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Originally published as JCO Early Release 10.1200/JCO.2009.22.2919 on May 18 2009 © 2009 American Society of Clinical Oncology.
Oxaliplatin or Irinotecan As Adjuvant Therapy for Colon Cancer: The Results Are InNational Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA 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,1,2 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 al1 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 al3 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 89803,4 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.1 We await these exploratory analyses with interest. André et al2 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 among stage II patients. Furthermore, among the stage III patients there was no significant survival benefit for females, patients 65 years or older, those with T4 tumors, N1 disease, carcinoembryonic antigen 5 or higher, or patients with poorly differentiated tumors or tumors with vascular invasion. Should patients in any of these categories be denied treatment with FOLFOX based on these subset analyses? It is remarkable that the US Food and Drug Administration approved oxaliplatin combined with FU and LV as adjuvant therapy only for patients with stage III disease based on a subset analysis in this single randomized clinical trial. Grothey and Sargent eloquently discussed the possibility that some patients with stage II colon cancer may benefit from FOLFOX adjuvant therapy, and shined a spotlight on the questionable regulatory decision of the US Food and Drug Administration5 based on the original report by André et al.6 It is also instructive that a significant survival advantage emerged only after a median follow-up of 81.9 months in the study reported by André et al2 in this issue of Journal of Clinical Oncology. This may well be related to the improved survival after tumor relapse in patients undergoing adjuvant treatment for colon cancer due to more effective surgical and systemic therapy of metastatic disease as described in a recent publication by the ACCENT (Adjuvant Colon Cancer End Points) group.7 Future adjuvant studies in colon cancer will require more than 5 years of follow-up to reliably evaluate potential survival benefit. Ultimately we strive not to focus on methodologic or administrative issues related to an individual clinical trial, but rather to seek the truth. The results of National Surgical Adjuvant Breast and Bowel Project C-078 are useful in further evaluating the benefits of adding oxaliplatin to FU/LV as adjuvant therapy of patients with stage II and III colon cancer. This study randomly assigned 2,492 patients to receive a bolus regimen of FU and LV (Roswell Park Regimen) alone or in combination with oxaliplatin (bolus FU, LV, and oxaliplatin [FLOX] regimen) after a potentially curative resection. Like the MOSAIC (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study reported by André et al,2 a significant benefit was seen in the primary study end point (DFS) with FLOX (the 4-year DFS rates were 73.2% and 67.3%, respectively; HR, 0.80; log-rank P < .004).9 Like the MOSAIC study, with a median follow-up of 42.5 months, there was no significant difference in survival between treatment groups. An analysis of survival is planned in 2009 to determine whether the survival benefit which emerged with longer follow-up in MOSAIC will also be observed in NSABP C-07. Like MOSAIC, there was no significant stage by treatment interaction —and like MOSAIC the study was not powered to detect an improvement in patients with stage II disease. In subset analyses, a significant improvement in DFS could only be demonstrated in stage III patients treated with FLOX. What is the take home message here for clinicians and patients? We believe that either FOLFOX or FLOX is more effective than the respective regimens without oxaliplatin as adjuvant therapy for colon cancer. In patients with node-positive colon cancer the combination of FU, LV, and oxaliplatin unequivocally improves DFS and can be recommended in clinical practice. These studies do not rule out benefit for patients with stage II colon cancer, although the absolute magnitude of benefit is likely to be small in unselected patients. Stage II patients with high-risk features, such as poorly differentiated tumors, T4 tumors, and tumors with vascular invasion, may be the best candidates to receive oxaliplatin as part of their adjuvant therapy regimen, but this decision needs to be individualized based on the overall clinical assessment of the patient. Let us return to the question of why irinotecan has failed to demonstrate an advantage in the colon cancer surgical adjuvant setting while oxaliplatin is clearly of benefit. First, although the two head-to-head comparisons of FOLFOX and infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) in metastatic