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Originally published as JCO Early Release 10.1200/JCO.2006.10.4323 on September 17 2007 © 2007 American Society of Clinical Oncology. End Points for Colon Cancer Adjuvant Trials: Observations and Recommendations Based on Individual Patient Data From 20,898 Patients Enrolled Onto 18 Randomized Trials From the ACCENT Group
From the Departments of Health Sciences Research and Medical Oncology, North Central Cancer Treatment Group, Mayo Clinic, Rochester, MN; Biostatistics Center, National Surgical Adjuvant Breast and Bowel Project Statistical Center and Operations Office, Pittsburgh; Abramson Cancer Center, University of Pennsylvania; the Department of Human Oncology, Allegheny General Hospital Philadelphia, PA; Southwest Oncology Group Statistical Center; Fred Hutchinson Cancer Research Center, Seattle, WA; Eastern Cooperative Oncology Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard University, Boston, MA; Department of Hematology/Oncology, University of North Carolina, Chapel Hill, NC; Quick and Simple and Reliable Collaborative Group, Clinical Trials Unit, University of Birmingham, Birmingham and the Department of Clinical Pharmacology, University of Oxford, Oxford, United Kingdom; International Drug Development Institute, Brussels Belgium; Unit Medical Oncology, Ospedali Riuniti, Bergamo; Medical Oncology Division, Institute of Internal Medicine, University of Siena, Siena, Italy; Gastroenterology Unit, C.H.U. la Timone; University of the Mediterranean, Marseilles; Hospital Saint Antoine, Paris, France; and the National Cancer Institute of Canada Clinical Trials Group, Queens University, Kingston, Ontario, Canada Address reprint requests to Daniel J. Sargent, PhD, Mayo Clinic, 200 First St SW, Harwick 8-27, Rochester, MN 55905; e-mail: sargent.daniel{at}mayo.edu
Purpose The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency. Methods Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model. Results DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients. Conclusion DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.
Colorectal cancer is the third most common cancer in the United States, with approximately 145,000 new cases diagnosed annually. A significant number of these patients are diagnosed at a stage for which surgical resection is possible. However, approximately half of those who undergo resection with node-positive disease will experience relapse and eventually die as a result of their disease, if no interventions are performed after primary surgery. Randomized clinical trials have demonstrated that adjuvant chemotherapy can both reduce the likelihood of recurrence and improve overall survival in these patients, making it a vital component of colorectal cancer management. During the last decade, there has been considerable progress in adjuvant chemotherapy. The first approved regimen, 12 months of fluorouracil (FU) and levamisole,1 has been improved by replacing levamisole with leucovorin, reducing therapy duration to 6 months,2,3 and more recently, with the addition of oxaliplatin to FU and leucovorin.4 Capecitabine, an oral formulation of FU, is an alternative to intravenous FU and leucovorin for patients with stage III disease.5 There is great interest in the potential role of biologic agents such as bevacizumab6 and cetuximab7 coupled with chemotherapy in the adjuvant setting based on their benefit in metastatic colorectal cancer. There are a number of ongoing and completed adjuvant trials testing these strategies. An important milestone in the conduct of adjuvant colorectal cancer trials is the demonstration that valid results may be provided at an earlier time point than 5 years. In particular, based on our previous pooled analysis of 18 randomized clinical trials involving 20,898 patients, it was established that a shorter term end point, disease-free survival (DFS), assessed after 3-year median follow-up, is a valid surrogate marker for the standard end point of 5-year overall survival (OS).8 In the past, OS was widely accepted as the primary end point for adjuvant trials, with 5-year results considered adequate to demonstrate long-term efficacy. Although improving long-term OS clearly is clinically meaningful, 5 years is a long period to wait before concluding that a regimen is effective. In addition to the longer time interval required to assess OS, given the activity of newer agents in delaying progression and death after recurrence, as well as the potential for surgical resection and long-term survival after recurrence, DFS may be a more sensitive indicator of the effectiveness of adjuvant therapy. Given that more effective treatment options in the metastatic setting can now prolong median survival to close to 2 years,9 OS is likely to be influenced by salvage regimens and might not reliably or fully reflect the specific benefits of adjuvant therapy. In recent and ongoing adjuvant trials, 3-year DFS has been chosen as the primary end point. On the basis of these considerations, it is critical to explore whether there are additional, even earlier end points that could accelerate further the clinical trial process. Accurate, early predictions of efficacy may allow for a more efficient allocation of resources. We have explored this issue by examining the end points of both DFS and OS at 1-, 2-, and 3-year median or minimum follow-up. An area of ongoing debate in the treatment of colorectal cancer is the postsurgical management of patients with stage II disease.10 Given that most adjuvant trials have enrolled fewer stage II than stage III patients, meta-analyses and pooled analyses have been performed for stage II patients.11-15 Because of the lower event rate, lower absolute benefit, and greater risk of death as a result of competing causes, the relationship between DFS and OS may differ between patients with resected stage II and stage III disease. Therefore, we investigated separately the association between DFS and OS end points in patients with stage II and stage III disease.
