HALLE, Germany-Oral capecitabine(Drug information on capecitabine) (Xeloda) plus radiation is a highly effective and well-tolerated neoadjuvant treatment for locally advanced rectal cancer. The results of an interim analysis of a German multicenter, phase II study were reported by Juergen Dunst, MD, of Martin- Luther-Universitat Halle-Wittenberg, Halle, Germany (ASCO abstract 1113). In describing the basis for the phase II study, Dr. Dunst explained, "As shown in our previous phase I dose-finding study (J Clin Oncol 20:3983-3991, 2002), the concurrent administration of daily capecitabine with radiotherapy appears to be feasible and effective in advanced rectal cancer. The specific rationale for this combination is based on experimental findings that thymidine phosphorylase, necessary for the final conversion of capecitabine and predominantly present in tumor cells, is upregulated by radiotherapy in malignant but not in healthy tissue." Study Objective "The objective of the present expanded phase II trial is to establish the use of this combined modality approach in a multicenter setting, focusing on its application as neoadjuvant treatment of cT3, cT4, fixed or primarily inoperable tumors," Dr. Dunst continued. "Oral capecitabine simplifies chemoradiation by avoiding the need for timeconsuming and complicated IV infusions," Dr. Dunst noted. "Capecitabine is a highly effective, first-line treatment for metastatic colorectal cancer, and it has an improved safety profile compared with IV fluorouracil(Drug information on fluorouracil)/leucovorin in both the metastatic and adjuvant settings." Capecitabine/Radiotherapy A total irradiation dose of 50.4 to 55.8 Gy was administered in conventional daily doses of 1.8 Gy over a period of approximately 6 weeks. Capecitabine was given at an oral dosage of 825 mg/m2 bid on each day of the radiotherapy period, including the weekends, with the first daily dose given 2 hours before irradiation. So far, 46 patients (60% male, 40% female) have been recruited from six university clinics in Germany since June 2001. The mean age was 65 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1. Clinical staging revealed T3 tumors (48%) and T4 tumors (52%), and involved lymph nodes (cN+) in 53%. Data from 25 patients were available for the interim analysis. "Capecitabine/ radiotherapy achieved a high clinical response rate," Dr. Dunst reported. "There was a clinical complete response or partial response in 72% of patients. Only 12% experienced disease progression during neoadjuvant treatment. The high clinical response rate with capecitabine/radiotherapy was accompanied by a high rate of R0 resections and tumor downstaging." Dr. Dunst reported that the comparison of initial diagnosis and pathologic findings showed downstaging in 72% of patients, mainly from cT4 to pT3 to pT0. Only 8% of patients remained inoperable at the end of the irradiation period. Oral capecitabine was well-tolerated in combination with radiotherapy. The most commonly reported adverse events were diarrhea, local erythema, neurologic pain, and nausea. The only grade 3 adverse events were diarrhea in two patients and local erythema in one patient. There were no grade 4 adverse events. "Oral capecitabine/radiotherapy demonstrated a favorable and predictable safety profile," Dr. Dunst said. "The majority of adverse events were mild to moderate in intensity and there were no grade 4 adverse events or laboratory abnormalities." Summarizing the interim results, Dr. Dunst said, "Oral capecitabine/radiotherapy achieved clinical responses in 72% of patients, enabling R0 resections in 89% of patients undergoing surgery. Seventy-nine percent of patients undergoing resection experienced pathologically confirmed tumor downstaging. Oral capecitabine simplifies chemoradiation, avoiding the problems and inconvenience associated with IV fluorouracil."