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Originally published as JCO Early Release 10.1200/JCO.2006.08.2974 on April 30 2007 © 2007 American Society of Clinical Oncology. Oxaliplatin Combined With Weekly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for Stage II and III Colon Cancer: Results From NSABP C-07
From the National Surgical Adjuvant Breast and Bowel Project Operations Office and Biostatistical Center; Department of Biostatistics, University of Pittsburgh, Graduate School of Public Health; Allegheny General Hospital; Division of Hematology/Oncology, University of Pittsburgh, Cancer Institute; Department of Medicine, University of Pittsburgh, Pittsburgh, PA; Columbus Community Clinical Oncology Program (CCOP), Columbus, OH; Department of Surgery, Helen F. Graham Cancer Center, Newark, DE; Australasian Gastro-Intestinal Trials Group, University of Sydney, Sydney, Australia; Atlanta Cancer Care, Atlanta, GA; Southeast Cancer Control Consortium, Goldsboro; Surgical Oncology Service, Wake Forest University, Winston-Salem, NC; Division of Surgical Oncology, Harry and Jeanette Weinberg Cancer Institute at Franklin Square Hospital Center, Baltimore, MD; Cancer Research for the Ozarks (CCOP), Springfield, MO; Hematology/Oncology Department, Kaiser Permanente, Northern California, Vallejo, CA; Division Hematology/Oncology, Department of Medicine, Michigan State University, East Lansing, MI; Metro-Minnesota CCOP, Minneapolis, MN; CCOP Missouri Valley Cancer Consortium, Omaha, NE; Northwest CCOP, Tacoma, WA; and the Columbia River Oncology Program, Portland, OR Address reprint requests to Michael J. O'Connell, MD, NSABP East Commons Professional Bldg, Four Allegheny Center, Pittsburgh, PA 15212; e-mail: michael.o'connell{at}nsabp.org
Purpose: This phase III clinical trial evaluated the impact on disease-free survival (DFS) of adding oxaliplatin to bolus weekly fluorouracil (FU) combined with leucovorin as surgical adjuvant therapy for stage II and III colon cancer. Patients and Methods: Patients who had undergone a potentially curative resection were randomly assigned to either FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus leucovorin 500 mg/m2 IV weekly for 6 weeks during each 8-week cycle for three cycles (FULV), or the same FULV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). Results: A total of 2,407 patients (96.6%) of the 2,492 patients randomly assigned were eligible. Median follow-up for patients still alive is 42.5 months. The hazard ratio (FLOX v FULV) is 0.80 (95% CI, 0.69 to 0.93), a 20% risk reduction in favor of FLOX (P < .004). The 3- and 4-year disease-free survival (DFS) rates were 71.8% and 67.0% for FULV and 76.1% and 73.2% for FLOX, respectively. Grade 3 neurosensory toxicity was noted in 8.2% of patients receiving FLOX and in 0.7% of those receiving FULV (P < .001). Hospitalization for diarrhea associated with bowel wall thickening occurred in 5.5% of the patients receiving FLOX and in 3.0% of the patients receiving FULV (P < .01). A total of 1.2% of patients died as a result of any cause within 60 days of receiving chemotherapy, with no significant difference between regimens. Conclusion: The addition of oxaliplatin to weekly FULV significantly improved DFS in patients with stage II and III colon cancer. FLOX can be recommended as an effective option in clinical practice.
