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Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3311-3313 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.11.691
FOLFOX for Stage II Colon Cancer? A Commentary on the Recent FDA Approval of Oxaliplatin for Adjuvant Therapy of Stage III Colon Cancer1 Mayo Clinic College of Medicine, Departments of Medical Oncology, Rochester, MN
2 Mayo Clinic College of Medicine, Health Science Research, Rochester, MN For almost 15 years, adjuvant chemotherapy has been known to improve disease-free survival (DFS) and overall survival (OS) in colon cancer. The pivotal study, 1 published by Charles Moertel in 1990, demonstrated improved OS and DFS for 12 months of treatment with bolus fluorouracil (FU) and levamisole, and led to the first National Cancer Institute (NCI) consensus recommendation for stage III colon cancer.2 Subsequent studies conducted in the 1990s established 6 to 8 months of adjuvant therapy with bolus FU plus leucovorin (LV) as standard of care. The positive results of the international MOSAIC (Multi-center International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) trial,3 which enrolled both stage II and III patients, led to US Food and Drug Administration approval of oxaliplatin plus FU/LV (FOLFOX) for patients with stage III colon cancer in November 2004,4 which followed the European approval as "adjuvant treatment of stage III (Dukes C) colon cancer after complete resection of the primary tumor" in September 2004. The US Food and Drug Administration approval was based on the demonstration of the statistical superiority of FOLFOX to infusional plus bolus FU/LV (LV5FU2 regimen) in 3- and 4-year DFS in the stage III subgroup of patients in the MOSAIC trial.3,5 Whereas the approval of FOLFOX in the adjuvant setting is a welcome and clinically important addition to improving outcome in patients with locally advanced colon cancer, the restriction of the labeled approval (in the United States and Europe) to stage III disease alone warrants further discussion. The MOSAIC trial was designed to evaluate the efficacy of FOLFOX4 compared with LV5FU2 in patients with both stage II and stage III colon cancer.3 The study design assumed that 40% of patients enrolled would have stage II disease, with stage III disease in the remaining 60%. Randomization was stratified by stage, and this projected ratio was achieved exactly when the accrual goal of 2,248 patients was met. The protocol-specified primary end point for the trial was 3-year DFS for the entire study population, and although an analysis stratified by stage was planned, subset analyses comparing the efficacy of treatment within each stage were not. Thus, the approval of FOLFOX as adjuvant treatment solely for stage III colon cancer is based on an analysis that was neither protocol specified nor powered for this analysis. This practice is statistically questionable, and to our knowledge is unusual in the history of the US Food and Drug Administration. Accepting subgroup analysis of clinical trials as a basis for drug approval may open the door for potential future approaches to "rescue" an otherwise negative trial by demonstrating a statistically significant result in a specific subgroup of patients enrolled in the trial. Alternatively, a trial could have a positive (significant) overall result, but due to power considerations, fail to be positive in any specific subgroup. Previously, the US Food and Drug Administration has (rightfully) rejected subgroup analyses as a potential basis for drug approval. Therefore, it is of great interest to note that in the case of the MOSAIC trial, the US Food and Drug Administration departed from this well-established practice. The precedent of approval in a subset of patients might be understood if there was clear and compelling evidence of an interaction, in this case of treatment efficacy by stage, or if the subset of patients excluded was a small fraction of the total trial. However, neither of these factors exists in this case: the P value for a test of statistical interaction between treatment effect and stage is .77, and the hazard ratios by stage for DFS are almost identical: 0.76 (95% CI, 0.62 to 0.92) for stage III patients (60%) and 0.80 (95% CI, 0.56 to 1.15) for the 40% of patients who had stage II disease. Perhaps more important than the statistical or regulatory considerations, the decision to restrict approval of FOLFOX as adjuvant therapy to stage III colon cancer has severe clinical implications. The value of adjuvant therapy for stage II disease has