The researchers concluded that although longer follow-up is necessary, "these preliminary results suggest that preoperative chemoradiation with capeci-tabine is a safe, well-tolerated, and effective neoadjuvant treatment modality for locally advanced rectal cancer." The downstaging effect, they said, "can increase the possibility of sphincter preservation in distal rectal cancer."
German researchers conducted a phase I, dose-escalation study to determine the maximum tolerated dose of oral capecitabine(Drug information on capecitabine) given concurrently with standard pelvic radiotherapy in patients with rectal cancer treated in the adjuvant, neoadjuvant, or palliative setting. "In order to optimally exploit any potential synergistic effect of radiotherapy and capecitabine, the drug was planned to be administered continuously for the duration of irradiation," said Jürgen Dunst, MD, of Martin-Luther-Universi-tät, Halle, Germany, and his colleagues.
Radiotherapy was given to a total dose of 50.4 Gy in 1.8-Gy daily fractions, 5 days a week for approximately 6 weeks. The planned capecitabine dose escalation was from 250 to 1,250 mg/m2 twice daily, including weekends, with the first dose given approximately 2 hours before radiotherapy and the second dose 12 hours after the first.
The study recruited 36 patients, 92% of whom had newly diagnosed rectal cancer and the remainder relapsed disease. There were no dose-limiting toxicities up to the 825 mg/m2 twice daily dose level. At 1,000 mg/m2 twice daily, two patients had grade 3 hand-foot syndrome. Consequently, 825 mg/m2 twice daily is the recommended dosage for subsequent trials (J Clin Oncol 20:3983-3991, 2002).
Of 10 patients treated in the neoadju-vant setting for whom effects on the primary tumor could be assessed, 9 had a clinical partial response and one had stable disease. One patient treated at the 500 mg/m2 twice daily dose level had a histologic complete remission. Of three patients with relapsed disease treated palliatively, one had a partial remission at a dose level of 825 mg/m2 twice daily.
In this study, the acute side effects of radiotherapy, especially bowel and skin toxicity in the radiation field, "were not increased and were not dose limiting," the authors said, whereas bowel toxicity is the main toxicity of radiotherapy and concurrent standard 5-FU.
The authors noted that a multicenter phase II study has begun in Germany using the recommended capecitabine dose to evaluate concurrent capecitabine/radiotherapy in the neoadjuvant setting. Further, the treatment schedule developed in this phase I trial has been adopted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) for a planned large-scale trial in the preoperative setting of capecitabine/radiotherapy vs protracted 5-FU/radiotherapy.