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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

Barry C. Lembersky, H. Samuel Wieand, Nicholas J. Petrelli, Michael J. O'Connell, Linda H. Colangelo, Roy E. Smith, Thomas E. Seay, Jeffrey K. Giguere, M. Ernest Marshall, Andrew D. Jacobs, Lauren K. Colman, Atilla Soran, Greg Yothers, Norman Wolmark

From the National Surgical Adjuvant Breast and Bowel Project Operations and Biostatistical Centers; Allegheny General Hospital, Pittsburgh; The Regional Cancer Center, Erie, PA; Helen F. Graham Cancer Center, Newark, DE; Atlanta Cancer Care, Inc, Atlanta, GA; Cancer Centers of the Carolinas, Greenville, SC; Southeastern Medical Oncology Center, Goldsboro, NC; Virginia Mason Medical Center, Seattle; and the Northwest Community Clinical Oncology Program, Tacoma, WA

Address reprint requests to Michael J. O'Connell, MD, National Surgical Adjuvant Breast and Bowel Project, Four Allegheny Center, Pittsburgh, PA 15212; e-mail: michael.o'connell{at}nsabp.org

	ABSTRACT

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PURPOSE: The primary aim of this study was to compare the relative efficacy of oral uracil and tegafur (UFT) plus leucovorin (LV) with the efficacy of weekly intravenous fluorouracil (FU) plus LV in prolonging disease-free survival (DFS) and overall survival (OS) after primary surgery for colon carcinoma.

PATIENTS AND METHODS: Between February 1997 and March 1999, 1,608 patients with stage II and III carcinoma of the colon were randomly assigned to receive either oral UFT+LV or intravenous FU+LV.

RESULTS: Of the total patients, 47% had stage II colon cancer, and 53% had stage III colon cancer. Median follow-up time was 62.3 months. The estimated hazard ratio (HR) for OS of patients who received UFT+LV versus that of patients who received FU+LV was 1.014 (95% CI, 0.825 to 1.246). The estimated HR for DFS was 1.004 (95% CI, 0.847 to 1.190). Cox proportional hazards model analyses with regard to age (< 60 v 60 years), stage, or number of involved nodes (none v one to three v four nodes) revealed no interaction with OS or DFS. Toxicity was similar in the two groups. In the UFT+LV arm, 38.2% of patients experienced any grade 3 or 4 toxic event compared with 37.8% of patients in the FU+LV arm. Primary quality-of-life end points did not differ between the two regimens, although convenience of care analysis favored UFT+LV.

CONCLUSION: UFT+LV achieved similar DFS and OS when compared with an intravenous, weekly, bolus FU+LV regimen. The two regimens were equitoxic and generally well tolerated.

	INTRODUCTION

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In 1993, the National Surgical Adjuvant Breast and Bowel Project (NSABP) reported the results of a surgical adjuvant clinical trial (protocol C-03) that indicated significant prolongation in disease-free survival (DFS) and overall survival (OS) in stage II and III colon cancer patients who received fluorouracil (FU) plus leucovorin (LV) compared with patients who received semustine, vincristine, and FU.^1,2

NSABP protocol C-04 subsequently compared FU and levamisole (LEV) with FU+LV and ascertained whether adding LEV to FU+LV would result in additional benefit. Protocol C-04 demonstrated that, in patients with stage II and III carcinoma of the colon, treatment with FU+LV conferred a DFS advantage and a borderline prolongation in OS compared with treatment with FU+LEV. The addition of LEV to FU+LV provided no additional benefit over and above that achieved with FU+LV. These findings supported the use of adjuvant FU+LV as a therapeutic standard in patients with stage II and III carcinoma of the colon.³

After phase I and II studies with oral uracil and tegafur (UFT) plus LV,^4,5 NSABP protocol C-06 was begun. The primary aim of this protocol was to compare oral UFT+LV with standard intravenous FU+LV in prolonging DFS and OS. A secondary aim was to compare quality of life in patients with stage II and III carcinoma of the colon treated with either FU+LV or UFT+LV. The data presented here represent the first full report of the results of this study.