been debated for decades. However, recent data from large trials as well as pooled analyses are consistent.6-10 FU-based adjuvant chemotherapy in stage II patients is associated with a 2% to 4% benefit in 5-year DFS compared with surgery alone. Whether this difference is statistically significant in a particular trial is more a question of the sample size of the trial than of the actual efficacy of adjuvant therapy. Thus, further trials in unselected stage II patients to answer the question of whether adjuvant therapy benefits stage II patients are not required. Before the MOSAIC results, it was appropriate to propose that no treatment-control trials might still have been appropriate for patients who would decline therapy for this modest gain, and who seek a larger improvement. The new MOSAIC results, however, call the appropriateness of a no-treatment control group in stage II patients into further question. On the basis of the MOSAIC results, adjuvant therapy for stage II patients with FOLFOX provides an improvement of 2.7% in 3-year DFS and 3.8% in 4-year DFS compared with optimized (infusional) FU/LV therapy.3,5 On the basis of these findings, with an admitted between-trial extrapolation, the best estimate is that FOLFOX improves DFS by 6% to 7% compared with surgery alone in patients with stage II disease. This magnitude of benefit translates into a number needed to treat of approximately 15 patients for each DFS event prevented,11 which is modest compared with many interventions in oncology, and of a magnitude observed for FU/LV versus no treatment in stage III patients.12 If we postulate a 6% gain in 3-year DFS with FOLFOX in unselected stage II patients, this would translate in additional 1,250 patients free of disease every year in the United States (based on overall annual incidence of colon cancer in the United States of 105,000; 28% stage II; 3-year benefit of 6%; minus 30% nontreated patients).13 Future incremental advances in treatment could make the US Food and Drug Administration’s decision even less tenable. For example, in the current National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 trial, in which bevacizumab will be added to FOLFOX, a further 2% to 3% improvement for stage II patients compared to FOLFOX alone may not in and of itself be considered clinically relevant, despite a total patient benefit compared with no treatment that is clearly clinically important. The stage-limited approval of FOLFOX has an additional direct clinical consequence. Adjuvant therapy for colon cancer should be directed toward improving the outcome in patients at risk for recurrence. The American Joint Committee on Cancer stage is one tool that can help to assign patients to a certain risk group; however, it is surely not the only parameter that describes the individual risk of recurrence and death for a patient. In this context, clinical risk factors have already been identified that allow the classification of patients with stage II disease as being at high risk in clinical practice. These risk factors include T4 tumors, undifferentiated tumors, venous invasion, obstruction or perforation, and the number of lymph nodes examined in specimen.8,14-18 For example, in patients with stage II disease, a recent analysis demonstrated an improvement in 5-year OS from 73% to 87% on the basis of an increase in the number of lymph nodes recovered in the specimen from 1 to 10 to > 2015—a larger impact than any adjuvant treatment to date. It is well known that some patients with stage II tumors have a prognosis similar to or even worse than some stage III patients. The latest staging recommendations on colon cancer issued by the American Joint Committee on Cancer distinguish between lymph node-negative patients with T3 and T4 tumors as stage IIa and IIb, respectively.16 Similarly, lymph node-positive, stage III cancers are now classified into stage IIIa (T1to T2, N1), IIIb (T3 to T4, N1), and IIIc (any T, N2). It is of note that 72.2% of patients with stage IIb disease are alive after 5 years compared with 83.4% of patients with stage IIIa tumors.16 From a clinical perspective, it is obvious that a 56-year-old patient who presents with a T4 N0 G3 tumor that is obstructive, shows venous invasion, and in which only six lymph nodes can be found is at higher risk for recurrence and death than a 70-year-old patient with a T2, clinically uncomplicated tumor in which one of 22 lymph nodes is positive. If one is willing to use data from a trial to make such a point, a subset analysis of the MOSAIC trial demonstrated that high-risk