To the Editor:
The prospective randomized study by Lorenz et al 1 reported in the December 1998 issue of Annals of Surgery failed to demonstrate any overall survival or other clinical benefits from adjuvant selective intraarterial chemotherapy in patients undergoing curative liver resection for metastatic colorectal tumor. In this study, 226 patients with liver metastases from colorectal cancer were randomized to receive liver resection alone or resection in combination with intraarterial chemotherapy of 5-fluorouracil (5-FU). The authors should be congratulated for this important study. The search for an effective adjuvant therapy is of paramount importance at a time when major liver resection, the only treatment with proven efficacy, is still associated with a high recurrence rate (60%–80%). 2–4 However, this study, which was discontinued due to a high recurrence and mortality rate at the interim analysis, does not rule out a significant benefit for intraarterial chemotherapy. Some aspects of the study design and interpretation of the data require comments.
A more efficacious local effect might have been achieved by using floxuridine (FUDR) instead of 5-FU. Several studies have shown that the local efficacy of FUDR within the liver is superior to 5-FU due to its higher hepatic extraction. 5–8 In addition, the authors indicate that the schedule of intraarterial 5-FU might also be effective against systemic disease. Their intraarterial 5-FU protocol differs from established regimens of long-duration (6 weeks) low-dose infusions of 5-FU or protocols using a short-duration, high-dose schedule. The systemic efficacy of their regimen remains unclear. Therefore, a significant survival benefit for adjuvant intraarterial chemotherapy might have been missed in the study by using a less effective chemotherapeutic regimen.
We are concerned that the percentage of patients with synchronous metastases in this study is rather high (45% for the control group and 36% for the adjuvant treatment group). Synchronous metastases are associated with a less favorable prognosis in some studies. 9,10 We do not perform adjuvant intraarterial treatment in these patients. In addition, intraarterial chemotherapy was not started in 23% of the patients, and only 39% of the patients completed the adjuvant protocol. Furthermore, the authors do not provide data about the median follow-up time of the patients.
Data on the number of patients in each participating center would have been of interest. The high mortality rate of 7.5% in the adjuvant treatment group, including three patients dying from catheter-induced hemorrhage and 5 patients dying from chemotherapy-related complications, may indicate that some participating centers lacked sufficient experience for this protocol.
We would like to point out that, in contrast to the authors’ statement, a prospective randomized study evaluating adjuvant intraarterial chemotherapy after curative resection was published by Wagman et al in 1990. 11 These authors used intraarterial FUDR (0.5mg/kg/d) for 14 consecutive days of every month for 12 months and found significantly delayed recurrence, but failed to show a significant increase in patient survival. Lorenz et al 12 (first author of the multicenter study under discussion 1) also reported in 1997 a prospective study using adjuvant intraarterial FUDR or 5-FU after hepatic resection of colorectal metastases. In this earlier report, 12 in contrast to the recently published series, 1 the recurrence rate was significantly reduced and patient survival significantly prolonged in patients receiving more than 5 cycles of chemotherapy. These two studies 11,12 are not discussed in the present publication. Furthermore, a significant effect on tumor progression 13–15 and survival 16,17 has been shown in some randomized trials using intraarterial FUDR for palliative treatment of liver metastases from colorectal cancer. A critical comparison of the different results available in the literature would have added substantial information to this controversial topic.
In our opinion, a higher local efficacy with fewer systemic side effects could have been achieved by using a drug with high hepatic extraction such as FUDR, with or without folinic acid. Systemic disease should be approached by intensive preoperative diagnostic evaluation, including new techniques like positron emission tomography (PET) scans, to exclude patients with nonresectable disease or extrahepatic lesions. Additional aggressive systemic chemotherapy might be necessary in selected cases. Finally, other types of adjuvant therapy such as immunotherapy may provide additional benefit. 18
February 8, 1999
Pierre-A. Clavien MD, PhD
Markus Selzner MD
Michael A. Morse, MD
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