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Originally published as JCO Early Release 10.1200/JCO.2005.03.8166 on February 27 2006 © 2006 American Society of Clinical Oncology. Hepatic Arterial Infusion Versus Systemic Therapy for Hepatic Metastases From Colorectal Cancer: A Randomized Trial of Efficacy, Quality of Life, and Molecular Markers (CALGB 9481)
From the Memorial Sloan-Kettering Cancer Center, New York, NY; Cancer and Leukemia Group B Statistical Center, Durham, NC; University of Southern California, Los Angeles, Los Angeles; University of California at San Francisco, San Francisco, CA; Wake Forest University School of Medicine, Winston-Salem, NC; Dana-Farber Cancer Institute, Boston, MA; and Fox Chase Cancer Center, Philadelphia, PA Address reprint requests to Nancy E. Kemeny, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; e-mail: kemenyn{at}mskcc.org
PURPOSE: Hepatic metastases derive most of their blood supply from the hepatic artery; therefore, for patients with hepatic metastases from colorectal cancer, hepatic arterial infusion (HAI) of chemotherapy may improve outcome. METHODS: In a multi-institutional trial, 135 patients were randomly assigned to receive HAI versus systemic bolus fluorouracil and leucovorin. The primary end point was survival; secondary end points were response, recurrence, toxicity, quality of life, cost, and the influence of molecular markers.
RESULTS: Overall survival was significantly longer for HAI versus systemic treatment (median, 24.4 v 20 months; P = .0034), as were response rates (47% and 24%; P = .012) and time to hepatic progression (THP; 9.8 v 7.3 months; P = .034). Time to extrahepatic progression (7.7 v 14.8 months; P = .029) was significantly shorter in the HAI group. Quality-of-life measurements showed improved physical functioning in the HAI group at the 3- and 6-month follow-up assessments. Toxicity included grade CONCLUSION: HAI therapy increased overall survival, response rate, THP, and was associated with better physical functioning compared with systemic therapy. Additional studies need to address the overall benefit and cost of new chemotherapy agents versus HAI alone or the combination of HAI with new agents.
Metastatic spread to the liver occurs in approximately 60% of the 145,000 patients in the United States who develop metastatic colorectal cancer each year.1 Liver involvement is a major source of morbidity, and eventually leads to death in the vast majority of such individuals. Until the recent introduction of such new chemotherapeutic agents as irinotecan2 and oxaliplatin,3 intravenous fluorouracil (FU) and leucovorin (LV)4 was the standard treatment for metastatic, unresectable colorectal cancer. The median survival for patients treated with FU and LV was in the range of 12 months. Considerable interest has focused on the use of hepatic arterial infusion (HAI), given that hepatic metastases derive most of their blood supply from the hepatic artery, whereas the normal liver parenchyma derives its blood supply from portal vein circulation.5 HAI has been compared with systemic chemotherapy in several randomized studies. These clinical trials6-12 have demonstrated that HAI treatment results in a superior response rate (42% to 62%) when compared with systemic FU (0% to 21%). Such studies have been criticized because they have included relatively small numbers of patients, and because patients who experienced disease progression after receiving systemic therapy were allowed to cross over to HAI therapy, which confounded any opportunity to assess impact on survival. The majority of these efforts have emerged from single institutions, and in some the use of ports rather than pumps may have limited the number of patients who could receive HAI treatment.12,13 The first randomized trials used floxuridine (FUDR) as the HAI form of chemotherapy, whereas more recent studies have combined FUDR with LV or dexamethasone (Dex).14,15 Because of the uncertainty in drawing any definitive interpretation from these studies, a multicenter, cooperative group trial was designed to compare HAI treatment with FUDR, LV, and Dex versus systemic FU and LV. In this design, no cross-over was allowed, so the trial addresses the fundamental question of whether HAI therapy is more effective than systemic therapy for the treatment of liver metastases from colorectal cancer. The primary end point of the study was survival; secondary end points were tumor response, toxicity, quality of life (QoL), and cost effectiveness. Liver biopsies from the HAI patients were analyzed for thymidylate synthase (TS)16,17 and p5318 status to evaluate the utility of these molecular markers in predicting outcomes. We report here on all of the study end points except cost effectiveness, which will be reported separately.
