International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationRadiation Therapy Oncology Group 0247: A Randomized Phase II Study of Neoadjuvant Capecitabine and Irinotecan or Capecitabine and Oxaliplatin With Concurrent Radiotherapy for Patients With Locally Advanced Rectal Cancer
Introduction
Adenocarcinoma of the rectum is a common disease with >40,000 cases diagnosed each year in the United States (1). Despite the potentially high rate of curability with combined modality therapy, some patients experience significant treatment-associated morbidity, and other patients develop locoregional failure or distant metastasis. In addition to achieving cure, sphincter preservation is an important goal of therapy. Improvements in clinical outcome have been realized with wide acceptance of continuous infusion 5-fluorouracil (5-FU)–based neoadjuvant chemoradiotherapy (chemoRT) and the use of total mesorectal excision.
The results of large randomized trials comparing neoadjuvant pelvic radiotherapy (RT) alone versus RT plus concurrent 5-FU have demonstrated improvement in locoregional disease control with the addition of concurrent chemotherapy 2, 3. Attempts to improve on this approach have focused primarily on testing new agents added to the backbone of 5-FU plus RT to enhance the pathologic complete response (pCR) rate. Drugs with high activity in the metastatic disease setting have been of particular interest to apply to rectal cancer clinical studies. However, the integration of new RT techniques is also pertinent to this clinical research question.
The Radiation Oncology Group (RTOG) 0012 study was a Phase II trial in which patients were randomly assigned to either hyperfractionated pelvic RT plus continuous infusion 5-FU or standard pelvic RT plus continuous infusion 5-FU and irinotecan (4). That study was successful in that both arms achieved very high pCR rates, 26% in each arm. However, both arms were also associated with high rates of acute Grade 3 or greater toxicity (42% and 51%, respectively, for each arm), and therefore, neither regimen was suitable for further development.
The RTOG 0247 trial was designed to evaluate two experimental neoadjuvant chemotherapy regimens, capecitabine plus irinotecan or capecitabine plus oxaliplatin, with concurrent standard fractionated pelvic RT in a multicenter randomized Phase II trial. We sought to examine the efficacy of these two neoadjuvant regimens as determined by the primary endpoint, the pCR rate, and to evaluate the adverse events for these regimens.
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Patient characteristics
All patients gave written informed consent in accordance with each center’s institutional review board guidelines. The eligible patients were ≥18 years old. They had a Zubrod performance of 0–2; adequate hematologic, renal, cardiac, and hepatic function; potentially resectable adenocarcinoma of the rectum originating at or below 12 cm from the anal verge without evidence of distant metastases; and clinical Stage T3, as determined by endorectal ultrasonography, or clinical Stage T4, as
Results
A total of 146 patients from 59 institutions were entered into the study between March 2004 and February 2007. In January 2005, both arms were temporarily closed because of excessive GI AEs associated with neoadjuvant therapy. Of the 18 patients, 7 developed Grade 3-4 diarrhea in Arm 1. In Arm 2, 5 of 17 patients developed Grade 3 diarrhea and 1 patient died after hospitalization for diarrhea. The protocol was amended to decrease the duration of neoadjuvant capecitabine in both arms from 7 to 5
Discussion
The important goals of rectal cancer therapy include improvement of survival, local control, and sphincter preservation. For the development of new neoadjuvant approaches, overall survival is indisputably the reference standard study endpoint by which efficacy is measured. However, several studies have demonstrated that the pCR is predictive of other clinically relevant endpoints, including sphincter preservation, relapse-free survival, and a reduction in distant metastasis 7, 8, 9, 10, 11.
Conclusions
We have shown that neoadjuvant pelvic RT with capecitabine and oxaliplatin for clinical Stage T3 and T4 rectal cancer is associated with manageable toxicity and yields a high pCR rate. The National Surgical Adjuvant Breast and Bowel Project R04 trial is testing whether the oxaliplatin regimen in the RTOG 0247 trial is superior to infusion 5-FU/oxaliplatin and also whether the addition of oxaliplatin improves the pCR rate compared with fluoropyrimidines alone. Although the results of the RTOG
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Supported by Radiation Therapy Oncology Group U10 CA21661 and CCOP U10 CA37422 grants from the National Cancer Institute and Roche Laboratories.
Conflict of interest: none.