	PATIENTS AND METHODS

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Eligibility
Patients were accrued for this trial between February 1997 and March 1999. All participants were required to give written informed consent. Eligible patients were required to have undergone a potentially curative resection for stage II (T3-4N0M0) or stage III (T1-4N1-3M0) adenocarcinoma of the colon. The protocol stipulated an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 and that the interval between curative resection and random assignment be no greater than 42 days. Adequate postoperative bone marrow, renal, and hepatic function was required. Patients were excluded if they had any nonmalignant disease that precluded administration of the assigned chemotherapy.

Treatment
Patients were stratified according to the number of involved nodes (none, one to three, or four nodes) and randomly assigned to receive either FU+LV or UFT+LV. Patients randomly assigned to the FU +LV group received three 8-week cycles of intravenous chemotherapy. Each cycle consisted of LV 500 mg/m² administered as a 2-hour infusion and FU 500 mg/m² administered as an intravenous bolus 1 hour after the start of LV infusion and repeated weekly for six doses; the cycle was repeated after a 2-week rest period. Patients randomly assigned to the UFT+LV group received five 5-week cycles consisting of 4 weeks of oral chemotherapy administration and then a 1-week rest period. UFT was administered at a dose of 300 mg/m²/d, and LV was administered at a dose of 90 mg/d. The daily doses of both UFT and LV were divided into three doses administered 8 hours apart and taken together along with water. Patients were instructed to avoid food consumption between 1 hour before and 1 hour after each dose.

Follow-Up Requirements and Diagnosis of Treatment Failure
Before the administration of each cycle of chemotherapy, patients had a physical examination, CBCs, and chemistry profiles including hepatic and renal function studies. During active chemotherapy, patients in both groups underwent weekly CBCs.

Starting 6 months after the completion of protocol chemotherapy and continuing through 5 years after random assignment, patients were to be re-evaluated semiannually. Five years after random assignment, a status of disease report was required on a yearly basis.

An assessment of quality of life was to be performed in all patients using the treatment-specific symptom checklist and Eastern Cooperative Oncology Group Convenience of Care Scales, the Functional Assessment of Cancer Therapy–Colon (FACT-C) Version III, the Vitality Scale of the Medical Outcomes Study Short Form-36 instrument, and Return to Normal Activity and Overall Quality of Life scales.

The first treatment failure was diagnosed only when protocol-defined clinical and laboratory criteria were met. Whenever possible, recurrent tumor was proven by biopsy or positive cytology.

Statistical Methods
The statistical design for this study was based on data from NSABP protocol C-03, a study in which FU+LV offered a 10% absolute improvement in 5-year survival compared with methyl-CCNU, oncovin, and fluorouracil (MOF; from 0.64 to 0.74). The protocol C-06 design specified that there should be no more than a 15% chance of erroneously concluding that UFT+LV was equivalent to FU+LV if half of the benefit previously observed was lost (ie, if the 5-year survival difference decreased from 0.74 for FU+LV to 0.69 for UFT+LV, which also translates into a hazard ratio [HR] of 1.232 for UFT+LV v FU+LV). Final analysis was to occur 5 years after the last patient was entered unless 492 deaths occurred before that date. We chose that time point because data from previous trials showed there were few treatment-related deaths after 5 years. We expected that there would be approximately 492 deaths after 5 years so that analysis using a log-rank test that preserved the 0.15 probability of missing a worse HR of 1.232 for UFT+LV versus FU+LV would also have a 90% chance of concluding equivalence if the two regimens had no survival difference. In fact, only 362 deaths had occurred at the scheduled time of analysis, so the chance of concluding equivalence if the regimens had no survival difference decreased to 0.827, but the protocol-specified probability (P = .15) of erroneously concluding equivalence if the HR of UFT+LV versus FU+LV was 1.232 was preserved. The analysis that preserved these error rates was to compute a log-rank test (stratified by nodes) and to declare survival for FU+LV to be better than that of UFT+LV if the one-sided P value for that alternative was P < .173.

Our primary analyses include all patients who were eligible and had follow-up information (intent to treat). We also performed secondary analyses using only patients who received at least one dose of the assigned therapy. For the primary analysis, we presented the one-sided P value in accordance with the study design, but we also presented the two-sided P value and 95% CIs for all HRs.

