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© 2000 American Society for Clinical Oncology Randomized, Multicenter Trial of Fluorouracil Plus Leucovorin Administered Either Via Hepatic Arterial or Intravenous Infusion Versus Fluorodeoxyuridine Administered Via Hepatic Arterial Infusion in Patients With Nonresectable Liver Metastases From Colorectal CarcinomaFrom the Department of General and Vascular Surgery, Johann Wolfgang Goethe-Universität, Frankfurt am Main, and Institute for Medical Biometry and Epidemiology, Philipps-Universität, Marburg, Germany. Address reprint requests to Prof Dr Matthias Lorenz, Department of General and Vascular Surgery, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; email m.lorenz{at}em.uni-frankfurt.de
PURPOSE: To assess the efficacy and tolerability of three treatments for patients with documented adenocarcinoma of the colon and/or rectum who have undergone complete resection of primary tumor and have nonresectable liver metastases that do not exceed 75% of the liver volume. PATIENTS AND METHODS: A total of 168 patients at 25 treatment centers were enrolled onto this prospective, multicenter, randomized study. The three treatment arms were as follows: (1) fluorouracil (5-FU)/leucovorin (LV) administered via hepatic arterial infusion (HAI), (2) 5-FU/LV administered via intravenous (IV) infusion, and (3) fluorodeoxyuridine (FUDR) administered via HAI. RESULTS: Median times to disease progression for the three treatment arms were as follows: 9.2 months for patients treated with HAI 5-FU/LV, 6.6 months for IV 5-FU/LV, and 5.9 months for HAI FUDR. Median survival times for patients treated with HAI 5-FU/LV, IV 5-FU/LV, and HAI FUDR were 18.7 months, 17.6 months, and 12.7 months, respectively. There was a nearly two-fold increase in time to progression in addition to a survival benefit among patients with an intrahepatic tumor burden of less than 25% who were treated with HAI 5-FU/LV. The most common adverse events were stomatitis, nausea and vomiting, skin irritation, diarrhea, and elevated serum levels of liver enzymes. Some patients exhibited severe reactions, including biliary sclerosis and chemical hepatitis. CONCLUSION: Although the use of HAI 5-FU/LV as a means of treating liver metastases after resection of colorectal carcinoma warrants further investigation, it cannot be recommended as a routine therapeutic measure at this time.
COLORECTAL CANCER is one of the most common malignancies of both men and women in Europe and North America.1,2 In Germany, approximately 40,000 to 47,000 cases are diagnosed each year.3 As many as 50% of patients with colorectal carcinoma present with synchronous or will develop metachronous liver metastases.4-6 In approximately one half of these patients, metastatic disease is confined to the liver7,8; however, curative resection of liver metastases is possible in less than 25%.8,9 In patients with colorectal carcinoma and nonresectable isolated liver metastases, hepatic tumor burden, performance status, and site of the primary tumor are regarded as important prognostic factors.10-13 Because of the dual blood supply to the liver and the fact that liver metastases larger than 0.5 cm derive most of their blood supply from the hepatic artery, hepatic arterial infusion (HAI) of cytotoxic agents has been used since 1959 in an effort to maximize local concentration and improve response.14,15 The fluorouracil (5-FU) analog fluorodeoxyuridine (FUDR) is used for the intrahepatic treatment of liver metastases because of its favorable pharmacokinetic properties, nearly complete intrahepatic removal, and minimal systemic toxicity.16,17 An implanted FUDR infusion pump has facilitated treatment on an outpatient basis and has resulted in improved quality of life.18 The response rates with HAI FUDR in patients with metastatic colorectal carcinoma vary from 30% to 88% in phase II trials.19-23 These encouraging results led to the investigation of HAI FUDR (0.2 to 0.3 mg/m2/d for 2 weeks every 4 weeks) in randomized trials.24-30 In five of these seven trials, HAI FUDR was compared with FUDR administered systemically for 14 days every 28 days and 5-FU administered systemically for 5 days every 28 days. In the other two trials, treatment in the control group depended on physician and patient choices of either symptomatic treatment on an as-needed basis or conventional systemic 5-FU therapy. These studies have been reevaluated in two recently published meta-analyses.31,32 Both of these meta-analyses showed a significantly increased response rate and significantly longer survival time in patients treated with intrahepatic therapy than in patients in the control group. Unfortunately, some patients treated with HAI FUDR may develop irreversible local toxicity (primary biliary sclerosis).33,34 Five European studies of HAI 5-FU plus leucovorin (LV; folinic acid) demonstrated response rates that were similar to or better than those obtained with HAI FUDR, without associated major hepatic toxicity.35-39 The relative efficacy and safety of HAI FUDR compared with more recent chemotherapeutic regimens remain to be determined. The present study was undertaken to compare the efficacy and tolerability of HAI FUDR (the gold standard) with two newer treatment modalities: 5-FU plus LV administered via HAI and 5-FU plus LV administered via intravenous (IV) infusion. The dose of 5-FU used in the study was the greatest dose that was considered safe for continuous HAI or IV infusion. The primary efficacy variable was time to disease progression or progression-free survival after randomization. Secondary efficacy variables were survival rate, effect of treatment on tumor burden, and quality of life. In the design of the trial, intrahepatic tumor burden and site of the primary tumor were regarded as prognostic factors for stratification. A stratified confirmatory analysis and an additional exploratory analysis in strata were planned.
