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Originally published as JCO Early Release 10.1200/JCO.2006.09.9838 on April 30 2007 © 2007 American Society of Clinical Oncology.
The Hope for Today—The Promise for Tomorrow: Will Oncologists Meet the Challenge?
Department of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, IL The dawn of this century is witness to a paradigm of new treatment strategies for patients with colorectal cancer offering renewed hope for thousands of individuals. Hope is characteristically accompanied by the challenge of potentiating newly acquired gains. Advances should indeed form the construct of the next path toward additional change. In this issue of the Journal of Clinical Oncology, the National Surgical Adjuvant Breast and Bowel Project (NSABP) reports the results from study C-07, demonstrating the 3- and 4-year disease-free-survival (DFS) advantage for stage II and III colon cancer patients who received oxaliplatin combined with weekly bolus fluorouracil (FU) and leucovorin (FLOX) compared with those treated with the weekly bolus FU and leucovorin schedule known as the Roswell Park regimen, the control arm of previous studies.1 These results clearly redefine the superiority of an oxaliplatin-based regimen for adjuvant colon cancer therapy and confirm the results of the Adjuvant Treatment of Colon Cancer (MOSAIC) trial, which used the more widely embraced FU, leucovorin, and oxaliplatin (FOLFOX4) regimen using a continuous-infusion FU schedule.2 The 3- and 4-year DFS (76.1% v 78.2% at 3 years) and the percent difference in the 4-year DFS (6.2% v 6.6%) are similar for FLOX (C-07) and FOLFOX4 (MOSAIC), respectively. The two comparator arms for both trials, bolus FU (NSABP C-07) versus infusion FU (MOSAIC), have been widely used in the past and also resulted in a comparable DFS (71.8% v 72.9% at 3 years). There are differences in toxicity profiles among the four arms of NSABP C-07 and MOSAIC. For example, there is less neurotoxicity experienced by patients receiving FLOX compared with FOLFOX4, undoubtedly reflecting the decreased total dose of oxaliplatin in the FLOX regimen. However, grade 3 or 4 diarrhea was more commonly observed in the FLOX regimen compared with FOLFOX4 (38% v 10.8%). As expected, the Roswell Park regimen produced significantly more grade 3 or 4 diarrhea compared with the infusion FU regimen in the MOSAIC trial (32% v 6.6%). Additional analysis of the neurotoxicity experienced by patients who enrolled onto NSABP C-07 is provided in an accompanying article in this issue.3 The authors correctly note the inconsistency of the reversibility of oxaliplatin-induced neurotoxicity as reported from previous trials. NSABP C-07 and MOSAIC both have demonstrated lower grade neurotoxicity in significant numbers of patients that extends beyond 12 months. Given that the recommendation to offer patients adjuvant chemotherapy is with the intent to prolong survival further, the impact of neurotoxicity on long-term quality of life will require additional investigation and clearly is an important discussion point for patients considering oxaliplatin-based adjuvant treatment. Although 5-year survival data are not mature for either NSABP C-07 or MOSAIC, as the authors emphasized, a recent pooled analysis of more than 20,000 patients has demonstrated a strong correlation of 3-year DFS with 5-year overall survival for colon cancer adjuvant therapy.4 Therefore, the appropriate standard adjuvant chemotherapy regimen offered to the majority of qualified patients should be either FOLFOX or FLOX. The decision about which of the two oxaliplatin schedules should be chosen requires careful review of potential toxicity differences with the individual patient. The recent rapid evolution of colorectal cancer treatment strategies can now include with certainty combination therapy with oxaliplatin as an advancement for those individuals who would potentially benefit from adjuvant chemotherapy. NSABP C-07 and the MOSAIC trial included stage II and III resected colon cancer patients and demonstrated that a classic randomized phase III design still remains a valid tool. In other words, the design works. The challenge to clinical trialists, statisticians, practicing oncologists, and patients is to address whether this modus operandus works well enough. There is a growing body of evidence that questions a so-called one-size-fits-all strategy for patients with a given disease entity and stage. Colon cancer stage, in fact, remains perhaps the most powerful current predictor of prognosis. The American College of Pathologists has included both pT and pN status as category I level of evidence to support these factors as important prognostic tools.5,6 There are few other factors that reach this level of significance, including preoperative carcinoembryonic antigen and vascular and lymphatic invasion. However, even stage now defies generalized