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Irinotecan Fluorouracil Plus Leucovorin Is Not Superior to Fluorouracil Plus Leucovorin Alone As Adjuvant Treatment for Stage III Colon Cancer: Results of CALGB 89803

Leonard B. Saltz, Donna Niedzwiecki, Donna Hollis, Richard M. Goldberg, Alexander Hantel, James P. Thomas, Anthony L.A. Fields, Robert J. Mayer

From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; Departments of Medicine and Biostatistics, Duke University, Durham; Department of Medicine, University of North Carolina, Chapel Hill, NC; Department of Medicine, Loyola University, Chicago, IL; Department of Medicine, University of Wisconsin, Madison, WI; Department of Medicine, University of Alberta, Alberta, Canada; and the Dana-Farber Cancer Institute, Boston, MA

Address reprint requests to Leonard Saltz, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: saltzl{at}mskcc.org

	ABSTRACT

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Purpose Randomized studies have shown that irinotecan (CPT-11) extends survival in metastatic colorectal cancer patients when administered in second-line and when added to fluorouracil (FU) plus leucovorin (LV) in first-line therapy of metastatic colorectal cancer. When this study was initiated, FU plus LV was standard adjuvant treatment for stage III colon cancer. We evaluated the efficacy and safety of weekly bolus CPT-11 plus FU plus LV in the treatment of patients with completely resected stage III colon cancer.

Methods A total of 1,264 patients were randomly assigned to receive either standard weekly bolus FU plus LV regimen or weekly bolus CPT-11 plus FU plus LV. The primary end points of the study were overall survival (OS) and disease-free survival (DFS).

Results Treatment arms were well-balanced for patient characteristics and prognostic variables. There were no differences in either DFS or OS between the two treatment arms. Toxicity, including lethal toxicity, was significantly higher on the CPT-11 plus FU plus LV arm.

Conclusion The addition of CPT-11 to weekly bolus FU plus LV did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity. This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies.

	INTRODUCTION

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Studies performed in the late 1980s demonstrated that postoperative fluorouracil (FU) plus levamisole improved survival in patients with a resected stage III (T, any N1-2, M0) colon cancer.¹ Further studies performed in the mid-1990s established FU plus leucovorin (LV) administered for approximately 6 months as a standard postoperative treatment.²

Irinotecan (CPT-11), a topoisomerase I inhibitor, is active in metastatic colorectal cancer, both in first- and second-line treatment of metastatic disease.^3-5 A randomized trial in FU-refractory colorectal cancer patients of CPT-11 versus best supportive care (BSC) demonstrated a 1-year survival rate 2.5 times greater than that achieved with BSC.⁶ Two large randomized trials of first-line therapy using CPT-11 with or without FU plus LV demonstrated modest but statistically significant survival advantages for the combination regimen.^7,8 One of these trials used biweekly (every other week) infusional FU plus/minus biweekly CPT-11.⁷ The other trial utilized a weekly bolus FU schedule with CPT-11, and compared this to a standard bolus FU plus LV schedule.⁸ This trial showed the weekly CPT-11 plus FU plus LV schedule to produce superior response, progression-free survival, and overall survival (OS), with similar safety and toxicity to the FU plus LV control arm, including a 60-day all-cause mortality of 7% in each arm.⁹ As a result, the weekly CPT-11 plus FU plus LV regimen became standard for first-line metastatic colorectal cancer in the United States, and was declared the new reference standard by the US Food and Drug Administration. This led us to question whether the increased antitumor activity and modest survival advantage for this regimen in the metastatic setting would translate into an increased cure rate in the adjuvant setting. We performed a randomized controlled trial of the combination of weekly CPT-11 plus FU plus LV versus a standard weekly schedule FU plus LV in the adjuvant setting following curative resection of stage III colon cancer.

	METHODS

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Patient Characteristics
Eligible patients had completely resected stage III (T, any N1-2, M0) adenocarcinoma of the colon (rectal cancer patients were excluded), no radiographic or surgical evidence of distant metastases, no prior chemotherapy or radiotherapy, Zubrod performance scale 0 to 2, normal bone marrow function and bilirubin, and creatinine 1.5 x upper limit of normal, and were age 18 years. Treatment began no earlier than 21 days and no later than 56 days postresection. This protocol was reviewed by the institutional review board of each participating center, and all patients gave written informed consent before participation on this trial.