Patient Selection Recruitment of study patients took place between April 1991 and June 1995. Patients were eligible if they had histologic documentation of adenocarcinoma of the colon or rectum with complete resection of primary tumor and nonresectable liver metastases that did not exceed 75% of liver volume. Patients were required to be at least 18 years of age with a Karnofsky performance status of at least 70%. Exclusion criteria included a serum total bilirubin level greater than 4 mg/dL; a serum alkaline phosphatase level greater than 1,200 IU/L; a serum creatinine level greater than 2.5 mg/dL; presence of resectable liver metastases, extrahepatic metastases, or cirrhosis of the liver; signs of portal vein obstruction; and a history of prior chemotherapy. All patients who were deemed eligible for study entry underwent an initial evaluation that included the following: history and physical examination; computed tomography (CT) and ultrasonography of the abdomen; chest radiograph; complete blood count with differential; plasma cholinesterase; chemistry profile that included AST, ALT, serum gamma-glutamyl transferase (SGGT), lactate dehydrogenase (LDH), and alkaline phosphatase; and serum assays for the tumor markers carcinoembryonic antigen (CEA) and CA 19-9. This study was conducted in accordance with the standards of the updated declaration of Helsinki. It was approved by the protocol review board of the German Cancer Society and by the human investigations/ethics committees at all participating institutions. Before study entry, all patients gave informed written consent. Patients who were randomized to receive HAI of either 5-FU/LV or FUDR underwent angiography to define the hepatic arterial supply and to exclude portal vein occlusion. Subsequently, laparotomy was performed to assess the extent of liver involvement and to rule out the presence of extrahepatic metastases. During the laparotomy, an intra-arterial catheter was implanted using the method described by Watkins et al40 and Curley et al41 and connected to a subcutaneous port overlying the right lower ribs. Total liver perfusion was controlled with the injection of fluorescein dye (5 mL) visualized by a Wood’s lamp. Intrahepatic infusion could be accomplished via either the implanted port and an external pump or an implanted pump. If intra-arterial catheter implantation was impossible because of technical difficulties, previously unrecognized arterial abnormalities, or locoregional disease, then systemic 5-FU/LV therapy via an IV port was used. After laparotomy, perfusion was controlled with technetium-99–labelled macro-aggregated albumin. Patients who were randomized to receive IV 5-FU/LV underwent placement of a subcutaneous IV port under local anesthesia. Subsequently, 5-FU/LV was administered on an outpatient basis. In all patients, treatment was started on postoperative day 14. Patients who were randomized to receive 5-FU/LV either via HAI or IV infusion received a continuous infusion of 5-FU 1,000 mg/m2/d and a 15-minute infusion of LV 200 mg/m2/d for 5 days every 28 days. Due to a high rate of intolerable stomatitis in seven patients who were treated with IV 5-FU/LV, the protocol was amended in December 1993 to reduce the dose of 5-FU to 800 mg/m2/d. For patients who were treated with FUDR administered via HAI, the dose of FUDR was reduced after three courses from 0.2 to 0.15 mg/kg/d for 14 days every 28 days. Dose modifications were made in accordance with the World Health Organization (WHO) toxicity criteria.42 If grade 3 or 4 systemic toxicity occurred in any patient, chemotherapy was halted until complete disappearance of symptoms and then resumed at a dose level of 80% of the original dose. If chemical hepatitis, peptic ulcer disease, or biliary sclerosis occurred, then a dose reduction of 50% was required. Before reinitiating chemotherapy, a symptom-free interval of at least 2 weeks was required in the case of chemical hepatitis, 4 weeks for peptic ulcer disease, and 6 weeks for biliary sclerosis. Treatment was continued until either complete response was attained or generalized progression of disease (intrahepatic or extrahepatic) was noted. If a complete response was attained, then two cycles of maintenance therapy were administered. The initial therapy was continued in cases of successful treatment in the liver and the development of minimal new extrahepatic lesions. In cases of disease progression or technical complications, further treatment was at the investigator’s discretion.