The methods used in this study are a continuation of the retrospective pooled end points analysis of the Adjuvant Colon Cancer End Points (ACCENT) Group.8 ACCENT identified and obtained individual patient data from 18 phase III adjuvant colon clinical trials. These trials were conducted from 1978 to 1999, involved 20,898 patients, and included 43 distinct treatment arms (34 active treatment arms, nine surgery-only arms). Tables 1 and 2 list details regarding trial and patient characteristics.
We enlarged the scope of the previous analysis by comparing the association between DFS after 3-year median follow-up and OS with 5-year median follow-up separately for stage II and stage III patients, using methods described previously.8 In addition, in an effort to identify an optimal time point, DFS and OS were calculated and compared for each arm and within each trial for additional time points, including 1-year minimum follow-up, 2-year median follow-up, 2-year minimum follow-up, and 3-year minimum follow-up. OS, based on 5-year median follow-up, served as the standard for all analyses. Measures used included the correlation of hazard rates within trial arms, correlation of hazard ratios from within-study comparisons, trial level concordance based on significance testing (log-rank test),16 and trial level association from a formal surrogacy model.17 Briefly, the formal surrogacy model uses the individual patient data to estimate the relationship between the risk of recurrence and the risk of death, at both the individual and the trial levels. This approach, while powerful statistically, requires additional assumptions compared with the other methods investigated. Because of inconsistent long-term follow-up, all data were censored at 8 years.
Stage II Versus Stage III Of the 20,898 patients, 66% were stage III and 33% were stage II. Stage II patients tended to have recurrences later than stage III patients (Fig 1). During the 8-year follow-up period, 74% of stage II patients (1,075 of 1,458) who experienced recurrence had the recurrence in the first 3 years, compared with 82% of stage III patients (4,751 of 5,811). A larger proportion of deaths occurred without documented recurrence in stage II patients (32%) compared with 16% in stage III patients (P < .001). Not surprisingly, the association between DFS with 3-year median follow-up and OS with 5-year median follow-up was weaker in stage II patients than in stage III patients, with correlation between the hazard ratios for DFS and OS of 0.70 (95% CI, 0.44 to 0.80) compared with a correlation between the DFS and OS hazard ratios of 0.92 (95% CI, 0.83 to 0.95) in stage III patients (Fig 2).
The trial level association, measured on a scale from 0 to 1, based on a formal surrogacy model, was lower for patients with stage II disease, at 0.70 (95% CI, 0.47 to 0.93), compared with 0.88 (95% CI, 0.78 to 0.98) for stage III patients. We examined the trial-level concordance of outcomes measure separately, based on log-rank testing within the subgroups of stage II and stage III patients. Of the 25 within-trial comparisons, the results were concordant between the end points of 3-year DFS and 5-year OS in 22 of 25 comparisons for stage II patients, and in 20 of 25 comparisons for stage III patients. These log-rank testing results must be viewed cautiously, however, because they represent subgroup analyses within each individual trial, which do not retain the power initially designed for the trial when analyzed as a whole. In addition, for stage II patients, only one within-trial comparison was positive (as judged by P < .05) for both OS with 5-year follow-up and DFS with 3-year follow-up.