disease10,11 failed to show a significant difference in progression-free survival (PFS), each of these studies was remarkably underpowered to rule out a clinically meaningful difference between these regimens. Thus, the lack of adequately powered head-to-head comparisons between FOLFOX and FOLFIRI leaves open the possibility that FOLFOX may be superior to FOLFIRI. Although intergroup study N9741 found a significant improvement in PFS for FOLFOX compared to the IFL regimen,12 it must be kept in mind that the markedly different schedules of FU and LV used in these regimens precludes the use of this trial as a direct comparison of irinotecan to oxaliplatin efficacy. Second, it is possible that metastatic colon tumors may have different biochemical and molecular characteristics compared to primary and/or micrometastatic colon tumors (eg, different levels of topoisomerase I) that could explain greater efficacy of irinotecan in patients with metastatic disease, although this is merely speculation. Definitive noninferiority studies comparing FOLFOX and FOLFIRI in patients with advanced colorectal cancer have simply not been done. Finally, what can we envision as the future of colon cancer adjuvant therapy? Clearly, there is much interest in evaluating targeted monoclonal antibodies such as bevacizumab and cetuximab combined with chemotherapy. The efficacy results of NSABP C-08, which compares FOLFOX with or without bevacizumab, is expected in the near future. The AVANT trial, which compares FOLFOX with or without bevacizumab, and capecitabine and oxaliplatin (CAPOX) plus bevacizumab, has completed accrual. Intergroup trial N0147, comparing FOLFOX with or without cetuximab, is nearing its accrual target. Eastern Cooperative Oncology Group 5202 is actively accruing stage II patients based on molecular markers to direct management to observation or a random assignment between FOLFOX with or without bevacizumab. As we look toward future generations of colon cancer adjuvant trials, the concept of individualized therapy based on prognostic and predictive molecular markers to better select patients who would benefit from a specific intervention is likely to be integral. Likewise, laboratory data to stratify colon cancer into several subtypes based on genetic and epigenetic factors is emerging. Colon cancer is becoming more complex as we advance our understanding about fundamental biology at the molecular level. These advances are likely to require collaboration on a global level to accrue the necessary number of patients to answer different therapeutic questions in the various subtypes of colon cancer. We have come a long way since the first demonstration of effective adjuvant chemotherapy for colon cancer in 1990 by Moertel et al.13 The prospect for further advances seems to be within our reach, and will be demonstrated by well conducted phase III clinical trials as reported in this issue of the Journal. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Michael J. O'Connell, Sanofi Aventis (U) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Van Cutsem E, Labianca R, Bodoky G, et al: Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 27:3117–3125, 2009. 2. André T, Boni C, Navarro M, et al: Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109–3116, 2009. 3. Ychou M, Raoul JL, Douillard JY, et al: A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol 20:674–680, 2009. 4. Saltz LB, Niedzwiecki D, Hollis D, et al: Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: Results of CALGB 89803. J Clin Oncol 25:3456–3461, 2007. 5. Grothey A, Sargent D: FOLFOX for stage II colon cancer? A commentary on the recent FDA approval of oxaliplatin for adjuvant therapy of stage III colon cancer. J Clin Oncol 23:3311–3313, 2005. 6. André T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351, 2004. 7. O'Connell MJ, Campbell ME, Richard M, et al: Survival following recurrence in stage II and III colon cancer: Findings from the ACCENT data set. J Clin Oncol 26:2336–2341, 2008. 8. Kuebler JP, Wieand HS, O'Connell MJ, et al: Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II, and III colon cancer: Results from NSABP C-07. J Clin Oncol 25:2198–2204, 2007. 9. Sharif S, O'Connell MJ, Yothers G, et al: FOLFOX and FLOX regimens for the adjuvant treatment of resected stage II and III colon cancer. Cancer Invest 26:956–963, 2008.[CrossRef][Medline] 10. Colucci G, Gebbia V, Paoletti G, et al: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23:4866–4875, 2005. 11. Tournigand C, André T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229–237, 2004. 12. Goldberg RM, Sargent DJ, Morton R, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30, 2004. 13. Moertel CG, Fleming TR, Macdonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med, 352–358, 1990.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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