NEW ORLEANS-Capecitabine (Xeloda) shows encouraging activity when given with preoperative radiation for locally advanced rectal cancer, according to multiple investigations. Use of the oral agent could also avoid the need for daily intravenous infusions and the associated inconvenience and risks. Five separate phase II investigations added a considerable amount of support for using capecitabine(Drug information on capecitabine) preoperatively in patients with locally advanced rectal cancer. Two of the investigations evaluated capecitabine plus oxaliplatin(Drug information on oxaliplatin) (Eloxatin), while three others evaluated single-agent capecitabine in this setting. Capecitabine Plus Oxaliplatin "As an oral agent, capecitabine can greatly simplify chemoradiation, avoiding the need for time-consuming and potentially complicated daily intravenous infusions," according to Robert Glynne-Jones, MBBS. Dr. Glynne-Jones, consultant clinical oncologist with Mount Vernon Hospital, Northwood, United Kingdom, is the principal investigator in one of the two trials suggesting that capecitabine/oxaliplatin has promising efficacy and acceptable safety for patients with locally advanced rectal cancer (abstract 3575). Capecitabine/ oxaliplatin has already been shown to be well tolerated and "highly effective" in first-line treatment of metastatic colorectal cancer, Dr. Glynne- Jones and colleagues indicated in their presentation. The phase I/II trial, which is known as SOCRATES (from the Scottish Cancer Registration System) is designed to evaluate the combination of oral capecitabine, IV oxaliplatin, and standard radiotherapy to the pelvic region (XELOX-RT) followed by surgery in histologically confirmed rectal adenocarcinoma. In the phase I portion of the trial, investigators determined the recommended doses of capecitabine (650 mg/m2 twice daily for 5 weeks) and oxaliplatin (130 mg/m2 on days 1 and 29). Data show that XELOX-RT enhanced surgical resection, according to the investigators. Of 16 patients undergoing surgery, an R0 resection was achieved in 14. Complete responses were observed in five patients. In the phase II portion, 62 patients have been enrolled. While pathology data from phase II are not yet mature, safety data reported suggest the recommended dose is well tolerated. Grade 3-4 adverse events were seen in only 10 of 41 patients evaluable for safety. Hand-foot syndrome (grade 1) was observed in only two patients. Belgian Investigation In a separate phase II study, Belgian investigators reported preliminary results suggesting that preoperative capecitabine/oxaliplatin plus radiotherapy was feasible, with diarrhea being the only clinically relevant toxicity (abstract 3552). Lionel R. Duck, MD, Université Catholique de Louvain, Brussels, Belgium, reported that among 17 resected rectal specimens, one specimen indicated a pathological complete remission, and five specimens had only microfoci of residual tumor. All specimens were reviewed by the same pathologist. Treatment in this trial consisted of radiotherapy 5 days a week for 5 weeks for a total dose of 45 Gy, plus oxaliplatin 50 mg/m2 IV weekly, plus oral capecitabine 825 mg/m2 twice daily. Patients received more than 90% of the planned dose of both oxaliplatin and capecitabine. In two patients, radiotherapy was interrupted because of diarrhea. German Study Update A German study group reporting at ASCO 2003 (abstract 1113) that capecitabine plus standard radiotherapy was "highly effective" as neoadjuvant therapy for locally advanced rectal cancer, provided an update in 2004. The update confirmed that the oral agent is "an adequate substitute" for continuous infusion 5-FU in preoperative chemoradiation regimens. "Oral capecitabine simplifies chemoradiation, avoiding the unwanted risks and inconvenience associated with IV 5-FU," reported Juergen Dunst and colleagues from the department of radiotherapy at Martin-Luther- University, Halle, and other study sites in Germany. The interim analysis of a phase II trial included clinical response data for 69 patients. By intent-to-treat analysis, capecitabine chemoradiation resulted in clinical complete or partial remissions in 42 patients (61%). This enabled R0 resections in 89% of patients undergoing surgery. Tumor downstaging was achieved in 62%. A "low incidence" of grade 3-4 adverse events was reported by the German researchers. The most common adverse event, diarrhea, occurred in 46% of patients, but only four patients (7%) experienced diarrhea that was of grade 3-4 intensity. Italian and French Trials Italian and French research groups also reported results for phase II investigations of capecitabine chemoradiation. Encouraged by the positive results previously reported by the Germans, the Italian group, led by Antonio De Paoli, MD, of the National Cancer Institute-CRO in Aviano, tested a similar regimen (abstract 3540). In 53 patients evaluable for safety and efficacy, complete or partial clinical response was seen in 31 (58%). Tumor downstaging was achieved in 29 of 51 patients (57%). Only six of these patients had grade 3 toxicity and none had grade 4. French researchers with the GERCOR (Oncology Multidisciplinary Research Group) group also reported their phase II experience with preoperative capecitabine chemoradiation (abstract 3538). Among the 51 study patients, 50 underwent surgery and 1 refused. Histopathology showed that 24% had complete response, while 12% had persistence of minimal tumor cell foci and 23% had additional tumor downstaging. Tumor-free resection margins were achieved in every patient. Adverse events were mainly gastrointestinal, including three cases of grade 3 diarrhea. "Capecitabine chemoradiotherapy is well tolerated, and the efficacy supports further exploration, as a single agent and as part of new therapeutic strategies with chemo- and biological therapies," investigators concluded.