Trial Structure and Organization
The trial was written and coordinated by the Cancer and Leukemia Group B (CALGB) with participation by the North Central Cancer Treatment Group, National Cancer Institute of Canada Clinical Trials Group, Eastern Cooperative Oncology Group, Southwest Oncology Group, and the National Cancer Institute Cancer Trials Support Unit. The CALGB data safety–monitoring board reviewed safety data quarterly and efficacy data at protocol-specified intervals in accordance with CALGB policies and procedures.

Statistical Plan
Patients were randomly assigned centrally through their participating cooperative group or through the National Cancer Institute Cancer Trials Support Unit. Stratified factors included lymph node involvement (one to three nodes v four or more nodes), histology (poorly or undifferentiated v well or moderately differentiated), and preoperative carcinoembryonic antigen (CEA; < 5 v 5 ng/mL v unknown).

Sample size and power estimates were based on OS measured from beginning of treatment until death from any cause. We targeted an accrual of 1,260 patients to provide 82% power to detect an improvement in median survival from 8.0 years with FU plus LV alone to 10.5 years with CPT-11 plus FU plus LV (hazard ratio [HR], 1.3; log-rank test, one-sided = .05). Additional assumptions were exponential survival, a 2.8-year accrual period, and 3 years of follow-up.

Intent-to-treat analyses of OS, disease-free survival (DFS), and recurrence-free survival (RFS) include all 1,264 patients (629 in the FU plus LV group and 635 in the CPT-11 plus FU plus LV group) as randomly assigned. OS is measured from study entry until death from any cause. DFS is defined as time from study entry until documented tumor recurrence or death from any cause. RFS is defined in this trial as the time from study entry until documented recurrence, occurrence of a new primary colon tumor, or death with evidence of recurrent colon cancer. For RFS, patients who died without known tumor recurrence are censored at the last documented evaluation. A stratified Cox proportional hazards regression was used to compare treatment arms controlling for the actual stratification factors. Survival probability estimates were calculated using the Kaplan-Meier method.

Analyses for OS were planned beginning when approximately 15% of the expected deaths had occurred and every 6 months thereafter to coincide with meetings of the CALGB Data Safety Monitoring Board. The Lan-DeMets analog of the O'Brien-Fleming group sequential boundary truncated at 2.58 was employed to allow for early reporting of the study. A total of 356 deaths were expected at the end of the projected 2.8-year accrual and 3-year follow-up periods. A futility analysis also was conducted at each interim analysis. The futility boundary would be crossed if the targeted OS HR of 1.3 were greater than the (two-sided) 99% upper confidence limit. No adjustments were made to the CI for multiple looks. SAS 9.1 (SAS Institute, Cary, NC) was used for all statistical analyses. All analyses were conducted on the study database frozen on May 19, 2006. Quarterly reports were submitted by the CALGB Statistical Center to the Cancer Therapy Evaluation Program of the National Cancer Institute (Bethesda, MD). Patient registration, data collection, and data analysis were performed by the CALGB Statistical Center (Durham, NC). Data quality was ensured by auditing according to the standard operating procedures of each participating cooperative group and by careful review of data by CALGB Statistical Center staff and the study chairperson.

Treatment
Eligible and registered patients were randomly assigned by computer (randomized fixed block) using central registration to receive either CPT-11 plus FU plus LV or FU plus LV. The FU plus LV group received the Roswell Park regimen consisting of LV 500 mg/m² by intravenous (IV) injection over 2 hours, with a bolus of FU 500 mg/m² administered by IV injection at 1 hour after initiation of LV. Treatments were administered weekly for 6 consecutive weeks, followed by a 2-week rest, for a total of four cycles over 32 weeks. The CPT-11 plus FU plus LV group received CPT-11 125 mg/m² over 90 minutes followed by an IV bolus injection of LV 20 mg/m² and then FU 500 mg/m², also by IV bolus injection. Treatment was scheduled to be administered for four consecutive weeks followed by a 2-week rest for five cycles or a total of 30 weeks.

Supportive Medications and Dose Modifications
Atropine 0.25 mg to 1 mg intravenously was recommended for cholinergic symptoms of CPT-11. Intensive-course loperamide according to the recommendations made by Abigerges et al¹⁰ was to be used for treatment of diarrhea on either arm. For diarrhea not abating within 24 to 36 hours, deodorized tincture of opium drops every 4 hours was to be added.

