Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial

Summary

Background

The liver is the most frequent site for metastases of colorectal cancer, which is the second largest contributor to cancer deaths in Europe. We did a randomised trial to compare an intrahepatic arterial (IHA) fluorouracil and folinic acid regimen with the standard intravenous de Gramont fluorouracil and folinic acid regimen for patients with adenocarcinoma of the colon or rectum, with metastases confined to the liver.

Methods

We randomly allocated 290 patients from 16 centres to receive either intravenous chemotherapy (folinic acid 200 mg/m², fluorouracil bolus 400 mg² and 22-h infusion 600 mg/m², day 1 and 2, repeated every 14 days), or IHA chemotherapy designed to be equitoxic (folinic acid 200 mg/m², fluorouracil 400 mg/m² over 15 mins and 22-h infusion 1600 mg/m², day 1 and 2, repeated every 14 days). The primary endpoint was overall survival, and analysis was by intention to treat.

Findings

50 (37%) patients allocated to IHA did not start their treatment, and another 39 (29%) had to stop before receiving six cycles of treatment because of catheter failure. The IHA group received a median of two cycles (0–6), compared with 8·5 (6–12) for the intravenous group. 45 (51%) IHA patients who did not start or did not receive six cycles switched to intravenous treatment. In both groups, grade 3 or 4 toxicity was uncommon. Median overall survival was 14·7 months for the IHA group and 14·8 months for the intravenous group (hazard ratio 1·04 [95% CI 0·80–1·33], log-rank test p=0·79). Similarly, there was no significant difference in progression-free survival.

Interpretation

Our results showed no evidence of an advantage in progression-free survival or overall survival for the IHA group; thus continued use of this regimen cannot be recommended outside of a clinical trial.

Introduction

Colorectal cancer is the second largest contributor to cancer deaths in Europe, with around 150 000 new cases per year. Although surgery of curative intent is undertaken in 60–75% of patients, 50% will relapse with local recurrence, peritoneal carcinomatosis, or distant metastases. The liver is the most common site of metastasis; about 80% of patients who die have hepatic disease, and up to 20% of patients presenting at first relapse have disease macroscopically confined to the liver.¹

For patients with advanced disease, there is no doubt that systemic chemotherapy with fluorouracil is still the therapeutic mainstay some 40 years after it was introduced. This drug has greater survival and quality-of-life benefits than the best supportive care.² At the time this trial was designed—i.e., before the emergence of new drugs such as irinotecan and oxaliplatin—the treatment approach was to provide an optimum dose, schedule, and mode of delivery, of fluorouracil and folinic acid.3, 4 Intrahepatic arterial (IHA) chemotherapy relies on the premise that cytotoxic drugs have steep dose-response curves, and that fluorouracil undergoes arterial extraction at first pass, thus generating high drug concentrations in the liver (an 80–100-fold advantage compared with intravenous administration). The liver has a dual blood supply, and metastatic nodules more than 1 cm in diameter are vascularised via the hepatic artery. Therefore, there is a compelling pharmacological rationale for IHA chemotherapy for hepatic metastases.5, 6, 7, 8, 9

Before we started this trial, seven randomised trials comparing IHA with intravenous infusion of fluoropyrimidines (fluorouracil or floxuridine) or best supportive care had been published.10, 11, 12, 13, 14, 15, 16 However, several features of these trials have made interpretation difficult: most trials allowed crossover from intravenous adminstration to IHA; the trials tended to be underpowered; in two trials, the comparator group was best supportive care or ad hoc chemotherapy; and the drugs, doses, and schedules used often differed substantially between IHA and intravenous groups. Floxuridine is not licensed for use in the UK and the implantable pumps required for its delivery were prohibitively expensive; therefore, a fluorouracil-based schedule was developed.

One of the most widely used European intravenous regimens, the de Gramont regimen,⁴ combines fluorouracil and folinic acid, administered for 48 h every 2 weeks. This regimen has served as the standard group in consecutive trials done by the Medical Research Council's (MRC) colorectal cancer group. An IHA regimen was tested in a phase 1 clinical and pharmacokinetic study, with the same agents and schedule as the de Gramont regimen, adjusted to induce the same level of toxicity and steady-state venous fluorouracil concentrations as that in the intravenous regimen.¹⁷ 43 patients who had not had previous chemotherapy participated in the trial. Objective responses were seen at each dose level, and there was an overall response rate of 52%, which compares favourably with other IHA regimens.5, 6, 7, 8, 9

In this multicentre randomised trial, we compare IHA with intravenous 48-h infusional fluorouracil and folinic acid, to test the hypothesis that IHA chemotherapy offers a clinically relevant survival advantage.