P values obtained for survival comparisons were computed using the log-rank test or a Cox proportional hazards model. The time to an event was measured from the date of surgery. When P values were obtained for comparisons of categoric data, they were computed using Fisher's exact test or Pearson's 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 ² statistic obtained by subtracting –2 log likelihood for the model with only treatment and covariates in the model from –2 log likelihood for the model with treatment, the covariates, and the treatment by covariate interaction terms. Statistical comparisons of quality-of-life scales used repeated measures analyses controlling for age (< 60 v 60 years), sex, race (white v nonwhite), and baseline score. All of the statistical computations were performed using packages from the SAS/STAT User's Guide, Version 8 (SAS Institutes Inc, Cary, NC).

	RESULTS

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Patient Characteristics
The study accrued 1,608 patients (803 to the FU+LV arm and 805 to the UFT+LV arm). Fifty patients (3.1%) were deemed ineligible (27 were assigned to the FU+LV arm, and 23 were assigned to the UFT+LV arm). Seven other patients (six assigned to the FU+LV arm and one assigned to the UFT+LV arm) had no follow-up data, and thus, were not included in the analyses. Thus, 1,551 patients (96.5% of those randomly assigned) were included in the analyses, 770 on the FU+LV arm and 781 on the UFT+LV arm. The patient characteristics for this cohort of patients are listed in Table 1. Eighteen of the eligible patients with follow-up (1.2%) refused the assigned therapy (11 FU+LV patients and seven UFT+LV patients).

View larger version (17K): [in this window] [in a new window]   Fig 1. Percentage of patients receiving each dose category of either (A) fluorouracil or (B) uracil and tegafur. Each shaded region represents the percentage of patients receiving the indicated proportion of the ideal dose per protocol on a given cycle.

Toxicities
The toxicity tables were based on data from the 1,533 patients (759 FU+LV and 774 UFT+LV patients) who received therapy using the 1958 version of the National Cancer Institute toxicity criteria. Fifteen patients died while receiving protocol therapy (nine FU+LV patients [1.2%] and six UFT+LV patients [0.8%]). The toxicities for the two regimens were quite similar (Table 2). In fact, on each arm, 38% of patients experienced a grade 3 or higher nonhematologic toxicity of some type as their worst toxicity, and 20% experienced a grade 4 or higher nonhematologic toxicity of some type as their worst toxicity. The most frequently observed severe toxicity was diarrhea. In each arm, 29% of the patients had severe or greater diarrhea at some point during therapy. Four percent of the FU+LV patients and 7.0% of the UFT+LV patients had elevated bilirubin (grade 3 in two UFT+LV patients). Ten FU+LV patients (1.3%) and five UFT+LV patients (0.6%) experienced febrile neutropenia. Eight FU+LV patients (1.1%) and 10 UFT+LV patients (1.3%) experienced grade 3 or 4 skin toxicity, including hand-foot syndrome in 0.2% and 0.7% of patients, respectively.

Survival
All patients had entered the study at least 5 years before this analysis. Three hundred sixty-two of 1,551 eligible patients with follow-up died (Table 3). Among the surviving patients, the median follow-up time was 62.3 months. All but 20 of the patients (1.3%) included in the analysis had more than 2 years of follow-up. The survival curves for these 1,551 patients are shown in Figure 2A. The P value for a two-sided log-rank test (stratifying for number of nodes; none, one to three, or four nodes) was .90. The estimated HR for UFT+LV versus FU+LV was 1.014 (95% CI, 0.825 to 1.246). The absolute survival rate at 5 years was 78.7% for FU+LV and 78.5% for UFT+LV. The protocol-specified analysis (see Statistical Methods) called for declaring UFT+LV to be essentially equivalent to FU+LV if the one-sided P value for the log-rank test looking for improved survival with FU+LV exceeded P = .173. This P = .45, so by the protocol-specified analysis, we would declare equivalence.

View larger version (5K): [in this window] [in a new window]   Fig 2. Survival for (A) all patients, (B) stage II patients, and (C) stage III patients in National Surgical Adjuvant Breast and Bowel Project trial C-06. FU, fluorouracil; UFT, uracil and tegafur; LV, leucovorin.

The survival curves for the stage II and stage III patients are consistent with the finding of no interaction (Figs 2B and 2C). The 5-year survival rates for stage II and stage III patients were 87.0% and 71.5% for FU+LV, respectively, and 88.4% and 69.6% for UFT+LV, respectively.