Routine use of antiemetics before treatment with FU plus LV was not recommended, but antiemetic use was left to the discretion of the treating physician if nausea or vomiting developed. Patients on CPT-11 plus FU plus LV received dexamethasone 10 mg by IV, unless there was a relative contraindication to corticosteroids. Based on what was the standard practice at the time, the protocol specifically recommended against routine use of 5-hydroxytryptamine-3 blockers, such as ondansetron or granisetron, except in those patients who demonstrated nausea or vomiting despite treatment with dexamethasone.

Adverse events were rated according to the National Cancer Institute Common Toxicity Criteria version 2.0. For FU plus LV, the starting dose of FU was 500 mg/m², and dose levels were decreased in 20% increments. For CPT-11 plus FU plus LV, FU also was decreased by 20% increments for dose levels, and CPT-11 was decreased by 25 mg/m² for each dose level. Patients experiencing grade 4 hematologic or nonhematologic toxicity had their treatment held until resolution of toxicity to grade 1 and were permitted to proceed with treatment with a two-dose–level reduction. Patients with grade 3 hematologic or nonhematologic toxicity had treatment held until toxicity was grade 1 and proceeded with a one-dose–level reduction. Initially, the study was written such that if a patient was found to have grade 2 toxicity on the day of a planned midcycle treatment, the treatment was to be administered on that day with a one-dose–level reduction. The trial was suspended to accrual in April 2001 because of unexpectedly severe toxicity. Subsequently, in May 2001, based on toxicity and mortality rates that were found to be unacceptable, the schedule was modified, so patients experiencing grade 2 toxicity on a day of planned treatment had treatment held until resolution of toxicity (grade 1) and preceded with a one-dose–level reduction (same modifications for grades 2 and 3 toxicity when occurring midcycle). In addition, the schedule was revised such that, for patients receiving CPT-11, if grade 3 or greater neutropenia occurred following the first dose of treatment, then CPT-11, FU, and LV were held until toxicity resolved to grade 1. Treatment then proceeded with a two-dose–level reduction (the initial treatment modification schema had called for a one-dose–level reduction in this setting).

Patients who had one weekly treatment omitted (held) from their 6-week cycle were to have a 1-week break at the end of treatment, so as to maintain the 6-week schedule. For example, if week 3 was omitted, chemotherapy was administered on weeks 4 and 5. Week 6 was then a rest week, and then a new cycle began. If omission of week 4 was required on the CPT-11 plus FU plus LV arm, patients were to receive treatment on a 5-week schedule, such that treatment was administered on weeks 1, 2, and 3 with rest weeks on weeks 4 and 5. These scheduling modifications were consistent with the modifications used in the development of this regimen in the metastatic setting.

Follow-Up
Physical examinations were required on day 1 of each 6-week cycle and 6 weeks after the final treatment dose. Post-treatment follow-up called for evaluation every 3 months for 2 years, then every 4 months for 2 years, then yearly for 3 years, for a total of 7 years follow-up. Patients on treatment had toxicity assessment before each chemotherapy dose. CEA was measured before treatment, 6 weeks after final treatment, and with each post-treatment follow-up. Chest x-rays were obtained annually for 5 years. First recurrence was to be confirmed by biopsy. Computed tomography scanning was left to the discretion to the investigator.

	RESULTS

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Between April 1999 and April 2001, 1,264 patients were randomly assigned, 629 to FU plus LV and 635 to CPT-11 plus FU plus LV. Approximately half of the total accrual occurred in the last 6 months, between November 2000 and April 2001. Nineteen patients (1.5%) were ineligible—seven had metastatic disease, six had rectal cancer, three had positive margins, two had lab values outside limits, and one was delayed too long after resection before starting therapy. Patient characteristics were well balanced for gender, age, performance status, elevated preoperative CEA level, T and N stage, median number of nodes reported, the presence of small-vessel invasion, and high-grade histology (Tables 1 and 2).

View this table: [in this window] [in a new window]   Table 3. Toxicities Where Either Arm Experienced 10% Frequency of Grade 3

Efficacy Results
The OS futility boundary was crossed and reported at the fifth interim analysis in June 2003. The data was subsequently released by the CALGB DSMB for analysis. Median follow-up currently is 4.8 years. The median OS and DFS have not yet been reached.