Outcome Measures for Earlier End Points
On the correlation of hazard ratios metric, OS with 3-year minimum follow-up was the most accurate predictor of 5-year OS, with an R2 value of 0.93 (95% CI, 0.85 to 0.95). Three-year minimum OS had slightly reduced trial level concordance and positive predictive value compared with 3-year median DFS, and the CIs for the correlation of hazard ratios for 3-year minimum OS overlapped with those for 3-year median DFS. However, OS at time points earlier than 3-year minimum follow-up (such as 3-year median or 2-year minimum follow-up) provided a less accurate predictive end point, with reduced association with 5-year OS rates and hazard ratios.
Adjuvant chemotherapy in colorectal cancer is a significant advance in the treatment of patients after surgical resection because of the consequent substantive survival improvement provided. Coupled with the prevalence of the disease, this therapy results in a large number of lives saved. In the past, trials were judged by the end point of OS, which translated to the ultimate goal of cure. On the basis of individual patient pooled analyses, the ACCENT Group previously proposed and validated the concept of DFS, measured at a time point of 3-year median follow-up, as a valid surrogate marker for OS. This new paradigm has contributed to the development of adjuvant strategies, allowing the faster completion of clinical trials, and has been accepted as a valid end point on which to base new drug applications in this treatment setting by the US Food and Drug Administration. In this study, we have extended and expanded our original analyses to ascertain whether there are even earlier time points and/or end points that can be used to reliably predict trial outcomes without compromising the validity of the study. Of the earlier end points evaluated, DFS evaluated at 1-year minimum and 2-year median follow-up have the greatest possible clinical utility. In these trials, DFS with 1-year minimum follow-up proved to be a perfect negative predictive marker; no trial that was negative for DFS at 1-year minimum follow-up was positive for 5-year OS. However, the positive predictive value was inferior to DFS with 3-year median follow-up, and the degree of overall association between DFS with 1-year minimum follow-up and OS with 5-year median follow-up was reduced compared with that of 3-year DFS. This finding suggests the ability to predict a negative (futility) outcome of a clinical trial rapidly, enabling the early discontinuation of negative studies through protocol-specified interim analyses, and thus the earlier initiation of a new trial. For each of the measures considered, DFS assessed after 2-year compared with 3-year median follow-up retained an excellent concordance with 5-year OS outcomes. The association between DFS at 2-year median and OS at 5-year median follow-up was reduced slightly for all measures considered compared with 3-year DFS; however, 23 of 25 within-trial comparison conclusions were consistent between 2-year DFS and 5-year OS, the same rate (23 of 25) as when 3-year DFS is used. These findings suggest DFS assessed at a 2-year median follow-up may be an appropriate primary end point for future trials. OS as an end point has obvious appeal: it is simple and unambiguous. In contrast, DFS requires some subjective judgement, and may require central review to classify a patient definitely as experiencing a recurrence. We therefore explored OS at earlier time points. On the association of the hazard ratios metric, OS with 3-year minimum follow-up demonstrated excellent association with 5-year OS, although it was not meaningfully improved compared with 3-year median DFS. However, for OS at earlier time points, such as 3-year median or 2-year minimum follow-up, the association and concordance measures reflected poor prediction, compared with 3-year DFS. In practice, the difference between performing analyses at a median follow-up versus a minimum follow-up can be profound; in this set of trials, the median calendar time between achieving 3-year median versus 3-year minimum follow-up was 1.2 years. Therefore, we prefer DFS with 3-year median follow-up to OS with 3-year minimum follow-up as an end point for future trials, given that the DFS end point is achieved earlier without sacrifice in accuracy. The trials included in this analysis enrolled patients from 1977 to 1999; therefore, we must consider whether these results apply to current clinical practice with combination chemotherapy, increased surveillance, and newer radiographic techniques. With the refinement of imaging techniques, we may be able to detect recurrences sooner, making 1-, 2-, and 3-year DFS even more sensitive end points. However, if new therapies such as biologic agents delay recurrence, as opposed to preventing recurrence, these earlier end points may be less reliable. In addition, in contrast to the earlier work on 3-year DFS, which was a prespecified hypothesis, these findings regarding 