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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3347-3353 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.1317 Randomized Controlled Trial of Reduced-Dose Bolus Fluorouracil Plus Leucovorin and Irinotecan or Infused Fluorouracil Plus Leucovorin and Oxaliplatin in Patients With Previously Untreated Metastatic Colorectal Cancer: A North American Intergroup Trial
From the Division of Hematology and Oncology, University of North Carolina, Chapel Hill, NC; Divisions of Biostatistics and Medical Oncology, Mayo Clinic, Rochester, MN; Iowa Oncology Research Association Community Clinical Oncology Program, Des Moines, IA; Department of Oncology, Dana-Farber Cancer Center Institute, Boston, MA; Division of Medical Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA; Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, KS; and the National Cancer Institute of Canada, Saint Catherines, Ontario, Canada Address reprint requests to Richard M. Goldberg, MD, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, CB # 7305, 3009 Old Clinic Bldg, Chapel Hill, NC 27514; e-mail: Goldberg{at}med.unc.edu
PURPOSE: Previously, we reported results of Intergroup N9741, which compared standard bolus fluorouracil (FU), leucovorin, plus irinotecan (IFL) with infused FU, leucovorin, plus oxaliplatin (FOLFOX4) and irinotecan plus oxaliplatin in patients with untreated metastatic colorectal cancer. High rates of grade  3 toxicity on IFL (resulting in some deaths) led us to reduce the starting doses of both irinotecan and FU by 20% (rIFL). This article compares rIFL with FOLFOX4. PATIENTS AND METHODS: The primary comparison was time to progression, with secondary end points of response rate (RR), overall survival, and toxicity. RESULTS: Three hundred five patients were randomly assigned. The North Central Cancer Treatment Group Data Safety Monitoring Committee interrupted enrollment at a planned interim analysis when outcomes crossed predetermined stopping boundaries. The results were significantly superior for FOLFOX4 compared with rIFL for time to progression (9.7 v 5.5 months, respectively; P < .0001), RR (48% v 32%, respectively; P = .006), and overall survival (19.0 v 16.3 months, respectively; P = .026). Toxicity profiles were not significantly different between regimens for nausea, vomiting, diarrhea, febrile neutropenia, dehydration, or 60-day all-cause mortality. Sensory neuropathy and neutropenia were significantly more common with FOLFOX4. Approximately 75% of patients in both arms received second-line therapy; 58% of rIFL patients received oxaliplatin-based second-line therapy, and 55% of FOLFOX4 patients received irinotecan-based regimens as second-line therapy. CONCLUSION: FOLFOX4 led to superior RR, time to progression, and overall survival compared with rIFL. The survival benefit for FOLFOX4 observed in the earlier stage of the study was preserved with equal use of either irinotecan or oxaliplatin as second-line therapy.
In 2005, approximately 150,000 Americans were diagnosed with colorectal cancer, the third leading cause of cancer death worldwide.1 For years, advanced colorectal cancer therapy was limited to fluorouracil (FU). In the 1990s, two additional agents, irinotecan and oxaliplatin, were found to have activity against advanced colorectal cancer. Irinotecan inhibits topoisomerase I, impeding DNA uncoiling and causing double-stranded DNA breaks.2 Initial treatment with irinotecan and either bolus (North American preference) or infused (European preference) FU plus leucovorin significantly improved outcomes compared with FU plus leucovorin.3,4 The bolus irinotecan and FU plus leucovorin regimen (IFL) produced a 39% response rate (RR), 7-month median time to progression, and median overall survival time of 14.8 months.3 In March 2000, the US Food and Drug Administration approved this combination delivered by either the North American or European protocols as indicated for first-line therapy for advanced colorectal cancer. The Oncologic Drugs Advisory Committee recommended to the US Food and Drug Administration that this combination should be considered a regulatory standard to which new regimens should be compared based on a pharmaceutical company–sponsored phase III trial. Oxaliplatin, a platinum-based drug, forms DNA adducts blocking replication and transcription.5,6 Oxaliplatin inhibits colorectal tumor cell lines resistant to cisplatin and carboplatin.7 When oxaliplatin was coupled with infused FU plus leucovorin (FOLFOX4) an RR of 51% and time to progression of 9.0 months were observed. These results were significantly better that the results observed in the cohort enrolled onto the FU plus leucovorin arm of the trial.8 The increase in median survival from 14.7 to 16.2 months did not reach statistical significance. We developed this randomized multicenter trial to compare combinations of FU plus leucovorin, irinotecan, and oxaliplatin in patients with previously untreated metastatic colorectal cancer. In April 2000, the trial had three arms, the control regimen of IFL compared with two experimental regimens, FOLFOX4 and oxaliplatin and irinotecan. The results of this phase of the trial have been previously reported.9 In April 2001, through implementation of a previously described real-time toxicity monitoring program that required faxed notification of grade 4 or 5 toxic events or patient hospitalizations within 24 hours of the event, we detected an imbalance in the number of deaths by arm within the first 60 days of treatment.10 We observed that 4.6% of IFL patients in the control arm died within 60 days of study enrollment compared with 2.6% of patients in the other two study arms.11,12 Consequently, accrual to that stage of the trial was stopped. An amended version of the study continued as a two-arm comparison of IFL and FOLFOX. In the new version of the study, the doses in the IFL regimen were reduced by 20% for both irinotecan (125 to 100 mg/m2) and FU (500 to 400 mg/m2), leading to the reduced-dose IFL regimen (rIFL). We report comparative efficacy and toxicity data in 305 patients concurrently randomly assigned to rIFL or the best performing experimental regimen from the prior stage of the study, FOLFOX4.