DFS
Of the 1,551 eligible patients with follow-up data, 531 experienced treatment failure (Table 3), which was defined as the first recurrence, second primary, or death. Time to treatment failure was defined as the time to the first of these events. All other patients were censored at the time to last follow-up. The DFS curves for these 1,551 patients are shown in Figure 3. The P value for a two-sided log-rank test (stratifying for number of nodes; none, one to three, or four nodes) was .96. The HR for UFT+LV versus FU+LV was 1.004 (95% CI, 0.847 to 1.190). The 3- and 5-year DFS rates were 74.5% and 68.2% for FU+LV, respectively, and 74.5% and 67.0% for UFT+LV, respectively.

View larger version (6K): [in this window] [in a new window]   Fig 3. Disease-free survival in National Surgical Adjuvant Breast and Bowel Project trial C-06. FU, fluorouracil; UFT, uracil and tegafur; LV, leucovorin.

Second Primary Cancers
Fifty-three of the FU+LV patients (6.9%) experienced a second primary as a first event, as did 47 of the UFT+LV patients (6.0%). The most common sites were the prostate (12 patients on each arm), breast (11 FU+LV patients and eight UFT+LV patients), and trachea, bronchus, and lung (11 FU+LV patients and two UFT+LV patients). Nine patients had a second primary colon cancer as a first event (five FU+LV patients and four UFT+LV patients).

	DISCUSSION

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The composition of UFT is 1-(2-tetrahydrofuryl)-5-fluorouracil (ftorafur [FT] or tegafur) and uracil in a molar ratio of 1:4. FT was synthesized by Giller et al⁶ and is converted to FU in vivo. Fujii et al⁷ found that the coadministration of uracil enhanced both the concentration of FU in tumors and the resulting antitumor activity of FT. In vitro studies demonstrated that uracil strongly reduced the degradation of FU to 2-fluoro-beta-alanine through reversible dihydropyrimidine dehydrogenase inhibition. Once absorbed, FT is metabolized to FU by one of two different pathways and enzyme systems, thereby behaving as a prodrug to FU.⁸

Two phase III trials in patients with previously untreated metastatic colorectal cancer investigated the efficacy of UFT+LV.^9,10 Each compared UFT+LV administered for 28 days every 35 days to FU+LV administered intravenously for 5 days every 4 or 5 weeks. No statistically significant differences in time to progression, tumor response rates, or survival were observed between treatments in either study. Patients treated with UFT+LV experienced significantly less myelosuppression, resulting in fewer episodes of febrile neutropenia and less documented infection. There was also significantly less diarrhea, stomatitis, and vomiting associated with UFT+LV.

The results of NSABP C-06 have revealed that an oral UFT+LV regimen and a weekly bolus FU+LV regimen (Roswell Park regimen) were equitoxic and generally well tolerated in the surgical adjuvant setting. Furthermore, oral UFT+LV resulted in equivalent DFS and OS when compared with intravenous FU+LV and was associated with improved convenience of care.

UFT is commonly used in Japan, where it has been demonstrated that UFT administered at doses of 300 to 600 mg/d is well tolerated and has shown evidence of antitumor activity in a wide variety of solid tumors.¹¹ In colorectal cancer, a recent meta-analysis of 5,233 patients participating in three randomized Japanese clinical trials of 1 year of postoperative oral fluorinated pyrimidine chemotherapy, including UFT, documented a significant reduction in tumor relapse and death after surgery for colon cancer.¹²

The recent capecitabine adjuvant colon cancer trial¹³ evaluated oral capecitabine compared with intravenous FU+LV in patients with stage III resected colon cancer. This study demonstrated that capecitabine was not inferior to the Mayo Clinic (Rochester, MN) intensive-course bolus FU+LV regimen, illustrating the effectiveness of another oral fluorinated pyrimidine treatment in the adjuvant setting. Capecitabine was also associated with a significantly lower frequency of diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia. However, there was a higher frequency of hand-foot syndrome in the capecitabine regimen.

Two recent clinical trials have documented improved DFS when oxaliplatin is added to the combination of FU and LV^14,15 in patients with stage II and III colon cancer. Therefore, this three-drug combination has become the preferred treatment option for most patients who are candidates for aggressive combination chemotherapy after surgery. Oral UFT+LV has been demonstrated by NSABP C-06 to be an acceptable alternative to a weekly bolus FU+LV regimen in patients with stage II and III colon cancer and represents another option for fluorinated pyrimidine adjuvant chemotherapy in clinical situations where it is important to avoid the risk of increased toxicity associated with oxaliplatin. UFT+LV is not currently approved by the US Food and Drug Administration, although it is available for clinical use in many other countries worldwide.

