Should Oxaliplatin Be Added to Preoperative Chemoradiation?
Oxaliplatin radiosensitizes human colon carcinoma cells in preclinical models, and it has been shown to improve the efficacy of fluoropyrimidines (FPs) in the treatment of metastatic and radically resected, early-stage colon cancer. Its combination with 5-fluorouracil (FU) and radiation in the preoperative treatment of rectal cancer may thus result in improved control of micrometastases at distant sites and increased local tumor shrinkage before surgery. High rates of tumor sterilization at surgery were indeed observed in multiple phase I–II studies testing the combination of oxaliplatin with FPs and preoperative radiation, particularly when a weekly schedule was used for oxaliplatin administration. Seven randomized trials have then been launched to investigate the addition of oxaliplatin to preoperative radiation and concomitant fluorouracil or capecitabine. Safety and activity data have now been reported. The results consistently indicate that adding oxaliplatin to a fluoropyrimidine does not improve primary tumor response to preoperative chemoradiation with only one study showing a statistically significant, but limited, improvement in the rate of complete tumor sterilization at surgery and other measures of response to neoadjuvant chemoradiation similarly distributed between the groups treated with or without oxaliplatin in all of these studies. Conversely, toxicity was significantly increased when oxaliplatin was added to standard, FP-based preoperative chemoradiation. Data on clinical outcome have been so far published for four out of seven studies and show a small improvement in 3- or 5-year DFS that reaches statistical significance in only one study. There was no impact on local control, while distant metastases were slightly reduced in the three studies reporting on this endpoint (with statistical significance in one of them). While further follow-up of these trials and clinical outcome data of STAR-01 and PETACC-6 are awaited to fully understand the role of oxaliplatin added to preoperative chemoradiation, alternative strategies are being developed to incorporate oxaliplatin in the preoperative treatment of locally advanced rectal cancer, including neoadjuvant chemotherapy before chemoradiation and consolidation chemotherapy in the interval between chemoradiation and surgery.
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