No Differences in Surgical Outcomes With Four Different Chemotherapy Regimens Plus Preoperative Radiotherapy in Rectal Cancer
As reported in the Journal of Clinical Oncology by O’Connell et al, the National Surgical Adjuvant Breast and Bowel Project (NSABP) Trial R-04 is assessing four chemotherapy regimens given concurrently with preoperative radiotherapy in order to help identify optimal treatment in patients with stage II or III rectal cancer. The findings for surgical outcomes show no differences in pathologic complete response, sphincter-sparing surgery, or downstaging to sphincter-sparing surgery for continuous intravenous (IV) fluorouracil (5-FU) vs capecitabine or for regimens with vs without oxaliplatin, but indicate an increased frequency of severe diarrhea with oxaliplatin. Analyses of local tumor control, disease-free survival, and overall survival have not yet been performed.
Study Details
In the trial, 1,606 patients undergoing preoperative radiation therapy (45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions) were randomly assigned between September 2004 and August 2010 to receive continuous IV 5-FU at 225 mg/m2 on 5 days per week with (n = 329) or without oxaliplatin at 50 mg/m2 once per week for 5 weeks (n = 477) or oral capecitabine at 825 mg/m2 twice per day on 5 days per week with (n = 330) or without oxaliplatin (n = 472). The protocol was changed in 2005 to add the oxaliplatin vs no oxaliplatin randomization. Surgeons indicated prior to randomization whether patients were eligible for sphincter-sparing surgery based on clinical staging.
Across the four groups, 56% to 61% of patients were aged ≤ 59 years and 39% to 44% ≥ 60 years, 67% to 68% were male, 61% to 62% had stage II disease and 38% to 39% stage III disease, and surgical intent was sphincter-sparing in 73% to 74%.
No Differences in Surgical Outcomes
For the continuous IV 5-FU vs capecitabine comparison, there were no significant differences in pathologic complete response rate (17.8% vs 20.7%, P = .14), sphincter-sparing surgery rate (59.4% vs 59.3%, P = .98), rate of surgical downstaging to sphincter-sparing surgery (21.3% vs 21.1%, P = .95), or frequency of grade 3 to 5 diarrhea (11.7% vs 11.7%, P = 1.00).
For the oxaliplatin vs no oxaliplatin comparison, there were no significant differences in pathologic complete response (19.5% vs 17.8%, P = .42), sphincter-sparing surgery (57.8% vs 61.0%, P = .24), or surgical downstaging (17.9% vs 23.5%, P = .20). Patients receiving oxaliplatin had a significantly greater frequency of grade 3 to 5 diarrhea (16.5% vs 6.9%, P < .001), with death due to diarrhea occurring in two patients receiving capecitabine plus oxaliplatin.
The investigators concluded, “Administering capecitabine with preoperative [radiation therapy] achieved similar rates of [pathologic complete response], sphincter-sparing surgery, and surgical downstaging compared with [continuous IV 5-FU]. Adding oxaliplatin did not improve surgical outcomes but added significant toxicity. The definitive analysis of local tumor control, disease-free survival, and overall survival will be performed when the protocol-specified number of events has occurred.”
Michael J. O’Connell, MD, of the National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by National Institutes of Health grants, Sanofi-Synthélabo, and Roche Laboratories. Norman Wolmark, MD, reported a consultant or advisory role with sanofi-aventis.
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