All patients were required to have histologically confirmed colorectal carcinoma with unresectable liver metastases occupying less than 70% of the liver parenchyma and no radiologic evidence of extrahepatic disease. Patients who had previously received chemotherapy were excluded, except for prior adjuvant therapy with FU/LV, completed 12 months before protocol therapy. Patients who had received radiation to the liver, or had portal vein occlusion or ascites were also excluded. Patients could not have a previous or concurrent malignancy and had to have total bilirubin  2x upper limit of normal, with normal hematologic and renal function. A biopsy was required before registration to document liver involvement with metastatic disease unless the patient met one of the following criteria: carcinoembryonic antigen more than 30 ng/mL or tumor determined by computed tomography or magnetic resonance imaging scan to involve more than 50% of the liver. For patients in the HAI group, two biopsies were performed during surgery and half of each sample of normal liver and tumor tissue was frozen in liquid nitrogen. Each patient was asked to complete health-related quality-of-life instruments before treatment and every 3 months during participation on the study until month 18. The following instruments were used: Rand 36-Item Health Status Profile19; the Memorial Symptom Assessment Scale20; the Medical Outcomes Study Social Support Questionnaire21; and the Medical Outcomes Study Sexual Functioning Scale.22
Drug Doses and Schedule A fixed dose of heparin 30,000 U was added to saline at each filling. A 14-day infusion of drug was alternated with 14 days of heparinized saline. Treatment was repeated every 28 days if hepatic enzymes were not elevated. Dose adjustment by hepatic enzyme elevation has been previously described.24 Systemic chemotherapy consisted of intravenous LV 20 mg/m2 followed immediately by FU 425 mg/m2, both given as intravenous infusion for 5 consecutive days every 4 weeks. If no GI or hematologic toxicity occurred during cycle 1, FU was increased by 15% at cycle 2.
Molecular Marker Evaluation p53 protein expression was assessed by immunohistochemistry using paraffin sections with DO7 antibody. Patients with greater than 10% of positive nuclei with moderate or strong staining were considered positive, whereas all others were negative.
Statistical Methods
Patient disease characteristics and baseline laboratory values were compared using the Overall survival (OS), time to progression (TTP), time to hepatic progression (THP), and time to extrahepatic progression (TEP) were calculated from the time of random assignment using the Kaplan-Meier method and compared using the log-rank test.30,31 TTP was defined as documented progression of disease at any site or death as a result of any cause, THP was defined as documented progression of disease in the liver, and TEP was defined as progression outside the liver. These were intent-to-treat analyses with the inclusion of all patients registered. Both the log-rank test and the Cox proportional hazards model30,31 were used to assess the association of OS, TTP, THP, and TEP, with the clinical and histologic variables.
In the evaluation of molecular markers, p53 expression was measured as a dichotomous variable (negative or positive), TS expression was measured as a continuous variable, and the logarithmic transformation was used. TS level was also categorized a priori as less than 4.0 and The study was designed with four primary QoL end points, which were measured by four subscales of the Rand-36 Item Health Status Profile: Physical Functioning, Role Functioning-Emotional, Social Functioning, and General Health Perceptions. We hypothesized that patients in the HAI arm would have better physical and social functioning, fewer role limitations due to their emotional health, and better health perceptions than patients in the systemic treatment arm. In an effort to account for the effect of patient attrition and missing data, a pattern-mixture model was used to examine treatment differences in QoL over time.32,33 Patient strata or dropout patterns were defined by the time of patient dropout from the QoL assessments. Patients were classified into different stratum: I or early dropouts, with the last assessment at 3, 6, or 9 months after random assignment (more indicative of patients who were more ill and/or who died early in the follow-up period); II or late dropouts, with the last assessment at 12 or 15 months; and III or completers, with the last assessment at 18 months. A stratified repeated-measures model, which included a term describing the interaction between treatment, time and stratum group, was fit to the data for each of the four primary outcomes. When the interaction between treatment, time and strata was statistically significant, meaning that the impact of treatment varied by the time of patient dropout (stratum 1 to 3), a separate repeated-measures model was fit to the data in each stratum. When the interaction between treatment, time and stratum was not statistically significant in the stratified repeated-measures analysis, strata were pooled and a repeated-measures analysis was conducted. The significance level of .0125, which is adjusted for multiple comparisons using a Bonferroni adjustment, was used in the comparisons of treatment x time interactions of the four outcome variables. Patient registration and data collection were managed by the Cancer and Leukemia Group B Statistical Center. Members of the Data Audit Committee visited all participating institutions at least once every 3 years to review source documents and verify compliance with federal regulations. On-site review of medical records was performed in 18% of patients on this study. Another outside reviewer of all patient data found seven patients (four patients in the HAI group and three in the systemic treatment group) who were initially determined to be eligible but were determined subsequently to have had evidence of metastatic disease outside the liver at trial entry. (Initial computed tomography scans were read as no extrahepatic disease but follow-up scans reported growth.) These patients were included in the analysis. Each participant signed an informed consent approved by the respective institutional review boards.