There were no significant differences between CPT-11 plus FU plus LV and FU plus LV in OS, DFS, or RFS (Table 4). Survival curves are presented in Figures 1, 2, and 3. The probability of OS at 3 years was 0.80 for CPT-11 plus FU plus LV and 0.81 for FU plus LV, and the 5-year OS probability was 0.68 for CPT-11 plus FU plus LV and 0.71 for FU plus LV. The probability of DFS at 3 years was 0.66 for CPT-11 plus FU plus LV and 0.69 for FU plus LV. Five-year DFS probability was 0.59 for CPT-11 plus FU plus LV and 0.61 for FU plus LV. RFS showed a similar lack of benefit for the CPT-11–containing regimen, with the probability of relapse-free survival at 3 years being 0.68 for CPT-11 plus FU plus LV and 0.71 for FU plus LV. Five-year RFS probabilities were 0.62 for CPT-11 plus FU plus LV and 0.65 for FU plus LV. Subset analyses evaluating the impact of CPT-11 plus FU plus LV on patients with four versus one to three nodes, Eastern Cooperative Oncology Group performance status 0 or < 0, or left- versus right-sided cancers all failed to identify a subgroup with significant benefit from CPT-11 plus FU plus LV. No survival differences were observed by gender or race.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival by treatment arm (all patients). FU, fluorouracil; LV, leucovorin; CPT-11, irinotecan.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Disease-free survival by treatment arm (all patients). FU, fluorouracil; LV, leucovorin; CPT-11, irinotecan.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Recurrence-free survival by treatment arm (events include progression, new colon primary, or death with evidence of disease). FU, fluorouracil; LV, leucovorin; CPT-11, irinotecan.

	DISCUSSION

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There were no apparent imbalances in clinicopathologic variables, which would help explain the lack of benefit seen. The toxicity of the CPT-11 plus FU plus LV arm is similar to that reported in the initial study in metastatic disease by Saltz et al.⁸ The 60-day all-cause mortality from that trial was 6.7%, with the FU plus LV control arm of that study displaying 7.3% 60-day all-cause mortality. These levels are consistent with all-cause mortality reported with bolus FU regimens throughout the 1990s.⁹ Nevertheless, the on-treatment mortality rate of 1% seen with FU plus LV is consistent with that seen in previous North American adjuvant trials involving bolus FU plus LV, whereas the 2.8% seen with the CPT-11 plus FU plus LV arm is unacceptably high mortality in the adjuvant setting.

The control arm for this study was selected from the arms of intergroup trial 0089 based on its more favorable toxicity profile and its weekly administration schedule, which provided symmetry with CPT-11 plus FU plus LV.² The efficacy and toxicity results in the control arm of our study are similar to those reported for intergroup 0089, and the 3-year DFS of 69% that we observed for FU plus LV is not substantially different from the 65.5% 3-year DFS reported in the control arm of the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer trial, which demonstrated that the addition of oxaliplatin to infusional FU plus LV in the adjuvant setting in colon cancer does improve DFS.¹³ Thus, the lack of benefit for the CPT-11–containing arm cannot be explained by any unexpectedly favorable results in the control arm.

Initial hopes that an infusional FU regimen with CPT-11 would prove superior in the adjuvant setting do not appear to have been borne out either. The ACCORD II trial randomized 400 patients with high-risk stage III colon cancer, defined as either four or more positive lymph nodes (N2 disease) or one to three nodes plus a perforated or obstructing primary, to biweekly infusional FU plus LV alone, or with biweekly CPT-11.¹⁴ The event-free survival was not significantly different between arms, with a trend toward slight inferiority for the CPT-11–containing arm. In the Pan-European Trial in Adjuvant Colon Cancer 3 trial, 2,333 stage III colon cancer patients were randomly assigned to adjuvant treatment with biweekly infusional FU, either alone, or with biweekly CPT-11 (FOLFIRI).¹⁵ There was no significant difference in 3-year DFS, the prespecified primary end point of the trial (59.9% for FU plus LV; 62.9% for FOLFIRI; P = .1). While these infusional FU plus CPT-11 combinations have not shown the unacceptable toxicity levels seen in this trial of bolus CPT-11 plus FU plus LV, they have nonetheless failed to demonstrate a significant DFS or OS advantage for the combination in the adjuvant setting.

The results of our trial demonstrate the dangers of jumping to conclusions before completion of the formal clinical trial assessment. Before and during this trial, many oncologists chose to adopt CPT-11 plus FU plus LV as their routine choice for adjuvant therapy, based on its superiority in metastatic disease. No data are available on how many patients were exposed, with the best of intentions, to the toxicity of adjuvant CPT-11 plus FU plus LV for no benefit. More tragically, it is likely that some toxic deaths occurred due to use of adjuvant CPT-11 plus FU plus LV. This study illustrates why we must await clinical trial results before adopting a new therapy for routine use, and why we cannot assume that what works in metastatic disease will automatically work in the adjuvant setting.