1- and 2-year DFS were not prespecified. In addition, any time savings gained by earlier analyses must be weighed against a possible increase in required trial sample size due to earlier analyses with an accompanying higher proportion of censoring. Hence, although promising, more current data and prospective validation are needed before we recommend the use of earlier end points such as 1-year DFS routinely in clinical trials. In the past, limited treatment options were available for metastatic disease. New palliative chemotherapy options have prolonged survival significantly from approximately 12 months to approximately 2 years. In addition, an increasing number of patients are being treated with potentially curative surgical resection after recurrence of disease. These factors raise the question of whether the association between DFS and OS will be as robust in future trials, in which OS will be more heavily influenced by salvage therapy, and may result in an attenuation of the treatment effect between DFS and OS, at least when OS is considered at the 5-year time point. This was illustrated in the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer, in which the previous standard of FU/leucovorin (LV) was compared with infusional FU, LV, and oxaliplatin (FOLFOX4). The primary end point was 3-year DFS, which was improved with FOLFOX4 at 78.2%, compared with 72.9% in the FU/LV arm (P = .002).4 In January 2005, after 56.2 months of median follow-up, updated information regarding DFS and OS was available. At 4 years, there continued to be a significant difference in the DFS between the two arms (76.4% v 69.8%, respectively). However, the difference in OS between the two regimens was not statistically significant, with an absolute difference of 2.1% (hazard ratio, 0.91; 95% CI, 0.75 to 1.1; P = .91).18 This result possibly may be explained by an imbalance in the number of patients alive after a recurrence (7.4% in the FOLFOX4 arm compared with 11.9% in the FU/LV arm), emphasizing the importance of salvage therapies (such as treatment with FOLFOX in those initially treated with FU/LV). Additional follow-up is required to determine the ultimate long-term OS benefit from FOLFOX4, for which long-term OS may need to be redefined as OS at 6, 7, or even 8 years. Alternatively, the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer trial may demonstrate that in an era of effective salvage therapy, OS end points are unreliable indicators of adjuvant therapy benefit, and make the additional case for moving to DFS as a primary end point in the adjuvant setting. If DFS is used as a primary end point, OS should always be included as a secondary end point. We also examined the influence of stage on the association between DFS and OS. Not surprisingly, there were fewer recurrences in the first 3 years in patients with stage II as compared with stage III disease. In addition, a greater proportion of deaths in patients with stage II disease were unrelated to cancer recurrence. As a result, there was a reduced association between DFS at 3-year median follow-up and OS at 5-year median follow-up in stage II compared with stage III patients. This has to be put in the perspective that patients with stage II disease have a heterogeneous prognosis. In patients with identified risk factors such as depth of penetration (T4), poorly differentiated tumor, presence of venous invasion, and a small number of lymph nodes examined (< eight to 12),19 the concordance between 3-year DFS and 5-year OS may improve, although this was not explored in our study. Our findings reinforce that for trials limited to patients with stage III disease, or a mix of stage II and III patients, DFS after 3-year median follow-up remains an appropriate primary end point. As a result of the factors discussed, however, the reduced association between DFS and OS in patients with stage II disease suggests that stage II–specific trials powered for a DFS end point may not demonstrate a significant OS effect. Thus, if OS remains the ultimate clinical end point, it should likely remain the primary clinical end point for stage II–specific trials. Alternatively, the demonstration of a clinically meaningful improvement in DFS may be adequate evidence of clinical benefit in patients of either stage, in which case DFS is appropriate as a primary end point regardless of its formal surrogacy with OS. In summary, in this expanded analysis of the ACCENT database, we have validated that for trials in patients with stage III disease, or a mix of stage II and III disease, DFS after 3-year median follow-up is a valid and appropriate primary end point. For trials in the stage II–only population, at this time OS remains an appropriate primary end point. The earlier end points of 1-year minimum DFS, as an early indicator of a negative outcome, and 2-year median DFS, as a primary end point, are promising and should be validated in future trials.
The author(s) indicated no potential conflicts of interest.