Response Evaluation
Statistical Analysis
Patient characteristics were compared using the Fisher’s exact test and the Wilcoxon-Mann-Whitney test. Analysis of time to progression and survival was performed using the Kaplan-Meier method. Mantel-Cox log-rank tests were used to compare the resulting curves of the treatment groups on an intention-to-treat basis, and 95% confidence intervals (CIs) for the hazard ratios were calculated. The statistical model implemented a 2 x 2 matrix to adjust the data for known prognostic factors as follows: first, patients were selected according to the amount of intrahepatic tumor involvement (< 25% v Applying the Bonferroni-Holm procedure to adjust the global type I error level of 5% for three two-sided comparisons (closed-test principle), using the method described by Schoenfeld and Richter,43 and allowing for no more than 10% of patients to withdraw from the study due to protocol deviation, a minimum of 168 patients were required to detect the postulated difference in a fixed comparison with a statistical power of 80%. Adjusting for an interim analysis and correcting for overly optimistic assumptions, the target recruitment was 195 patients. The interim analysis was planned according to Fleming’s stopping rule44 and was performed in 1993 on the local type I error level of 0.5% without stopping the trial. The remaining local type I error level for this final analysis was 4.8%. All patients had to be observed until the end of the trial (18 months after randomization of the last recruited patient) or death. Secondary efficacy variables were survival rate and effect of treatment on tumor burden, analyzed with Fisher’s exact test. Efficacy-evaluable patients were those who were randomized to a treatment arm (as-randomized population). Safety-evaluable patients were those who received one or more courses of therapy (as-treated population).
Assignment
Patient Characteristics Between April 1991 and June 1995, 168 patients at 25 treatment centers were enrolled in the study. Fifty-seven patients were randomized to receive 5-FU/LV via HAI, 54 were randomized to receive FUDR via HAI, and 57 were randomized to receive 5-FU/LV via IV infusion. Recruitment was terminated at the end of June 1995 because the benefit of regional treatment was overestimated and because fear arose regarding biliary sclerosis secondary to intrahepatic FUDR infusion. Follow-up in surviving patients was a minimum of 18 months. As of the date of this report, 145 patients have died and only four have survived progression-free.
The characteristics of enrolled patients are listed in Table 1. Approximately two thirds of the patients in each group were men. Patients in all randomization arms were well balanced with regard to age, performance status, symptoms at initial evaluation, intrahepatic tumor burden, and location of primary tumor. Liver metastases were synchronous and diffuse in the majority of patients on each treatment arm. Intrahepatic tumor burden was assessed by laparotomy in all patients who were randomized to receive HAI and by CT scan and abdominal ultrasonography in patients who were randomized to receive IV therapy, provided they had no synchronous primary tumor resection. A total of 112 patients (67%) had an intrahepatic tumor burden of
Patient characteristics at the time of inclusion were examined for prognosis. For time to progression, only tumor burden of the liver was confirmed as a prognostic factor (P = .0358). The primary analysis adjusted for this factor by stratification. In addition to tumor burden of the liver, the Karnofsky performance status was a prognostic factor for survival. After adjustment for the Karnofsky performance status, results were robust. Several patients in each treatment group required a change of planned therapy or received no therapy because of the detection of extrahepatic disease, difficulty with catheter implantation, or postoperative complications (Figs 1 and 2). Extrahepatic disease was detected in 10 patients in the HAI 5-FU/LV group (five had peritoneal carcinomatosis, four had positive para-aortic lymph nodes, and one had lung metastases), in eight patients in the HAI FUDR group (six had peritoneal carcinomatosis and two had positive para-aortic lymph nodes), and in three patients in the IV 5-FU/LV group (all had peritoneal carcinomatosis). Catheter implantation was not possible in five patients because of the presence of abnormal blood vessels that were not detected by angiography. Postoperative complications occurred in 15 patients, and tumor progression before the initiation of therapy occurred in two patients.