Postoperative adjuvant chemotherapy for patients with high-risk colon cancer has been demonstrated to improve patient outcome by a series of clinical trials dating back to 1990,1-8 and has become the standard of care in the United States. A clinical trial (Multicenter International Study of Oxaliplatin/5-Fluorouracil, Leucovorin in the Adjuvant Treatment of Colon Cancer [MOSAIC]) reported by Andre et al7 revealed that adding oxaliplatin to a regimen of bolus and continuous-infusion fluorouracil (FU) combined with leucovorin (LV; FOLFOX4) produced a significant improvement in 3-year disease-free survival (DFS) compared with the same regimen of FU and LV administered alone (FULV). Additional follow-up has demonstrated that the advantage for FOLFOX4 has been maintained.8 Based on the results of the MOSAIC trial, the US Food and Drug Administration has approved the FOLFOX4 regimen for postoperative adjuvant therapy in patients with stage III colon cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) launched a parallel clinical trial in 2000 (protocol C-07, Consolidated Standards of Reporting Trials [CONSORT] diagram; Fig 1) to evaluate the addition of oxaliplatin to a weekly Roswell Park regimen of bolus FU and LV (FLOX)9,10 previously shown to be effective as surgical adjuvant therapy for patients with stage II and III colon cancer,3 and widely used in clinical practice in the United States. The preliminary results of this trial were reported at the 41st Annual Meeting of the American Society of Clinical Oncology (2005).11 This report presents the results at 675 events for the primary end point (DFS), the protocol-specified criteria for the definitive analysis.
Eligibility Patients eligible for this trial had either stage II (T3-4, N0, M0) or stage III (T1-4, N1-2, M0) colon cancer and had undergone potentially curative surgical resection with no evidence of residual malignant disease within 42 days before random assignment. The distal end of the tumor had to be more than 12 cm from the anal verge. Adequate hematologic, renal, and hepatic function were required. Patients with clinically significant peripheral neuropathy (grade 2 or higher; National Cancer Institute Common Toxicity Criteria Version 2.0), those with other medical conditions that would preclude chemotherapy administration, and patients with a history of colon cancer or other invasive cancers were excluded. Laparoscopic colectomy was allowed only for patients who were also enrolled onto one of two phase III clinical trials designed to evaluate the efficacy of laparoscopic colon resection. This trial was approved by local human investigations committees or institutional review boards in accordance with assurances filed with and approved by the Department of Health and Human Services. Written informed consent was required for participation in the trial.
Pretreatment Evaluation and Follow-Up
Randomization Procedures
Treatment FLOX regimen. FU and LV were administered exactly as described for FULV. In addition, oxaliplatin 85 mg/m2 was administered as a 2-hour infusion before LV and FU on days 1, 15, and 29 of the treatment cycle. Patients were to receive three cycles of therapy for a total treatment duration of 6 months.
Statistical Methods
The time to an event was measured from the date of random assignment. When P values were obtained for comparisons of categoric data, they were computed using Fisher's exact test or Pearson's
Patient Disposition and Characteristics The study accrued 2,492 patients (1,245 to the FULV arm and 1,247 to the FLOX arm) from February 1, 2000, to November 15, 2002. Fifty-eight patients (2.3%) were deemed ineligible (23 assigned to the FULV arm and 35 assigned to the FLOX arm). Twenty-seven other patients (15 assigned to the FULV arm and 12 assigned to the FLOX arm) had no follow-up data (25 were consent withdrawals) and were not included in the analyses. Thus, 2,407 patients (96.6% of those randomly assigned) were included in the analyses (1,207 in the FULV arm and 1,200 in the FLOX arm). The patient characteristics for this cohort are listed in Table 1. Twenty-five (10%) of the eligible patients with follow-up failed to begin their assigned therapy (nine FULV patients and 16 FLOX patients). These patients were included in the efficacy analysis.
All patients had entered the study at least 34 months before this analysis. Three hundred eighty-five (16%) of 2,407 eligible patients with follow-up died. Among the surviving patients, the median follow-up was 42.5 months. As listed in Table 1, demographics and disease characteristics were well balanced across treatment arms.
