HOUSTON-Preoperative radiotherapy with continuous infusion fluorouracil (5-FU) is known to improve sphincter preservation and produce pathologically complete remissions in 10% to 30% of patients with locally advanced rectal cancer. A preliminary safety analysis from a phase II study suggests that chemoradiation with capecitabine appears to be very well tolerated and may replace preoperative radiotherapy with 5-FU in this setting. This interim analysis was reported by Edward H. Lin, MD, assistant professor gastrointestinal medical oncology, and Nora Janjan, MD, professor of radiation oncology, at the M. D. Anderson Cancer Center, Houston (ASCO abstract 1152). Dr. Lin described how "randomized studies comparing preoperative vs postoperative 5-FU-based chemoradiation in locally advanced rectal cancer appeared to favor preoperative chemoradiation for local control because the intact tumor is better vascularized and oxygenated, allowing for better drug delivery. The preoperative approach offers the potential for sphincter-sparing resection and it is better tolerated because of reduced radiation exposure to the small bowel. Furthermore, it produces evidence of 5-FU chemosensitivity in contrast to the postoperative approach." Additive Effect Capecitabine is preferentially converted to 5-FU in tumor tissue by three enzymatic conversions. Thymidine phosphorylase is responsible for the last step of conversion and can be 70-fold higher in tumor tissue than in normal tissue. TP activation of capecitabine increases 5-FU concentrations in the tumor. Radiotherapy also upregulates TP in tumor tissue. The effect of capecitabine is at least additive when combined with radiotherapy in xenograft models. "Capecitabine is preferentially converted by thymidine phosphorylase, which is then activated up to 17-fold by radiation in the tumor," Dr. Lin explained. "This relation ship may allow greater delivery of 5-FU to the tumor tissue." Dr. Lin pointed out that capecitabine mimics continuous infusion 5-FU in its superior response rate and safety profiles compared to bolus 5-FU. Continuous infusion 5-FU, however, "is cumbersome, expensive, and is associated with catheter and pump-related complications. Capecitabine simplifies chemoradiation by its oral administration and is highly appealing to patients," Dr. Lin said. Phase II Study Based on phase I data that capecitabine is safe and appears to be effective, "we initiated a phase II study of oral capecitabine 825 mg/m² twice daily with radiotherapy 45 Gy/25 fractions to the pelvis and 52.5 Gy/30 fractions to the primary and perirectal nodes in 54 patients with locally advanced rectal cancer," Dr. Lin said. "All patients will have surgery, and an interim efficacy analysis for the first 19 patients is planned. Eligible patients will also receive 4 months of adjuvant capecitabine postoperatively." The primary objective of the study is to determine the rate of pathologic response, and the secondary objectives are safety, tolerability, overall survival, quality of life, and biomarkers. Patients with T3 or T4, N0 or N1 disease on endoscopic ultrasound are eligible. Preliminary Results "Preliminary results suggested that capecitabine provided many advantages without compromising efficacy, compared with the less convenient infusional 5-FU plus radiation regimen," Dr. Lin said. "As of May 2003, 19 patients have been enrolled in the study and completed chemoradiation, and all are evaluable for toxicities. Fifteen of these patients underwent surgery and are evaluable for pathologic response. Two patients have completed the fourth 21-day cycle of adjuvant treatment with capecitabine, and five additional patients are completing their third cycle," he reported. No reduction in capecitabine dose was necessary for 12 patients, and 4 patients required only minor dose modification due to diarrhea or hand-foot syndrome. Clinical Downstaging Effective downstaging with capecitabine and radiation was observed (see Table 1). The overall pathological response was 87% (n = 15). Pathologic response rates included complete response (20%), microscopic residual tumor (27%), greater than 70% reduction in tumor volume (40%), and stable/progressive disease (13%). Overall pathologic downstaging was seen in 73%: primary tumor (47%) and node (57%). Of the six patients with locally advanced rectal cancer who received capecitabine chemoradiation off protocol, all had clinical downstaging, with three patients achieving pathologic complete response. "The results in terms of pathologic downstaging (87%) with pathologic complete response (20%) and microscopic residue (27%) suggest that this treatment regimen is better or at least equivalent to the historical M. D. Anderson experience with continuous infusion-5-FU plus radiation in this regard," Dr. Lin said. The most common toxicities are of grade 1 in nature and include fatigue, radiation dermatitis, diarrhea, nausea and anorexia. Grade 2 toxicities are less common, about 10% to 15%, and included three cases of nausea/vomiting, two cases each of radiation dermatitis, diarrhea, and hand-foot syndrome, and one case of fatigue. Serious grade 3 and 4 toxicities are rare at 5% to 6% and included two patients with diarrhea and one patient each with nausea/vomiting, deep venous thrombosis, radiation enteritis, dehydration, and renal failure. "Although grade 3/4 toxicities are rare, they do seem to cluster in elderly patients," Dr. Lin said. "Therefore, caution should be exercised for those patients who are 65 years or older and receiving chemoradiation with capecitabine."