Overall, 12 patients who were randomized to receive HAI 5-FU/LV were switched to IV 5-FU/LV (six because of extrahepatic metastases, two because of abnormal vessels, two because of misperfusion, and one because of primary catheter occlusion; no reason was given for one patient). A nonstudy treatment was initiated on two occasions, once because of lung metastases and once in addition to HAI because of patient preference. In addition, five patients who were randomized to the HAI 5-FU/LV arm received no therapy because of postoperative complications (one because of misperfusion, one because of primary catheter occlusion, and one because of hepatic artery thrombosis) or early death (one died because of decreased performance status and progression in the liver, and one died because of cardiac infarction). In 40 patients, the assigned treatment was continued for a median of six cycles. The minimum, first quartile, third quartile, and maximum numbers of cycles were one, three, nine, and 30 cycles, respectively. First-line chemotherapy was discontinued in all surviving patients. One patient in the HAI FUDR group received HAI 5-FU/LV erroneously. Seven patients were switched to IV 5-FU/LV therapy because of the presence of extrahepatic disease (n = 2), abnormal blood vessels (n = 2), and misperfusion (n = 3). One patient received nonstudy chemotherapy because of abnormal blood vessels. Eight patients received no chemotherapy. Of these, four died early (one as a result of extrahepatic metastases, one as a result of cardiovascular failure after IV port implantation due to extrahepatic metastases, one as a result of insufficiency of the anastomosis after colon resection, and one as a result of pulmonary embolism). Of the remaining four patients, one died after port dislocation with erosion of the hepatic artery into the duodenum and subsequent bleeding and liver failure, and three had extrahepatic disease (one of whom refused systemic chemotherapy after IV port implantation). In 37 patients, the assigned treatment was given for a median of six cycles. The minimum, first quartile, third quartile, and maximum numbers of cycles were two, three, eight, and 21 cycles, respectively. At the time of this report, only one patient was still receiving first-line chemotherapy (18 cycles were administered). Among patients who were randomized to receive IV 5-FU/LV, one received HAI 5-FU/LV erroneously and four received no chemotherapy (one had extrahepatic metastases and died early as a result of progression in the liver, two had extrahepatic disease, and one refused chemotherapy because of pain after port implantation) (Figs 1 and 2). In 71 patients, the assigned treatment was given for a median of six cycles. The minimum, first quartile, third quartile, and maximum numbers of cycles were one, four, 12, and 21 cycles, respectively. After this report, two patients will have been continued on first-line therapy (14 and 21 cycles administered).
Time to Progression
Subgroup analysis revealed a nearly two-fold increase in the time to progression among patients with an intrahepatic tumor burden of less than 25% who were treated with HAI 5-FU/LV, with 11.6 months versus 6.1 months after HAI FUDR and 5.5 months after HAI 5-FU/LV treatment. No clinically significant differences between treatment groups in time to progression were observed among patients with an intrahepatic tumor burden of  25%. The prognosis was poor for all patients with an intrahepatic tumor burden of 25%; the median time to progression for these patients was approximately 7 months (Table 2).
Subsequent Therapy In the HAI 5-FU/LV group, treatment was terminated in one patient after R0 resection of liver metastases. In the HAI FUDR group, one patient received further treatment with HAI FUDR after R0 resection of liver metastases, and in one patient, treatment was terminated after complete response. In the IV 5-FU/LV group, the initial treatment was continued in two patients and restarted in three patients; information regarding subsequent therapy was not available for one patient. After termination of treatment because of disease progression, technical complications, toxicity, and patient preference, 86 patients were given either chemotherapy that was different from the first-line treatment or chemoembolization (25 in the HAI 5-FU/LV group, 23 in the HAI FUDR group, and 38 in the IV 5-FU/LV group). Four patients received radiation only (one in the HAI 5-FU/LV group and three in the IV 5-FU/LV group). After progression, palliative resection (R2) of liver metastases was performed and chemotherapy was terminated in two patients (one in the HAI FUDR group and one in the IV 5-FU/LV group). Except for symptomatic therapy, 13 patients in the HAI 5-FU/LV group, 11 in the HAI FUDR group, and 23 in the IV 5-FU/LV group received no further treatment. In the HAI 5-FU/LV group, five patients received modified weekly high-dose HAI 5-FU (2,600 mg/m2)/LV (500 mg/m2) therapy, 14 received the study therapy IV 5-FU/LV, three received weekly high-dose IV HAI 5-FU/LV therapy, one received regional and systemic treatment, and two received a combination of conventional chemoembolization with mitomycin. In the HAI FUDR group, 11 patients were given the study regimen of HAI 5-FU/LV, three received weekly high-dose HAI 5-FU/LV, six received the study therapy IV 5-FU/LV, and three received weekly high-dose IV 5-FU/LV. In the IV 5-FU/LV group, five patients received the study therapy HAI 5-FU/LV, one received a modification of the IV 5-FU/LV therapy, 28 received weekly 24-hour high-dose IV 5-FU/LV, one received weekly 24-hour IV 5-FU, one received weekly combination therapy with IV 5-FU/LV and mitomycin, one received conventional chemoembolization with mitomycin, and one patient was given irinotecan.