	Authors' Disclosures of Potential Conflicts of Interest

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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.

	Author Contributions

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Conception and design: H. Samuel Wieand, Nicholas J. Petrelli, Roy E. Smith, Norman Wolmark Administrative support: Roy E. Smith, Norman Wolmark Provision of study materials or patients: Thomas E. Seay, Jeffrey K. Giguere, M. Ernest Marshall, Andrew D. Jacobs Collection and assembly of data: Barry C. Lembersky, H. Samuel Wieand, Roy E. Smith, Jeffrey K. Giguere Data analysis and interpretation: Barry C. Lembersky, H. Samuel Wieand, Roy E. Smith, Linda H. Colangelo, Michael J. O'Connell, Greg Yothers Manuscript writing: Barry C. Lembersky, H. Samuel Wieand, Nicholas J. Petrelli, Roy E. Smith, Michael J. O'Connell, Atilla Soran, Norman Wolmark Final approval of manuscript: Barry C. Lembersky, H. Samuel Wieand, Nicholas J. Petrelli, Roy E. Smith, Linda H. Colangelo, Michael J. O'Connell, Thomas E. Seay, Jeffrey K. Giguere, M. Ernest Marshall, Andrew D. Jacobs, Lauren K. Colman, Atilla Soran, Greg Yothers, Norman Wolmark Other: Atilla Soran [Comprehensive review]

 

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other H. Samuel Wieand Taiho (A) Norman Wolmark Taiho (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required

	ACKNOWLEDGMENTS

 
We thank Barbara C. Good, PhD, Director of Scientific Publications of the National Surgical Adjuvant Breast and Bowel Project, for editorial assistance.

	NOTES

 
Supported by Public Health Service Grant Nos. U10CA-12027, P-U10CA-37377, U10CA-69651, and U10CA-69974 from the National Cancer Institute, Department of Health and Human Services, and Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, and Taiho Pharmaceutical Co, Ltd, Tokyo, Japan.

Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 13-17, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. 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[Abstract/Free Full Text]

2. O'Connell MJ, Wolmark N, Yothers G, et al: Durable improvement in disease-free survival (DFS) and overall survival (OS) for stage II or III colon cancer treated with leucovorin-modulated fluorouracil (FL): 10-year follow-up of National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03. J Clin Oncol 23:248s, 2005 (suppl; abstr 3511)[CrossRef]

3. Wolmark N, Rockette H, Mamounas E, 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[Abstract/Free Full Text]

4. Pazdur R, Lassere Y, Rhodes V, et al: Phase II trial of uracil and tegafur plus oral leucovorin: An effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol 12:2296-2300, 1994[Abstract/Free Full Text]

5. Saltz LB, Leichman CG, Young CW, et al: A fixed-ratio combination of uracil and ftorafur (UFT) with low dose leucovorin. Cancer 75:782-785, 1995[CrossRef][Medline]

6. Giller SA, Zhuk RA, Lidak, MI: Analogs of pyrimidine nucleosides: I. N1-(alpha-furanidyl) derivatives of natural pyrimidine bases and their antimetabolites. Dokl Akad Nauk SSSR 176:332-335, 1967[Medline]

7. Fujii S, Kitano S, Ikenaka K, et al: Studies on coadministration of uracil or cytosine on antitumor activity of FT-207 or 5-FU derivatives. Jpn J Cancer Chemother 6:377-384, 1979

8. Au JL, Sadee W: Activation of ftorafur (R,S-1-[tetrahydro-2furanyl]-5-fluorouracil) to 5-fluorouracil and gamma-butyrolactone. Cancer Res 40:2814-2819, 1980[Medline]

9. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3617-3627, 2002[Abstract/Free Full Text]

10. Douillard JY, Hoff PM, Skillings JR, et al: Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3605-3616, 2002[Abstract/Free Full Text]

11. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmacol 22:333-338, 1988[Medline]

12. Sakamoto J, Ohashi Y, Hamada C, et al: Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials. J Clin Oncol 22:484-492, 2004[Abstract/Free Full Text]

13. 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[Abstract/Free Full Text]

14. 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[Abstract/Free Full Text]

15. 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 LBA3500)[CrossRef]

Submitted October 28, 2005; accepted February 16, 2006.

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