categorization or grouping of individuals as if their risk of recurrence were the same. The American Joint Committee on Cancer staging system has been revised to include two subsets of stage II patients and three subsets of stage III patients based on prognosis using pT and pN.7 Numeracy models have emerged, incorporating multiple factors, including stage, tumor grade, and lymph node status as examples to better quantitate risk of recurrence and to facilitate treatment discussions between clinician and patient.8,9 The primary analyses for NSABP C-07 and MOSAIC are predicated on a combination of stage II and III patients, rather than an analysis of individual subsets. The traditional argument has been that there is no biologic reason for a difference between these two stages and that the benefit of therapy is evident in both groups. NSABP C-07 reports "no interaction of treatment with the covariates," including presence or number of metastatic lymph nodes—a point that is emphasized throughout the publication. Both NSABP C-07 and a recent presentation of the MOSAIC 4-year DFS data suggest that the greatest percent difference between the two treatment arms was seen in the highest risk patients with N2 disease (10.8% [stage IIIC], 11.5%, respectively).10 Although there was a difference for patients with stage II disease favoring both FLOX and FOLFOX, the absolute difference was small (3.2% v 3.5%, respectively). Indeed, the adjuvant treatment approach for patients with stage II colon cancer continues to generate controversy. A recent analysis by the Cancer Care Ontario Program and the American Society of Clinical Oncology concluded that the routine use of adjuvant chemotherapy for stage II colon cancer patients cannot be recommended.11,12 Rather, it was recommended that the clinician and patient have a thorough discussion of risks and benefits before making a treatment decision. Buyse and Piedbois13 have calculated that a stage II clinical trial design of 8,000 patients would be required to demonstrate a 2.5% risk reduction at 3 years, as an example of the number of patients that would be required to clearly delineate a relatively small difference in treatment benefit; such a calculation is routinely done in low-risk breast cancer patients. While we acknowledge the stunning introduction of multiple new agents for the treatment of colorectal cancer during the last decade, resulting in true clinical benefit for patients, it is time to accelerate the infusion of new clinical trial design constructs to more effectively evaluate newer drug effects. Although it is clear that adjuvant therapy has enhanced the survival prospects for many patients, it is equally true that many thousands of patients receive no benefit at a cost of significant toxicity from currently available agents. As new biologic agents, such as bevacizumab and cetuximab, move into the adjuvant arena, it is essential to define the population that will receive benefit appropriate to the added cost and potential risks. The US Food and Drug Administration has emphasized the need for different measures of drug efficacy, given the growing imbalance in the ratio of biologic drug development expenditure versus number of license applications and submissions for biologics.14 The complexity of revamping cancer clinical trial paradigms is daunting. Although elegant preclinical models have emerged, there are no human tumor data available to predict reliably which colon cancer patients are most likely to benefit from oxaliplatin, irinotecan, fluoropyrimidines, bevacizumab, cetuximab, or panitumumab. Furthermore, the reliance on advanced disease clinical trials to predict efficacy adequately in the adjuvant setting is imperfect, at best. Data from first- and second-line advanced-disease colorectal trials of both oxaliplatin and irinotecan would have predicted that both of these agents would lead to a survival advantage in the adjuvant setting. It is unclear why NSABP C-07 and MOSAIC have demonstrated the efficacy of oxaliplatin as adjuvant therapy, whereas three recent irinotecan adjuvant trials failed to reach their designated statistical end points.15-17 Perhaps the smaller numbers of patients who are evaluated in advanced-disease trials, compared with the significantly larger populations of patients who participate in adjuvant studies, are inaccurate predictors of potential adjuvant therapy effect. With the development of new biologic therapies, the need to define the biology of the tumor for an individual becomes increasingly apparent, particularly for adjuvant patients, for whom the goal is cure without long-term sequelae. The ability to recommend a specific drug combination and/or sequence of agents for an individual based on specific molecular characteristics of the patient's tumor is an important goal. Without the integration of biology—especially during the development of new biologic agents—the risk is