Therapy Received One thousand one hundred ninety-one eligible patients with follow-up data who had been randomly assigned to treatment with FLOX began FU therapy. The median dose of FU received was 7,003 mg/m2, with interquartile range from 5,911 to 8,647 mg/m2. The protocol specified an ideal cumulative dose of 9,000 mg/m2. One thousand one hundred eighty-four eligible patients with follow-up data who had been randomly assigned to treatment with FLOX began oxaliplatin therapy. The median dose of oxaliplatin received was 677 mg/m2, with interquartile range from 320 to 763 mg/m2. The protocol specified an ideal cumulative dose for oxaliplatin of 765 mg/m2.
Toxicities
Grade 3 nausea and grade 3/4 vomiting were seen more frequently among patients treated with FLOX (P < .001). Grade 3 neurosensory toxicity (peripheral neuropathy) was seen in 8.2% of patients and grade 4 neurosensory toxicity was seen in 0.2% of patients receiving oxaliplatin in the FLOX regimen, compared with 0.7% with grade 3 neurosensory toxicity and none with grade 4 toxicity treated with FULV (P < .001). At 1 year from random assignment, the rate of grade 3 neurotoxicity in patients receiving the FLOX regimen was 0.6%. Three hundred ninety-five patients participating in a substudy completed a validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Oxaliplatin-Specific Neurotoxicity Scale at baseline and at several subsequent times to include 18 months after random assignment. Each of 12 symptoms of neurotoxicity was graded at five possible levels: "not at all," "a little bit," "somewhat," "quite a bit," or "very much." Ten percent of the FULV patients and 20% of the FLOX patients (P = .036) reported at least one symptom that was three grades higher at 18 months than at baseline. A detailed analysis of neurotoxicity on NSABP Protocol C-07 appears in the article by Land et al.15
DFS
When age (  65 v < 65), sex, tumor location, and number of nodes (zero, one to three, or four) were included in a Cox proportional hazards model with treatment for the DFS end point, age 65 (HR, 1.31; P < .001; 95% CI, 1.12 to 1.53), one to three nodes versus zero nodes (HR, 1.85; P < .0001; 95% CI, 1.48 to 2.30), and four nodes versus zero nodes (HR, 3.67; P < .0001; 95% CI, 2.93 to 4.57) remained in the model (Table 4). After adjustment for age and number of nodes, the HR for FLOX versus FULV was 0.81 (95% CI, 0.69 to 0.94; P = .005). A global test for interaction of treatment with the covariates age, sex, tumor location, or number of nodes was not significant (P = .33), nor were any pairwise tests of interaction. Specifically, there was no significant interaction between treatment and the presence or number of metastatic regional lymph nodes. When the primary analysis (stratified log-rank test) was performed using all patients randomly assigned including those who were ineligible (2,492), the results were essentially unchanged (HR, 0.81; P = .0065). Treatment HR and 95% CI for DFS according to patient subsets defined by baseline prognostic factors significant in multivariate analysis are presented in Figure 3.
Relapse-Free Interval The relapse-free interval was a secondary end point of this clinical trial and showed results similar to those for DFS. Of the 2,407 eligible patients with follow-up, 538 have experienced relapse. Relapse-free interval was defined as the time from random assignment to relapse if relapse was the first event. All other patients were censored at the time of death or second primary (if this event occurred before a relapse), or at last follow-up. The P value for a two-sided log-rank test (stratifying for number of nodes: zero, one to three, or four) was .0092. The percentage of patients relapse free at 4 years was 72.9 for FULV and 78.1 for FLOX, respectively. The HR for FLOX versus FULV was 0.80 (95% CI, 0.67 to 0.95).