Patient Characteristics Between January 15, 1996, and December 29, 2000, 135 patients were randomly assigned: 68 to HAI and 67 to systemic therapy (Table 1). There were no statistical differences among baseline characteristics except for age (P = .04; median, 57 v 61 years for HAI and systemic treatment groups) and serum albumin (P = .03; median, 4.1 v 3.9 g/mL). Only 3% of patients had received adjuvant chemotherapy previously; 79% had synchronous metastatic disease. Seventy-six percent of the HAI treatment arm and 38% of the systemic arm underwent primary tumor resection after random assignment. All surgical procedures took place 3 to 4 weeks before treatment started.
Eighteen of the 135 randomly assigned patients never received protocol treatment (nine per treatment group). In the HAI group, three had pump catheter problems, two withdrew consent, two had extrahepatic disease, one underwent resection, and one was found to have a neuroendocrine tumor. In the systemic treatment group, five withdrew consent, two had rapid disease progression, one had no data submitted, and one suffered a stroke before treatment start. Nine sites enrolled patients. The median number of cycles received were three and four for the HAI and systemic treatment arms, respectively (two-sided P = .13).
Survival
A multivariate analysis based on the proportional hazards model was used to determine the impact of variables associated with survival on the significance of treatment arm (HAI v systemic treatment). Because postprogression therapy was significantly associated with survival, this variable was considered in these models. Other variables considered were percent liver involvement; number of liver lesions; WBC; lactate dehydrogenase (LDH), alkaline phosphatase, and albumin levels; performance status, location of primary tumor, and weight loss within 3 months (Table 2). Strong associations were apparent between percent liver involvement, and certain laboratory values (WBC, alkaline phosphatase, albumin, and LDH). Because of these associations, each of the variables significantly related to outcome in the univariate model was considered in a two-factor model with treatment arm.
Overall, treatment with HAI remains significantly related to survival when each of these variables is considered separately with treatment arm. Specifically, treatment with HAI remains significantly associated with survival (P = .005) when postprogression therapy is considered as a covariate. A multivariate analysis that adjusted for stratification factors (percent liver involvement and synchronous disease) continued to show an advantage for the HAI cohort (log-rank P = .01). There was an interaction between sex and treatment, with the median survival of 29.4 months for women receiving HAI and 20.1 months for those receiving systemic therapy; for men, median survival was 22.0 and 18.3 months, respectively (interaction P = .016). There was not an adequate number of nonwhites (n = 17) to evaluate treatment effect by race.
Response
Toxicity
QoL Assessment Analyses of data at 3 and 6 months, while most of the patients were receiving active protocol treatment, demonstrated that the physical functioning of the HAI patients was better than that of those receiving systemic therapy at both 3 (P = .038) and 6 months (P = .024). However, no differences between treatments were found in social functioning, role functioning-emotional, or general health perceptions. In comparing QoL differences across the remaining follow-up period, treatment arm differences among our four QoL outcomes were not evident, except for physical functioning at the 12-month assessment point. For physical functioning, the relationship between treatment and time varied significantly as a function of the time of dropout (Fig 4). Among late dropouts (strata 2), treatment differences were not evident until 12 months, when the level of physical functioning was much higher for those in the HAI arm (interaction P = .001).
Molecular Markers In HAI patients, biopsies from tumor in the liver were evaluated for TS (n = 40) and p53 (n = 42). For TS less than 4.0 and  4.0, median OS was 24.8 and 14.2 months, respectively (P = .17). When further stratified by sex, men with TS levels 4.0 appeared to have worse OS (stratified log-rank test, P = .014). Similarly, median THP was 10 and 5.3 months (P = .11) and median TEP was 7.8 and 4.2 months (P = .43) for tumor TS less than 4 and 4, respectively. Patients with enhanced immunohistochemical expression of p53 (positive) in tumor tissue had a median OS of 25.4 v 18.4 months for low expression p53 (negative; P = .7). THP was 9.7 v 6.2 months (P = .37), and TEP was 9.8 v 5.2 months (P = .03) when comparing p53-positive with p53-negative status, respectively. Tumor levels of TS and p53 were not associated with response.
