Oxaliplatin or Irinotecan As Adjuvant Therapy for Colon Cancer: The Results Are In
Authors: Michael J. O'Connell
Journal: Journal of Clinical Oncology (2009)

Both oxaliplatin and irinotecan are effective when combined with fluorouracil and leucovorin for the treatment of metastatic colorectal cancer, and both are approved by the US Food and Drug Administration for this indication. Yet, as we see in the mature results of two large clinical trials published in this issue of the Journal of Clinical Oncology, these two agents perform very differently in the adjuvant setting after surgical resection of a primary colon cancer. I will recap and comment on the primary findings of these two clinical trials, examine the results of other clinical trials using these agents in the adjuvant setting, speculate on reasons for the diverse findings, and take a brief look to the future of colon cancer adjuvant therapy. Van Cutsem et al reported a randomized phase III trial comparing biweekly infusional fluorouracil (FU) and leucovorin (LV) alone or with irinotecan in the adjuvant treatment of stage III colon cancer (PETACC-3). This carefully analyzed and conservatively interpreted study failed to demonstrate a significant improvement in the prespecified primary end point of disease-free survival (DFS) among 2,094 patients with stage III colon cancer treated with the LV25FU (de Gramont) regimen, with or without the addition of irinotecan. There was a trend in favor of the irinotecan combination (5-year DFS, 56.7% v 54.3%; hazard ratio [HR], 0.90; log-rank P .106). Combining irinotecan with LV5FU2 did not significantly improve overall survival (OS) compared with LV5FU2 alone (5-year rate, 73.6% v 71.3%; log-rank P .094). After adjustment for imbalances in the TNM status between treatment groups, a multivariate analysis “rendered” a statistically significant DFS advantage in favor of the irinotecan arm (risk adjusted HR, 0.86; P .021). If relapse-free survival was used in this patient group (rather than DFS), a highly significant advantage for the irinotecan regimen could be achieved (risk adjusted HR, 0.84; P .009). Severe gastrointestinal and hematologic toxicity was increased in patients receiving irinotecan. The authors appropriately conclude “Although it is possible that the lower relative dose intensity and the higher number of patients with a T4 tumor in the irinotecan/LV5FU2 group compared with the LV5FU2 group may have masked a significant advantage for the addition of irinotecan to LV5FU2, the current study fails to support the use of irinotecan-based regimens in the adjuvant setting.” They did not fall prey to overinterpretation of secondary or unplanned subset analyses. These negative results for irinotecan are mirrored in two other colon cancer adjuvant studies which have recently been reported. The multicenter adjuvant phase III trial published by Ychou et al evaluated the addition of irinotecan to LV5FU2 in colon cancer patients specifically at high risk of relapse. This study randomly assigned 400 patients with either N1 tumors with obstruction/perforation or N2 tumors to LV5FU2, with or without irinotecan. There was no evidence of improvement in DFS and OS in patients receiving irinotecan, and higher rates of grade 3 and 4 neutropenia. Saltz et al published the results of Cancer and Leukemia Group B study 89803, which demonstrated in 1,264 patients with stage III colon cancer that the addition of irinotecan to a bolus schedule of 5FU/LV in the bolus irinotecan, fluorouracil, and leucovorin (IFL) regimen failed to demonstrate any improvement in DFS or OS, but did show a significant increase in severe or lethal toxicity with the addition of irinotecan. We could not agree more with the take home message from this study as articulated by Saltz et al: “This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies.” One can only speculate how many patients were prematurely exposed to the toxic and ineffective IFL regimen as adjuvant therapy in clinical practice before the results of the CALGB trial became available. The possibility that irinotecan combined with FU and LV might be effective as adjuvant therapy in certain subsets of patients with colon cancer defined by various tumor markers was reasonably raised by van Cutsem et al. We await these exploratory analyses with interest. Andre Andre et al also report their results in an article in this issue of the Journal of Clinical Oncology. Among 2,246 patients randomly assigned, those receiving oxaliplatin in addition to the LV5FU2 regimen (FOLFOX) after resection of a stage II or III colon cancer experienced improved survival compared to patients treated with LV5FU2 alone (6-year OS rates were 78.5% and 76.0%, respectively; HR, 0.84; P .046). An update on DFS (the study primary end point) revealed a durable improvement with FOLFOX (5-year DFS rates were 73.3% and 67.4%, respectively; HR, 0.80; P .003). Subset analyses demonstrate a significant improvement in 5-year DFS and 6-year OS in patients with stage III disease, but failed to demonstrate a significant improvement in stage II. The authors concluded that adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II/III colon cancer, a conclusion with which we wholeheartedly agree. However, they indicate that FOLFOX should be considered only for patients with stage III disease. This is vexing, since the improvements in HRs for the primary end point (DFS) were similar between the two treatment groups in patients with stage II (HR, 0.84) and stage III disease (HR, 0.78), and the study was extremely underpowered to detect a significant benefit for FOLFOX JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 19 JULY 1 2009