A Role for Hepatic-Directed Chemotherapy in Colorectal Liver Metastases

Abstract

Recent advances in the systemic therapy of colorectal cancer seem to have made regional therapy of hepatic metastases passe. Although regional therapy of hepatic metastases from colorectal cancer can produce high response rates with control of liver disease, there seems to be minimal impact on survival because of development of limiting extrahepatic disease. Why bother with the complexities of regional treatment requiring a major surgical procedure and possessing a unique toxicity, biliary sclerosis, when intravenous chemotherapy administration can achieve a high response rate and improved survival by treating extrahepatic as well as hepatic cancer? Perhaps hepatic arterial therapy is best viewed as a potentially useful debulking technique for colorectal liver metastases with negligible effect on occult extrahepatic disease. That consideration is evident in the three studies reported by Kemeny et al, 1 Ducreux et al, 2 and Faynsod et al 3 in this issue of theJournal of Clinical Oncology. All three studies attempt to overcome the shortcomings of regional therapy by addressing the therapy of extrahepatic disease and the biliary toxicity accompanying hepatic arterial infusions (HAI) of floxuridine (FUDR). The results of the phase I trial by Kemeny et al 1 from the Memorial Sloan-Kettering Cancer Center reported in this issue concerning the treatment of unresectable colorectal liver metastases are extremely positive. In this trial, all patients had implantation of a hepatic arterial catheter and pump and received either a set fixed dose of HAI FUDR (with dexamethasone to diminish biliary toxicity) plus systemic (intravenous) oxaliplatin plus irinotecan (group A) or oxaliplatin plus fluorouracil with leucovorin (group B). In group A, oxaliplatin and irinotecan were escalated separately to determine the maximum-tolerated dose (MTD) of the combination. In group B, dose levels of a 48-hour infusion of fluorouracil were escalated to the MTD, with oxaliplatin held at a conventional dose level. The study successfully defined the MTD for each group. Systemic chemotherapy doses at MTD were within the usual dose range for group A, but the fluorouracil dose was lower in group B. Toxicities were as expected and primarily related to the systemic treatment, and there were no cases of bilirubin elevation noted at MTD. Although this was a phase I study and involved only 36 patients, the response rates and survivals that were achieved were excellent. The complete plus partial response rate was 90% and 87% for groups A and B, respectively. For groups A and B, the median survival from pump placement was 36 and 22 months, respectively, and the median survival from diagnosis of liver metastases was 47 and 35 months, respectively. The patients included in the study were highly selected and had unresectable hepatic metastases with no extrahepatic disease and, in most instances (89% of patients), had experienced failure with undefined previous systemic chemotherapy. It is of interest to examine these results with those reported for similar systemic regimens in the initial treatment of colorectal cancer metastatic to multiple sites including the liver. The results in group A compare favorably with the previously reported response rate and median survival for combined systemic irinotecan and oxaliplatin of 35% and 17.4 months, respectively. 4 The outcome in group B compares well with the response rate of 54% for initial systemic treatment with oxaliplatin plus fluorouracil and leucovorin. 5 Overall survival time in the Kemeny et al 1 HAI study of 35 to 47 months exceeds the approximately 21-month overall median survival time for sequential oxaliplatin plus fluorouracil and leucovorin and for irinotecan plus fluorouracil and leucovorin in previously untreated patients. 5 The response rate for the combination of HAI FUDR and systemic chemotherapy seems higher than what would be anticipated for either type of therapy alone, suggesting that the benefits of HAI FUDR may be additive to systemic therapy. The results of this small, phase I study of HAI FUDR plus systemic therapy require confirmation in larger, multicenter, phase III trials.