Survival
Subgroup analysis revealed a survival benefit among patients with an intrahepatic tumor burden of less than 25% who were treated with HAI 5-FU/LV. No clinically significant differences between treatment groups in survival were observed among patients with an intrahepatic tumor burden of 25% (Table 2).
Intrahepatic Response
Extrahepatic Progression
Adverse Events
Discontinuation of HAI 5-FU/LV was necessary in 16 patients and discontinuation of HAI FUDR was necessary in three patients because of technical complications or clinical conditions arising as a result of technical complications after a median of six cycles in the HAI 5-FU/LV group and after six, seven, or eight cycles in the HAI FUDR group. Complications/conditions included hepatic artery thrombosis, misperfusion, dissection of the hepatic artery, catheter leakage, catheter dislocation, and bleeding ulcer. Implanted pumps (n = 7) were used only in the HAI FUDR group. Three technical problems (bleeding in the pump pocket, flow reduction, and septum dislocation of the side port) did not necessitate discontinuation of treatment. The 30-day mortality rate among patients who were randomized to receive intrahepatic (HAI 5-FU/LV or HAI FUDR) therapy was seven (6.3%) of 111 patients, compared with one (1.8%) of 57 patients who were randomized to receive systemic therapy (with IV 5-FU/LV). Seven of eight early deaths were reported before chemotherapy was started. In addition, one patient in the HAI 5-FU/LV group died early because of pulmonary embolism after the start of chemotherapy.
Although colorectal carcinoma is potentially curable in approximately 70% of patients, it remains a therapeutic challenge because as many as 33% of patients who undergo radical surgery and almost 50% of patients overall will die of metastatic disease.45 Interest in intrahepatic therapy has been renewed recently, largely as a result of two widely-publicized meta-analyses.31,32 This study compared the efficacy and safety of intrahepatic FUDR therapy with two modes of administration of 5-FU/LV (intrahepatic and IV) after resection of primary tumor in patients with colorectal carcinoma and liver metastases. Because effective second-line treatments for metastatic colorectal cancer are available, including infusional 5-FU, irinotecan, and oxaliplatin,46,47 and because of ethical reasons, therapy after disease progression must be the free choice of both patient and physician. Time to progression rather than survival was thus selected as the primary efficacy variable. In contrast with previous reports that demonstrated favorable results with FUDR,32 treatment with HAI 5-FU/LV was associated with a prolongation of time to progression as compared with treatment with HAI FUDR and IV 5-FU/LV. This difference was more pronounced in patients with an intrahepatic tumor burden of less than 25%. The median time to progression was nearly twice as great after HAI 5-FU/LV. Sources of possible bias include the open (unblinded) study design (unavoidable in oncologic studies of this type), which leads, in turn, to an unblinded response evaluation. In contrast with a reported response rate as high as 83% in most phase II series, our study, like most other phase III HAI studies, demonstrates an average response rate of 43% to 45% with intrahepatic (5-FU/LV or FUDR) therapy. Of special interest is that our study detected a significant difference in the rate of extrahepatic disease progression between patients treated with intrahepatic 5-FU/LV (13%) and those who received intrahepatic FUDR (41%). Extrahepatic progression is a frequently reported problem with intrahepatic FUDR therapy,29,23 probably because FUDR is up to 95% metabolized in the liver and no relevant cytostatic systemic levels accumulate.16 Therefore, currently in the United States, systemic 5-FU/LV (Mayo Clinic, Rochester, MN) is combined with HAI FUDR for suppression or eradication of occult metastases outside the liver. A recent trial by the Cancer and Leukemia Group B evaluated targeted plus systemic treatment versus systemic treatment alone. The high rate of systemic side effects observed with intrahepatic 5-FU/LV indicates that cytotoxic levels are achieved in the systemic circulation, which may account for the significant reduction of extrahepatic disease. A high local response rate combined with a significant reduction of extrahepatic disease