Survival
The results of NSABP C-07 indicate a significant improvement in DFS, the primary study end point, for patients receiving FLOX compared with those treated with FULV. The strong correlation of DFS at 3 or 4 years with the traditional end point of 5-year survival for colon cancer adjuvant therapy has been shown recently in a pooled analysis of 20,898 patients participating in randomized clinical trials.16 Furthermore, the US Food and Drug Administration recently approved the use of oxaliplatin in the surgical adjuvant setting for patients with stage III colon cancer based on 3-year DFS data from the MOSAIC trial.7 Thus, the DFS data reported in this article for the FLOX regimen are highly relevant. The results of NSABP C-07 confirm and extend the results of the MOSAIC trial. There is a striking similarity in the DFS rates, as well as HR and absolute differences in DFS at 3 and 4 years between the published results of the MOSAIC trial and the C-07 results presented in this manuscript. These data from two independent large controlled clinical trials establish unequivocally the effectiveness of the oxaliplatin, FU, and LV combination as postoperative adjuvant therapy for stage II and III colon cancer. Longer follow-up of both studies will be required to determine the magnitude of survival benefit seen with the regimens including oxaliplatin. Given that neither study was powered to evaluate the efficacy of the oxaliplatin-containing regimens in patient subsets, no conclusions can be drawn. However, it can be noted that trends toward benefit from the addition of oxaliplatin were seen in all patient subsets defined by stratification factors identified before therapy in both studies. No significant interactions between stage (ie, stage II v III) and treatment effect were seen in either study. The toxicity profile of the FLOX regimen is distinct from that seen with FOLFOX4. More grade 3 neurotoxicity was reported with FOLFOX4 (12%) than with FLOX, as reported herein (8.2%). This may well be due to the lower cumulative dose of oxaliplatin in NSABP C-07 (nine planned doses of 85 mg/m2) compared with MOSAIC (12 planned doses of 85 mg/m2). Conversely, more diarrhea was seen with FLOX in NSABP C-07. Furthermore, the FLOX regimen was associated with an increased risk of BWI syndrome, which has not been reported for FOLFOX4. The death rate during therapy with each of the oxaliplatin-containing regimens was low and was the same as in the control arms (0.5% for FOLFOX4 in the MOSAIC study and 1.2% for FLOX in NSABP C-07). In addition, the risks, inconvenience, and expense of central venous catheters and ambulatory infusion pumps required for patients to administer the FOLFOX4 regimen need to be taken into consideration. At present, either the FLOX or the FOLFOX4 regimen can be recommended for use in clinical practice as adjuvant therapy after surgery for patients with stage II and III colon cancer. If the FLOX regimen is chosen, particular care needs to be taken to interrupt treatment for diarrhea until it has resolved, to aggressively treat diarrhea, to decrease the dose of FU, and to discontinue oxaliplatin if severe diarrhea occurs.
Although all authors completed the disclosure declaration, the following authors or their 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: J. Philip Kuebler, Sanofi-aventis; Michael J. O'Connell, Sanofi-aventis; Ramesh K. Ramanathan, Sanofi-Synthelabo; Patrick J. Flynn, Sanofi-aventis Stock: N/A Honoraria: J. Philip Kuebler, Sanofi-aventis; Michael J. O'Connell, Sanofi-aventis; Ramesh K. Ramanathan, Sanofi-Synthelabo; Patrick J. Flynn, Sanofi-aventis; Norman Wolmark, Sanofi-aventis Research Funds: Barbara A. Conley, Sanofi-aventis; Norman Wolmark, Sanofi-aventis Testimony: N/A Other: N/A
