Substitution of oral fluoropyrimidines for infusional fluorouracil with radiotherapy: how much data do we need?

Abstract

In this issue of the Journal of Clinical Oncology, Fernandez-Martos et al report the results of a large phase II study that evaluated orally administered UFT, a combination of uracil and ftorafur (a fluoropyrimidine), given concurrently with preoperative radiotherapy in locally advanced rectal cancer. This was a well designed and well conducted multi-institutional trial with results showing low acute toxicity rates as well as pathologic tumor response, local tumor control, and overall survival rates comparable with the results from other studies evaluating preoperative chemoradiotherapy. On this basis, oral UFT is a good candidate for phase III study in combination with radiotherapy, as is its counterpart, capecitabine, approved in the United States for metastatic colorectal cancer when single-agent fluoropyrimidine therapy is indicated. The National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial, a phase III study, was designed to compare an oral fluoropyrimidine with protracted venous infusional (PVI) fluorouracil (FU) in patients receiving preoperative radiotherapy for locally advanced rectal cancer. That study initially incorporated UFT, but when development of UFT was abandoned in the United States and capecitabine was approved, capecitabine replaced UFT in the design. The NSABP R-04 trial has been on hold for 2 years pending final approval by the National Cancer Institute for many reasons unrelated to the issue of capecitabine. PVI FU is the evidence-based standard chemotherapeutic agent used in conjunction with radiotherapy in postoperative concurrent chemoradiotherapy for rectal cancer. This standard was established by a randomized trial (North Central Cancer Treatment Group 86-47-51) in patients with resected rectal cancer who received either bolus FU (without leucovorin[LV]) or PVI FU plus postoperative radiotherapy. Although similar trials in patients with tumors at other gastrointestinal sites have not been conducted, the data derived from North Central Cancer Treatment Group 86-47-51 have been used to justify the use of PVI FU plus postoperative radiotherapy to treat other gastrointestinal malignancies. For example, PVI FU was incorporated as the standard chemotherapeutic agent in adjuvant concurrent chemoradiotherapy trials for pancreatic cancer (Radiation Therapy Oncology Group/ Intergroup[INT]97-04) and gastric cancer (Cancer and Leukemia Group B/INT 80,101). Two subsequent postoperative rectal chemoradiotherapy trials conducted evaluated the biochemical modulation of FU with LV and/or levamisole (INT 0114), and the incorporation of PVI FU before and after chemoradiotherapy (INT 0144). The results from those two studies, which accrued a total of 3,600 patients, indicated that the various ways to administer and modulate FU were indistinguishable in terms of overall survival. In fact, the results of INT 0144 further complicated the picture because patients who received bolus FU with LV and levamisole concurrently with radiation had survival outcomes that were statistically identical to those who received PVI FU with radiation. On this basis, biochemically modulated FU appears to have efficacy similar to PVI FU with radiotherapy. Following in the footsteps of these studies is the thoughtfully designed NSABP R-04 trial. It addresses the very clinically relevant question of whether the PVI FU during radiation could be replaced by capecitabine. The combination of capecitabine and radiotherapy was very well tolerated in a phase I trial, with minimal gastrointestinal and no JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 15 AUGUST 1 2004