stage II disease derived the same benefit from FOLFOX compared with LV5FU2 as unselected stage III patients (4-year DFS of 84.9% versus 79.8%, respectively; hazard ratio, 0.72).19 It must be made clear that we are not calling for the use of adjuvant chemotherapy in general, or FOLFOX in particular, in all patients with stage II colon cancer. But by not approving FOLFOX as an option for the treatment of stage II colon cancer, the US Food and Drug Administration has limited the treatment options for oncologists who, according to recently published American Society of Clinical Oncology guidelines,20 should discuss the risk:benefit ratio of adjuvant chemotherapy in patients with stage II disease with the individual patient. In view of the restrictive US Food and Drug Administration approval, for patients for whom reimbursement is a factor, this discussion between patient and physician will have to exclude the currently most effective adjuvant chemotherapy for colon cancer. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Axel Grothey, Genentech, Hoffmann-LaRoche, Sanofi-Aventis; Daniel J. Sargent, Baxter, Sanofi-Aventis. Honoraria: Axel Grothey, Genentech, Hoffmann-LaRoche, Sanofi-Aventis; Daniel J. Sargent, Baxter, Sanofi-Aventis. Research Funding: Axel Grothey, Sanofi-Aventis. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue. REFERENCES 1. Moertel CG, Fleming TR, Macdonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352-358, 1990[Abstract]
2. NIH consensus conference: Adjuvant therapy for patients with colon and rectal cancer. JAMA 264:1444-1450, 1990
3. Andre 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 4. Food and Drug Administration: Eloxatin: New or modified indication. Washington, DC, US Food and Drug Administration, 2004 5. de Gramont A, Boni C, Navarro M, et al: Oxaliplatin/5-FU/LV in stage II and III colon cancer: Updated results (as of January 04) for efficacy and neurotoxicity of the MOSAIC trial. Ann Oncol 15:III73, 2004 (abstr 275PD; suppl 3)
6. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer: International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol 17:1356-1363, 1999
7. Figueredo A, Charette ML, Maroun J, et al: Adjuvant therapy for stage II colon cancer: A systematic review from the Cancer Care Ontario Program in evidence-based care's gastrointestinal cancer disease site group. J Clin Oncol 22:3395-3407, 2004
8. Gill S, Loprinzi CL, Sargent DJ, et al: Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? J Clin Oncol 22:1797-1806, 2004 9. Gray R, Barnwell J, Hills R, et al: QUASAR: A randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. Proc Am Soc Clin Oncol 22:246, 2004 (abstr 3501)
10. Mamounas E, Wieand S, Wolmark N, et al: Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: Results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 17:1349-1355, 1999
11. Chatellier G, Zapletal E, Lemaitre D, et al: The number needed to treat: A clinically useful nomogram in its proper context. BMJ 312:426-429, 1996
12. Sargent DJ, Goldberg RM, Jacobson SD, et al: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345:1091-1097, 2001
13. Jemal A, Murray T, Ward E, et al: Cancer Statistics, 2005. CA Cancer J Clin 55:10-30, 2005 14. Compton CC, Fielding LP, Burgart LJ, et al: Prognostic factors in colorectal cancer: College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 124:979-994, 2000[Medline]
15. Le Voyer TE, Sigurdson ER, Hanlon AL, et al: Colon cancer survival is associated with increasing number of lymph nodes analyzed: A secondary survey of Intergroup trial INT-0089. J Clin Oncol 21:2912-2919, 2003
16. O'Connell JB, Maggard MA, Ko CY: Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 96:1420-1425, 2004 17. Steinberg SM, Barkin JS, Kaplan RS, et al: Prognostic indicators of colon tumors: The Gastrointestinal Tumor Study Group experience. Cancer 57:1866-1870, 1986[CrossRef][Medline] 18. Wolmark N, Wieand HS, Rockette HE, et al: The prognostic significance of tumor location and bowel obstruction in Dukes B and C colorectal cancer: Findings from the NSABP clinical trials. Ann Surg 198:743-752, 1983[Medline] 19. Hickish T, Boni C, Navarro M, et al: Stage II patients in the "MOSAIC" trial evaluating oxaliplatin/5-FU/LV as adjuvant treatment of colon cancer: A subpopulation analysis. Ann Oncol 15:III76, 2004 (abstr 284P; suppl 3)
20. Benson AB 3rd, Schrag D, Somerfield MR, et al: American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22:3408-3419, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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