Conception and design: J. Philip Kuebler, H. Samuel Wieand, Roy E. Smith, Linda H. Colangelo, Nicholas J. Petrelli, Barbara A. Conley, Norman Wolmark Administrative support: Roy E. Smith, Norman Wolmark Provision of study materials or patients: J. Philip Kuebler, Michael P. Findlay, James N. Atkins, Louis Fehrenbacher, Ramesh K. Ramanathan, Patrick J. Flynn, Gamini Soori, Edward A. Levine Collection and assembly of data: Michael J. O'Connell, Roy E. Smith, Linda H. Colangelo, Michael P. Findlay, John L. Zapas Data analysis and interpretation: J. Philip Kuebler, H. Samuel Wieand, Michael J. O'Connell, Linda H. Colangelo, Greg Yothers Manuscript writing: H. Samuel Wieand, Michael J. O'Connell, Roy E. Smith, Greg Yothers, Nicholas J. Petrelli, Michael P. Findlay, Norman Wolmark Final approval of manuscript: J. Philip Kuebler, H. Samuel Wieand, Michael J. O'Connell, Roy E. Smith, Linda H. Colangelo, Greg Yothers, Nicholas J. Petrelli, Michael P. Findlay, Thomas E. Seay, James N. Atkins, John L. Zapas, J. Wendall Goodwin, Louis Fehrenbacher, Ramesh K. Ramanathan, Barbara A. Conley, Patrick J. Flynn, Gamini Soori, Lauren K. Colman, Edward A. Levine, Keith S. Lanier, Norman Wolmark Other: J. Philip Kuebler [safety reviews], Michael P. Findlay [coordinated several aspects of this study in Australia and New Zealand], Keith S. Lanier [clinical contribution]
We thank the following coordinating center personnel and site investigators in Australia and New Zealand: AGITG: John Zalcberg; NHMRC Clinical Trials Centre: John Simes, Burcu Cakir, Haryana Dhillon; AGITG Site Investigators: Bridget Robinson, Christchurch, New Zealand; David Goldstein, Sydney, Australia; Guy van Hazel, Perth, Australia; Etesham Abdi, Towoomba, Australia; Vinod Ganju, Melbourne, Australia.
We dedicate this manuscript to the memory of H. Samuel Wieand, PhD, former director of the NSABP's biostatistical center. He is sorely missed. We thank Barbara C. Good, PhD, Director of Scientific Publications for the NSABP, for editorial assistance.
published online ahead of print at www.jco.org on April 30, 2007. Supported by Public Health Service Grants No. U10-CA-12027, U10-CA-37377, U10-CA-69974, and U10-CA-69651 from the National Cancer Institute, Department of Health and Human Services. Clinical Trial Registry Information: ClinicalTrials.gov ID#: NCT00004931, http://clinicaltrial.gov/ct/shows/NCT00004931?order=1. 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. O'Connell MJ, Mailliard JA, Kahn MJ, et al: Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 15:246-250, 1997 3. Wolmark N, Rockette H, Fisher B, et al: The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: Results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 11:1879-1887, 1993 4. 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 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. Lembersky BC, Wieand HS, Petrelli NJ, et al: Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: Results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol 24:2059-2064, 2006 7. 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 8. 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] 9. Petrelli N, Herrera L, Rustum Y, et al: A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5:1559-1565, 1987 10. Petrelli NJ, Rustum YM, Bruckner H, et al: The Roswell Park Memorial Institute and Gastrointestinal Tumor Study Group phase III experience with the modulation of 5-fluorouracil by leucovorin in metastatic colorectal adenocarcinoma. Adv Exp Med Biol 244:143-155, 1988[Medline] 11. Wolmark N, Wieand HS, Kuebler JP, et al: A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP Protocol C-07. J Clin Oncol 23:246s, 2005 (suppl; abstr 3500)[CrossRef] 12. SAS Institute Inc: SASOnlineDoc, Version 8. Cary, NC, SAS Institute Inc, 1999 13. Sanofi-aventis Oncology: Assessing neuropathy: NCI CTC classifications of sensory neuropathy. http://www.eloxatin.com/hcp/patient_management/assessing_neuropathy.aspx 14. Smith RE, Colangelo S, Wieand S, et al: The occurrence of severe enteropathy among patients with stage II/II resected colon cancer (CC) treated with 5-FU/leucovorin (FL) plus oxaliplatin (FLOX). Proc Am Soc Clin Oncol 22:294, 2003 (abstr 1181) 15. 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: doi:10.1200/JCO.2006.08.6652 16. 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 Submitted July 19, 2006; accepted January 4, 2007. Related Editorial
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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
2 test, with continuity correction when the samples were too large to use Fisher's exact test. The global test for interaction of treatment with covariates was computed using a 