Conception and design: Daniel J. Sargent, Marc Buyse, Axel Grothey, Michael O'Connell, Harry S. Wieand, Richard M. Goldberg, Aimery de Gramont Financial support: Daniel J. Sargent, Michael O'Connell Administrative support: Daniel J. Sargent, Daniel G. Haller, Michael O'Connell, Harry S. Wieand, Aimery de Gramont Provision of study materials or patients: Greg Yothers, Daniel G. Haller, Richard Gray, Jacqueline Benedetti, Roberto Labianca, Jean Francois Seitz, Christopher J. O'Callaghan, Guido Francini, Michael O'Connell, Paul J. Catalano, David Kerr, Harry S. Wieand, Aimery de Gramont Collection and assembly of data: Daniel J. Sargent, Richard Gray, Jacqueline Benedetti, Michael O'Connell, Harry S. Wieand Data analysis and interpretation: Daniel J. Sargent, Smitha Patiyil, Jacqueline Benedetti, Marc Buyse, Axel Grothey, Erin Green, Harry S. Wieand, Aimery de Gramont Manuscript writing: Daniel J. Sargent, Smitha Patiyil, Greg Yothers, Daniel G. Haller, Marc Buyse, Michael O'Connell, Richard M. Goldberg Final approval of manuscript: Daniel J. Sargent, Smitha Patiyil, Greg Yothers, Daniel G. Haller, Richard Gray, Jacqueline Benedetti, Marc Buyse, Roberto Labianca, Jean Francois Seitz, Christopher J. O'Callaghan, Guido Francini, Axel Grothey, Michael O'Connell, Paul J. Catalano, David Kerr, Erin Green, Harry S. Wieand, Richard M. Goldberg, Aimery de Gramont
The following institutions and investigators participated in the Adjuvant Colon Cancer End Points (ACCENT) Collaborative Group: D.J. Sargent, E. Green, A. Grothey, S.A. Alberts, S. Patiyil (Mayo Clinic, Rochester, MN), S. Wieand, G. Yothers (NSABP Statistical Center, Pittsburgh, PA), A. De Gramont (Hospital Saint Antoine, Paris, France), R. Gray, D. Kerr (QUASAR Collaborative Group, Birmingham and Oxford, United Kingdom), D.G. Haller (Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA), J. Benedetti (SWOG Statistical Center, Seattle, WA), M. Buyse (IDDI, Brussels, Belgium), R. Labianca (Ospedali Riuniti, Bergamo, Italy), J.F. Seitz (University of the Mediterranean, Marseilles, France), C.J. O'Callaghan (NCIC-CTG, Queens University, Kingston, ON, Canada), G. Francini (University of Siena, Siena, Italy), P.J. Catalano (ECOG Statistical Center, Boston, MA), C.D. Blanke (Oregon Health and Science University Cancer Institute, Portland, OR), T. Andre (GERCOR, Paris, France), R.M. Goldberg, H. Kelly (University of North Carolina, Chapel Hill, NC), A. Benson (University of Chicago, Chicago, IL), M.J. O'Connell, and N. Wolmark (NSABP Operations Office, Pittsburgh, PA).
published online ahead of print at www.jco.org on September 17, 2007. Supported by National Cancer Institute Grant No. CA25224. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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. Haller DG, Catalano PJ, Macdonald JS, et al: Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: Final report of Intergroup 0089. J Clin Oncol 23:8671-8678, 2005 3. Wolmark N, Rockette H, Mamounas EP, et al: Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: Results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 17:3553-3559, 1999 4. André T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, 5-fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004 5. Twelves C, Wong A, Nowacki MP, et al: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696-2704, 2005 6. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 7. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 35:337-345, 2004 8. Sargent DJ, Wieand 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 9. Kelly H, Goldberg RM: Systemic therapy for metastatic colorectal cancer: Current options, current evidence. J Clin Oncol 23:4553-4560, 2005 10. 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 11. 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 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. 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 14. Gray R, Barnwell J, Hills R, et al: QUASAR: A randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. J Clin Oncol 22:245s, 2004 (suppl; abstr 3501)[CrossRef] 15. 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 16. Begg CB, Leung DHY: On the use of surrogate end points in randomized trials. J R Stat Soc (Ser A) 163:15-24, 2000[CrossRef] 17. Burzykowski T, Molenberghs G, Buyse M, et al: Validation of surrogate end points in multiple randomized clinical trials with failure time end points. Appl Stat 50:405-422, 2001 18. 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] 19. André T, Sargent D, Tabanero J, et al: Current issues in adjuvant treatment of stage II colon cancer. Ann Surg Oncol 13:887-898, 2006[CrossRef][Medline] Submitted December 18, 2006; accepted May 23, 2007.
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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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ABSTRACT
INTRODUCTION