may, therefore, explain the superiority of intrahepatic 5-FU/LV in prolonging time to progression. The clinical significance of extrahepatic progression may be even more pronounced in this trial because, in contrast with other studies, more than two thirds of treated patients had synchronous metastases. Synchronous metastases signify early dissemination of disease; hence, they confer an unfavorable prognosis.9 The observed median survival of 12.7 months among patients treated with intrahepatic FUDR is similar to that reported by Allen-Mersh et al29 and Martin et al28 and is inferior to that of other studies,25-27,30,48,49 which reported a median survival of 15 to 18 months. The difference, however, may be explained by different prognostic parameters. In most of these studies of intrahepatic FUDR, use of an intrahepatic pump was mandatory. The fact that use of such an implantable pump was optional in the present study did not increase the rate of technical complications associated with intrahepatic FUDR treatment and, therefore, can be ruled out as a reason for the inferior outcome. Despite the fact that HAI 5-FU/LV was superior to IV 5-FU/LV in terms of response, the overall effect of HAI was disappointing. The doubling of the response rate did not result in a significant increase in time to progression or survival. This discrepancy may be explained by the higher mortality rate observed among patients who underwent intra-arterial port implantation than among those who received IV port implantation. The relatively high mortality rate of 6.3% in this study was, however, comparable to results reported by Burke et al50 and, therefore, is typical for this high-risk population. In addition, some patients who underwent abdominal surgery suffered fatal complications, and planned treatment had to be cancelled. Furthermore, extrahepatic disease was diagnosed intraoperatively in some patients. Overall, 34 (31%) of 111 patients did not receive the intrahepatic therapy that was planned for them. Similar difficulties with intrahepatic therapy were reported by Kemeny et al25 and O’Connell et al.51 In these studies, 63 (39%) of 162 patients and 17 (30%) of 57 patients, respectively, had to be withdrawn from study. These results demonstrate the difficulty that is inherent in identifying ideal candidates for intrahepatic therapy. Furthermore, the difficulty in maintaining intrahepatic 5-FU/LV therapy is a clear deterrent to the concept of arterial HAI for isolated intrahepatic disease. The rate of complications that stopped treatment was significantly higher with HAI 5-FU/LV (16 of 40 patients) compared with HAI FUDR (three of 37 patients). The direct negative influence on the patency of the hepatic artery may be explained by the 5-FU–induced protein C-kinase–mediated vasoconstriction of vascular smooth muscle and endothelial proliferation, which may be enhanced after continuous use of 5-FU.52 The toxicity of therapy was a substantial problem in all treatment arms. As reported in other trials,27,30,34,53 chemical hepatitis and biliary sclerosis were frequent complications of intrahepatic therapy. Despite an initial FUDR dose reduction from 0.3 mg/kg to 0.2 mg/kg and a further planned reduction after three cycles to 0.15 mg/kg, two patients died of biliary sclerosis. At the time of the study’s initiation in early 1991, the prevention of biliary sclerosis by comedication with dexamethasone was not yet known.53 In addition, combination therapy with HAI FUDR (7 days) and 5-FU bolus, providing the maximum possible dose with minimal toxicity, had not been identified.54 Therefore, the HAI FUDR treatment regimen used in the study was not optimal by today’s standards.55 In contrast with intrahepatic FUDR, intrahepatic 5-FU/LV caused predominantly systemic, not local, adverse effects. The most problematic of these was stomatitis. No severe elevations in serum total bilirubin or liver enzymes were recorded in patients treated with HAI 5-FU/LV. The relative paucity of hepatic complications from intrahepatic 5-FU/LV therapy may be explained by the elimination kinetics of 5-FU. The elimination of 5-FU is nonlinear, and both systemic clearance and hepatic metabolism of the drug decrease at high doses.56,57 This pharmacokinetic profile correlates with the reduced selective advantage of intrahepatic 5-FU that was observed when it was administered at the maximum-tolerated dose. Yet