. Because of the timing of randomization, a number of patients were found not to meet the eligibility criteria at the time of surgery. These patients were considered off-study and were treated at the discretion of the surgeon. Of the 56 patients in the control arm, 11 were taken off the study; four had more than three metastases, three had extrahepatic disease, two had unresectable disease, and two had no liver metastases. Of the 53 patients in the chemotherapy arm, 18 were taken off the study, four had more than three metastases, nine had extrahepatic disease, four had unresectable disease, and one had no liver metastases. There was no significant difference between the arms regarding the off-study criteria. There were two operative deaths (one from each group), and these were excluded from the analysis. Four patients in the chemotherapy arm did not receive a pump (two had no pump placed at surgery by the surgeon’s decision, and two refused pump placement). Comparisons were made between the intent-to-treat groups (whole population) and between the subjects who received treatment and were considered assessable (75 patients: 45 in the control group and 30 in the chemotherapy group).

The demographic characteristics of the patients entered onto this trial are listed in Table 1. Patients in general had good performance status, and the arms were well balanced for prior chemotherapy and for synchronous versus metachronous appearance of liver metastases (Table 2). The extent of hepatic involvement was similar in each arm (Table 3).

Toxicity
There were two postoperative deaths from operative complications—one on each arm. There was no effect of the pump or port placement on the incidence of operative complications (Table 5). The toxicities of the chemotherapy are listed in Table 6. Nine patients had grade 3 increases of liver enzymes (bilirubin 1.5 to 3.0 times normal levels; transaminases and alkaline phosphatase, five to 20 times normal levels). Two patients developed biliary sclerosis from intrahepatic therapy that required bile duct stenting. In the remaining seven patients, liver enzyme levels returned to normal on decreasing the dose or discontinuing the HA infusion. There were no fatal adverse effects of chemotherapy.

View larger version (12K): [in this window] [in a new window]   Fig 1. Time to recurrence (assessable patients; n =75).

View larger version (12K): [in this window] [in a new window]   Fig 2. Time to liver recurrence (assessable patients; n = 75).

View larger version (12K): [in this window] [in a new window]   Fig 3. Overall survival (assessable patients; n = 75).

View larger version (12K): [in this window] [in a new window]   Fig 4. Overall survival (all patients; n = 109).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Surgical resection of colorectal hepatic metastases is an important means of curing patients with advanced disease confined to the liver. If the disease is limited to three lesions and all tumor is surgically removed, the 5-year survival in modern series^17,18 is 25% to 35%. Only rare patients with resectable colorectal hepatic metastases will survive 5 years if their cancer is not removed.¹⁷ Fong et al¹⁹ reported a series of 1,001 consecutive patients submitted to liver resection for metastatic colorectal cancer from 1985 to 1998. Surgical mortality was 2.8%. The 5-year survival was 37%, and the 10-year survival was 22%.

Nordlinger et al¹⁸ reported on 1,568 patients from multiple institutions throughout France who underwent hepatic resections with 2- and 5-year survivals of 64% and 28%. Significant prognostic variables included size of the largest metastasis, CEA level, stage of the primary tumor, disease-free interval, number of metastases, and resection margin.

Although improved staging and advances in surgical technique have increased the survivorship and reduced the mortality of liver resections, the 5-year survival remains less than 35%. At least 60% of patients whose disease recurs will experience recurrence in the liver, either alone or as a component of widespread disease.^19,20 The adjuvant administration of systemic chemotherapy after hepatectomy is exceedingly unlikely to confer a benefit greater than that experienced in the adjuvant therapy of primary colorectal cancer. Hence, the survival is unlikely to be increased by more than 10%.

The response of unresectable liver metastases to HA chemotherapy ranges from 50% to 70%. A meta-analysis of HA chemotherapy confirmed that HA FUDR dramatically increased response rates compared with systemic therapy and resulted in a statistically significant improvement in survival.²¹

In 1988, ECOG initiated this prospective study, and the Southwest Oncology Group subsequently joined the effort. A regimen of chemotherapy that combined both local treatment to the liver and systemic therapy (because more than 90% of FUDR is extracted by the liver) was chosen. This study was powered to show a difference in the median recurrence-free survival and liver recurrence-free survival. It was not large enough to look at differences in overall survival.

Because of prerandomization, a number of patients were found at surgery to be ineligible for inclusion in the study. Therefore, the numbers compared were 45 in the control arm and 30 in the treatment arm. The patients were well matched for disease extent and timing of onset of liver metastases. Patients in the chemotherapy group had significant improvement in time to recurrence and in recurrence-free 4-year survival. Because the study was not powered to detect a difference in overall survival, the number of patients surviving for 5 years is small, and because in the control arm if patients recurred, they might have re-resection and intrahepatic treatment, there was no demonstrated significant difference in overall survival.

These data are consistent with a contemporaneous study at the Memorial Sloan-Kettering Cancer Center for patients with resected colorectal hepatic metastases.²² After liver resection, patients received either systemic chemotherapy (5-FU and leucovorin only) or systemic therapy plus HA FUDR and dexamethasone. The 2-year survival was 72% in the systemic chemotherapy arm and 86% in the HA infusion systemic chemotherapy arm (P = .03). The hepatic disease-free survival was 60% and 90%, respectively (P = .001).

A randomized trial from Germany investigated the use of HA treatment after surgery compared with a no-treatment control. This trial did not use the traditional treatment regimen of continuous-infusion FUDR for 14 days, but rather they used 5-FU (1,000 mg/m²/d for 5 days as a continuous infusion) and leucovorin (200 mg/m² given as a bolus for 5 days). They were both given every 28 days. This study indicated no difference in relapse rate in the liver, in contrast to this study and the study from the Memorial Sloan-Kettering Cancer Center, both of which demonstrated significant decreases in liver recurrence with the HA infusion of FUDR. The use of 5-FU instead of FUDR and the decrease of the infusion period from 14 to 5 days must be the explanation for this difference.²³

These trials demonstrate that intrahepatic therapy with FUDR significantly reduces the risk of hepatic recurrence after hepatic resection. This defines the current best regional adjuvant treatment for patients who have resection of one to three liver metastases. The use of systemic therapy seems justified by previous experience, although its contribution cannot be determined from the design of either of the two recent trials. Further follow-up of these groups of patients and accrual of larger numbers of identically treated patients are needed to determine the effect of this intervention on long-term disease-free survival and possible cure. This study is not large enough to define determinants of outcome that might improve the ability to tailor therapy. Accrual of larger numbers of patients with associated biologic studies should permit individualization of these strategies in the future.

Recently, combinations of irinotecan and 5-FU have produced response rates higher than 5-FU alone, and in one study they have produced prolonged survival.³ Similarly, combinations of 5-FU and oxaliplatin have activity greater than 5-FU alone.⁴ Collaborative trials in North America and Europe are integrating these new agents into clinical trials of HA therapy and new systemic agents after hepatic resection.

	ACKNOWLEDGMENTS

 
Coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service grant nos. CA35279, CA23318, CA17145, CA66636, and CA21115 from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services.

	NOTES

 
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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Submitted July 12, 2001; accepted November 21, 2001.

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