When the influence of tumor markers was combined, patients with low expression of p53 and elevated TS (
A comparison of HAI versus systemic therapy in patients with unresectable hepatic metastases from colorectal cancer indicates HAI therapy prolonged the median survival (24.4 v 20 months), and was associated with a greater likelihood of objective tumor responses in the liver (47% v 24%), enhanced time to hepatic progression (9.8 v 7.3 months), and improved physical functioning (QoL measurements). Patients reported better physical functioning during active treatment at 3 and 6 months, and also at 12 months among patients who completed 12 to 15 months of study follow-up. However, the regional approach was inferior to the systemic therapy in preventing extrahepatic metastatic progression (TEP, 7.7 v 14.8 months). These data appear to indicate that control of hepatic tumors can extend survival. The likelihood of longer survival was greater in patients with less significant elevations of serum LDH, alkaline phosphatase, and WBC counts.34 Although based on small numbers, liver biopsies in the HAI patients demonstrated that the patients with high TS and low p53 had the worst survival. Men with higher TS levels also exhibited worse survival. High levels of TS are usually associated with poorer survival,35,36 but to our knowledge it has not been reported previously and it is not known why men with higher TS levels might have a worse outcome. Generally, low levels of p53 predict better survival, though there are conflicting reports.37,38 A criticism of this study is that the systemic chemotherapy used was bolus FU/LV. New randomized studies have demonstrated that the addition of irinotecan,2 oxaliplatin,3 or bevacizumab39 added to FU/LV will increase survival compared with FU/LV alone. This Cancer and Leukemia Group B study was initiated in 1996, at which time FU/LV was the standard of treatment. The median survival of the systemic treatment group was 20 months, which is comparable to any of the new drug combinations perhaps because patients whose tumor progressed while they were receiving FU/LV could receive these new agents at the time of progression. Studies now demonstrate that access to all three drugs (FU, irinotecan, and oxaliplatin) increases survival.40 A new study in the United Kingdom41 suggests that patients receiving FU/LV first, with administration of the new drugs after tumor progression, will have similar survival to those who receive the new drug combinations up front. In this study, the survival advantage conferred by HAI over systemic chemotherapy suggests that HAI may represent a superior clinical treatment modality because both treatment groups had access to the new drugs. The significant difference in survival was shown in the multivariate analysis to be attributable to treatment arm, and remained significant even when postprogression therapy was considered in the model. This study emphasizes the importance of the method of drug delivery and the superiority of HAI over systemic therapy with the same drugs for patients with liver-only metastases.
TEP was decreased in the HAI group. One could postulate that the use of concurrent systemic therapy with the new agents in the HAI group would have improved results. Studies of HAI plus systemic irinotecan and oxaliplatin, even in previously treated patients, has produced response rates of Both the regional and the systemic treatments were reasonably well tolerated. Perhaps because of the addition of dexamethasone14 to the HAI program, only four patients experienced persistent jaundice. Patients allocated to receive the systemic FU/LV demonstrated a higher likelihood of grade 3 neutropenia, diarrhea, and stomatitis; however, the FU/LV treatment regimen (once daily for 5 days) used in this clinical trial has been shown subsequently to be more toxic than infusional FU treatments. One might propose that this was an unusual group of patients with a favorable prognosis, but we have clinical factors to suggest this was not the case. Historically, the development of liver metastases predicts a poor prognosis,44 with a median survival of 8 months, whereas patients with lung metastases have a median survival of 12 months.45 Moreover, 79% of patients had synchronous disease and 70% had extensive disease, with more than 30% of the liver involved with tumor (two other indicators of poor prognosis46,47). This study provides evidence that hepatic arterial infusional therapy provides superior survival with better physical functioning when compared with the same chemotherapeutic compound administered systemically (24.4 v 20 months; P = .0034). Whether this regional strategy can be enhanced further through the addition of concurrent systemic treatment will be the focus of future investigations.
The following institutions participated in this study: CALGB Statistical Center, Durham, NC—Stephen George, PhD, supported by CA33601; Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH—Marc S. Ernstoff, MD, supported by CA04326; Massachusetts General Hospital, Boston, MA—Michael L. Grossbard, MD, supported by CA12449; Memorial Sloan-Kettering Cancer Center, New York, NY—Clifford Hudis, MD, supported by CA77651; Medical University of South Carolina, Charleston, SC—Mark Green, MD, supported by CA03927; SUNY Upstate Medical University, Syracuse, NY—Stephen L. Graziano, MD, supported by CA21060; University of California at San Francisco, San Francisco, CA—Alan P. Venook, MD, supported by CA60138; University of Minnesota, Minneapolis, MN—Bruce A. Peterson, MD, supported by CA16450; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO—Michael C. Perry, MD, supported by CA12046; Weill Medical College of Cornell University, New York, NY—Scott Wadler, MD, supported by CA07968.
Although all authors completed the disclosure declaration, the following authors or their immediate famly members indicate a financial interrest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in information for Contributors.
Dollar Amonut Codes (A) < $10,000 (B) $10,000-$99,900 (C)
Supported in part by Grant No. CA31946 from the National Cancer Institute to the Cancer and Leukemia Group B (CALGB; Richard L. Schilsky, MD, Chairman) and Grant No. CA23318 to the Eastern Cooperative Oncology Group. The following institutions were supported by Grant Nos. listed in parentheses: Memorial Sloan-Kettering Cancer Center (CA77651); CALBG Statistical Center (CA33601); University of Southern California and University of California at San Francisco (CA60138); Wake Forest University School of Medicine (CA03927); Dana-Farber Cancer Institute (CA32291); and Fox Chase Cancer Center (CA27525). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 statistic and the nonparametric Van der Waerden