the intrahepatic administration of 5-FU/LV controlled the spread of extrahepatic disease in many cases. Therefore, what initially seemed to be a negative feature of regional arterial 5-FU/LV application turned out to be an overall advantage. Several intrahepatic and systemic 5-FU/LV regimens are currently under investigation. At the time when the protocol for our study was developed, a 5-day continuous treatment regimen seemed to be optimal. Today, 24- to 48-hour high-dose regimens are widely regarded as being more effective.36,58 One argument against the use of intrahepatic 5-FU/LV therapy, which is associated with many complications, is the fact that the median survival time among patients treated with IV 5-FU/LV (17.6 months) was similar to that achieved in patients treated with HAI 5-FU/LV (18.7 months). In conclusion, the use of HAI 5-FU/LV as a means of treating liver metastases after resection of colorectal carcinoma cannot be recommended at this time as a routine therapeutic measure. Intrahepatic application of these agents requires invasive surgery and is associated with serious clinical complications and mechanical difficulties if the procedure is not performed by experienced surgeons and oncologists. In particular, placement of the hepatic artery catheter is a complex technical procedure, and the incidence of technical failure is, therefore, directly correlated with the surgeon’s experience. For example, a five-fold increase in technical failure was observed when the surgeon had placed fewer than 10 pumps.59 However, because HAI 5-FU/LV was associated with the most favorable clinical outcome in our study, especially in patients with an intrahepatic tumor burden of less than 25%, further investigation seems to be warranted. It would be interesting to study whether results can be improved by using improved 5-FU regimens and/or by increasing the sensitivity of preoperative diagnostic techniques.
Members of the ALM Palliative Study Steering Committee: R. Engemann, Department of Surgery, University Würzburg, Würzburg; A. Knuth, MD, Department of General Medicine, Hospital Nordwest, Frankfurt; W. Lauchart, MD, Department of Surgery, Eberhard-Karls-University, Tübingen; K. Nagel, Department of Surgery, Marienhospital Aachen, Aachen; D. Schröder, Department of Surgery, University Hospital, Kiel; K. Schwemmle, Department of Surgery, Justus Liebig-University, Gießen; S. Walgenbach, Department of Surgery, Johannes Gutenberg-University, Mainz; N. Victor, Institute for Medical Biometry, Ruprecht-Karls-University, Heidelberg, Germany; W.D. Ensminger, Upjohn Center of Pharmacology, Ann Arbor, MI; U.T. Laffer, MD, Department of Surgery, Regional Spital Biel, Biel; and U. Metzger, Department of Surgery, Triemlispital, Zurich, Switzerland. Coinvestigators: Prof R. Bötticher (Fürth), Prof U. Fölsch (Kiel), PD H.J. Gassel (Würzburg), Prof A. Gläser (Halle), C. Gog (Frankfurt), Prof J. Hauss (Leipzig), Dr C. Hegelmaier (Stadthagen), Prof H.H. Hennekeuser (Trier), Prof A. Hirner (Bonn), F. Klein (Traunstein), Prof J. Klempnauer (Bochum), PD K. Ludwig (Dresden), Prof B. Lünstedt (Erfurt), Prof P. Mattes (Esslingen), Prof W. Mutschler (Homburg/Saar), Prof H. Nier (Offenbach), Prof K.F. Paquet (Bad Kissingen), Prof M. Schönfelder (Leipzig), Prof H. Schramm (Gera), Prof D.W. Schröder (Bonn), Prof K. Schwemmle (Gießen), Dr E. Staib-Sebler (Frankfurt), Prof W. Stelter (Frankfurt-Hoechst), Dr R. Stieger (St. Gallen), Prof R. Teschke (Hanau), and Prof C. Ulrich (Göppingen, Germany).
We thank Christof Hottenrott (Frankfurt) and Helmut Schäfer (Marburg), who contributed to the design of the study; Karin Zamzow (Marburg), who monitored and processed the data and assisted with the statistical analysis; Mechthild Waldeyer and Inga Rossion (Frankfurt), who monitored the documentation and assisted with the coordination; Gregor Vetter (Frankfurt), who aided the authors with the preparation of the manuscript; and the German Cooperative Group on Liver Metastases Steering Committee, which contributed to the study design, protocol development, and study proceedings.
Sponsored by the Donors Association for the Promotion of Sciences and Humanity in Germany (Essen) and supported by the German Cancer Society (Frankfurt am Main), B. Braun-Dexon GmbH (Spangenberg), and Wyeth-Lederle (Münster, Germany).
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ABSTRACT
INTRODUCTION