that we will administer the wrong or suboptimal agent or agents at the wrong dose, with the wrong schedule, to the wrong population of patients. There is an urgent need for both oncologists and patients to embrace the concept of biologically driven colon cancer trials, including risk assessment. It is true, unfortunately, that there is resistance to generate trials that will define limited subsets of patients who will achieve clinical benefit from a given intervention. There is a tension created between the pressure for rapid drug development and commercialization compared with the time commitment and costly investment inherent in conducting biologically driven trials. However, this is just the strategy that can lead to the development of individualized therapy. As an example of the commitment to colon cancer translational research, United States cooperative groups have integrated tumor acquisition as an important component of the most recent adjuvant colorectal cancer clinical trials. These trials have introduced biologic treatment in combination with FOLFOX: NSABP C-08 (bevacizumab), N0147 (cetuximab), and E5204 (bevacizumab). In addition, the US Intergroup has designed the first prospective trial for stage II colon cancer patients, which defines risk by molecular parameters (18q loss of heterozygosity, microsatellite instability) to determine intervention assignment. These trials are designed to move us closer to understanding the biology of colon cancer and the impact of adjuvant therapy for defined groups of patients. Will oncologists meet the challenge to support this current research direction vigorously? In doing so, we have the best opportunity to seize on the hope generated by recent treatment advances. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author or immediate family members 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. 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: N/A Leadership: N/A Consultant: Al B. Benson III, Sanofi-aventis, Pfizer Inc, Genentech, Amgen, ImClone Systems Inc, Roche, Bristol-Myers Squibb Co Stock: N/A Honoraria: Al B. Benson III, Sanofi-aventis, Pfizer Inc, Genentech, Amgen, ImClone Systems Inc, Roche, Bristol-Myers Squibb Co Research Funds: Al B. Benson III, Sanofi-aventis, Pfizer Inc, Genentech, Amgen, ImClone Systems Inc, Roche, Bristol-Myers Squibb Co Testimony: N/A Other: N/A NOTES published online ahead of print at www.jco.org on April 30, 2007. REFERENCES 1. 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 2. 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 3. Land SR, Kopec JA, Cecchini RS, et al: Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C-07. J Clin Oncol 25:2205-2211, 2007 4. Sargent DJ, Weind HS, Haller DG, et al: Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 23:8664-8670, 2005 5. Compton C, 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] 6. Compton CC: Key issues in reporting common cancer specimens: Problems in pathologic staging of colon cancer. Arch Pathol Lab Med 130:318-324, 2006[Medline] 7. American Joint Committee on Cancer. AJCC Cancer Staging Handbook (ed 6). New York, NY, Springer-Verlag, 2002 8. Gill S, Lopinzi 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. Desch CE, Benson AB III, Somerfield MR, et al: Colorectal Cancer Surveillance: 2005 Update of an American Society of Clinical Oncology Practice Guideline. J Clin Oncol 23:8512-8519, 2005 10. de Gramont A, Boni C, Navarro M, et al: Oxaliplatin/5FU/LV in the adjuvant treatment of stage II and stage III colon cancer: Efficacy results with a median follow-up of 4 years. J Clin Oncol 23:246s, 2005 (suppl; abstr 3501)[CrossRef] 11. Benson AB III, 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 12. 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 13. Buyse M, Piedbois P: Should Dukes' B patients receive adjuvant therapy? A statistical perspective. Semin Oncol 28:20-24, 2001 (1 suppl 1)[Medline] 14. US Department of Health and Human Services, Food and Drug Administration: Innovation–Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. Washington, DC, US Government Printing Office, March 2004 15. Saltz LB, Niedzwiecki D, Hollis D, et al: Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (Intergroup trial CALGB C89803). J Clin Oncol 22:245s, 2004 (suppl; abstr 3500)[CrossRef] 16. Van Cutsem E, Labianca R, Hossfeld D, et al: Randomized phase III trial comparing infused irinotecan/5-fluorouracil (5-FU)/folic acid (IF) versus 5-FU/FA (F) in stage III colon cancer patients (pts) (PETACC 3). J Clin Oncol 23:3s, 2005 (suppl; abstr 8) 17. Ychou M, Raoul J, Douillard J, et al: A phase III randomized trial of LV5FU2 + CPT-11 vs. LV5FU2 alone in adjuvant high risk colon cancer (FNCLCC Accord02/FFCD9802). J Clin Oncol 23:246s, 2005 (suppl; abstr 3502)[CrossRef] Related Articles
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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