The implication of our trial is clear—weekly bolus CPT-11 plus FU plus LV should not be used in stage III colon cancer. It is possible that the extensive correlative science studies that are being carried out in conjunction with this trial may identify subgroups in which the use of CPT-11 may appear to be beneficial. Such retrospective subgroup analyses, if in fact found to be positive, will need to be viewed as hypothesis-generating only and would need to be confirmed in prospective studies.

Currently, bevacizumab, cetuximab, and panitumumab have received approval for use in metastatic colorectal cancer. However, we do not yet know the safety or efficacy of any of these in the adjuvant setting. Large-scale clinical trials are ongoing or planned to assess these questions. Participation in these trials should be strongly supported; however, off-study use of regimens without established proof in the adjuvant setting can not be condoned.

	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.

Employment: N/A Leadership: N/A Consultant: Leonard B. Saltz, Pfizer; Richard M. Goldberg, Pfizer Stock: N/A Honoraria: N/A Research Funds: Leonard B. Saltz, Pfizer Testimony: N/A Other: N/A

	Author Contributions

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Conception and design: Leonard B. Saltz, Donna Niedzwiecki, Richard M. Goldberg, Robert J. Mayer

Administrative support: Alexander Hantel, James P. Thomas, Anthony L.A. Fields

Provision of study materials or patients: Alexander Hantel, James P. Thomas, Anthony L.A. Fields

Collection and assembly of data: Leonard B. Saltz, Donna Niedzwiecki, Donna Hollis, Alexander Hantel, James P. Thomas, Anthony L.A. Fields

Data analysis and interpretation: Leonard B. Saltz, Richard M. Goldberg, Robert J. Mayer

Manuscript writing: Leonard B. Saltz, Donna Niedzwiecki, Donna Hollis, Richard M. Goldberg, Robert J. Mayer

Final approval of manuscript: Leonard B. Saltz, Donna Niedzwiecki, Donna Hollis, Richard M. Goldberg, Alexander Hantel, James P. Thomas, Anthony L.A. Fields, Robert J. Mayer

	NOTES

 
Supported by National Cancer Institute Grant No. 2 U10 CA33601-25.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology Meeting, June 5-8, 2004, New Orleans, LA.

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

	REFERENCES

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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[Abstract/Free Full Text]

3. Pizzolato JF, Saltz LB: The camptothecins. Lancet 361:2235-2242, 2003[CrossRef][Medline]

4. Shimada Y, Yoshino M, Wakui A, et al: Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. J Clin Oncol 11:909-913, 1993[Abstract/Free Full Text]

5. Conti JA, Kemeny NE, Saltz LB, et al: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14:709-715, 1996[Abstract/Free Full Text]

6. Cunningham D, Pyrhönen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998[CrossRef][Medline]

7. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041-1047, 2000[CrossRef][Medline]

8. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000[Abstract/Free Full Text]

9. Miller L, Emanuel D, Elfring G, et al: 60-day, all-cause mortality with first-line irinotecan/ fluorouracil/leucovorin (IFL) or fluorouracil/leucovorin (FL) for metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol 21:129a, 2002 (abstr 515)

10. Abigerges D, Armand JP, Chabot GG, et al: Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 86:446-449, 1994[Abstract/Free Full Text]

11. Rothenberg ML, Meropol NJ, Poplin EA, et al: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: Summary findings of an independent panel. J Clin Oncol 19:3801-3807, 2001[Abstract/Free Full Text]

12. Rougier P, Van Cutsem E, Bajetta E, et al: Randomized trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in pateints with metastatic colorectal cancer. Lancet 352:1407-1412, 1998[CrossRef][Medline]

13. André 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]

14. Ychou M, Raoul J, Douillard JY, 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 23:16S, 2005 (abstr 3502)

15. Van Cutsem E, Labianca R, Hossfeld G, et al: Randomized phase III trial comparing infused irinotecan/5-fluorouracil (5-FU)/folinic acid (IF) versus 5-FU/FA (F) in stage III colon cancer patients (pts). (PETACC 3). J Clin Oncol 23:16S, 2005 (abstr LBA8)

Submitted February 19, 2007; accepted May 10, 2007.

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