Patients Five National Cancer Institute cooperative oncology groups collaborated in this study, including the North Central Cancer Treatment Group (lead group), Cancer and Acute Leukemia Group B, Eastern Cooperative Oncology Group, Southwest Oncology Group, and National Cancer Institute of Canada. Inclusion and exclusion criteria are listed in Table 1. The study was funded by the National Cancer Institute. Irinotecan was provided by Pharmacia (now Pfizer, New York, NY), and oxaliplatin was supplied by Sanofi-Synthelabo (now sanofi-aventis, Bridgewater, NJ). Both companies also provided funding for translational science aspects of the trial, which are reported elsewhere.
Patient Evaluation Physical examination and laboratory studies, including CBC with differential, serum liver function tests, prothrombin time (if receiving warfarin), actual or estimated creatinine clearance, and electrocardiography, were performed within 14 days of enrollment. Chest radiography and disease site imaging were completed within 30 days of enrollment. Women of childbearing potential had negative serum pregnancy testing within 7 days of registration. CBC with differential were monitored weekly. History, physical examination, and laboratory evaluation occurred before each cycle. Tumors were measured every 6 weeks for the first 42 weeks or until tumor response was confirmed. Thereafter measurements were required every 12 weeks.
Random Assignment and Stratification
Response and Progression Criteria Time to progression was calculated from study entry to disease progression, regardless of the patient's treatment status. In a post hoc sensitivity analysis, patients were censored for time to progression when they discontinued initial treatment. Deaths occurring within 30 days of treatment discontinuation were considered progressions in both analyses. Survival was calculated from enrollment to death or last contact. Without contradictory data, patients who died or were lost to follow-up were assumed to have experienced progression at the time they were last known to be progression free.
Treatment Plan Toxic effects (except paresthesias) were graded by the National Cancer Institute Common Toxicity Criteria version 2.0. Functional impairments that interfered with daily activities or caused disability were classified as grade 3 or 4 paresthesias, respectively. Any grade 3 or 4 toxic effect resulted in approximately a 20% dose reduction for subsequent cycles. Persistent grade 2 or worse toxic effects delayed therapy until toxicity resolved. If the toxic effect exceeded grade 1 for 2 weeks or more than two dose reductions were required, protocol therapy was discontinued. In patients enrolled onto the rIFL arm, dose escalation to the original dose of the IFL regimen was required if the patient experienced no more than grade 1 toxicity during the first 6-week cycle of protocol-directed therapy.
Statistical Considerations The main secondary end point of interest was overall survival. Additional secondary end points included confirmed tumor RR (complete response, partial response in measurable patients, or regression in assessable patients, confirmed at second evaluation), time to treatment discontinuation (time from random assignment to treatment cessation on assigned treatment), and toxicity.
The Kaplan-Meier method was used to describe the distribution of time to disease progression, overall survival time, and time to treatment discontinuation.14 Cox proportional hazards modeling was used to calculate hazard ratios and CIs.15
Patient Characteristics There were 305 patients enrolled between April 25, 2001 and April 23, 2002. The arms were well balanced with respect to stratification factors and other baseline characteristics (Table 2). There were three rIFL patients (2%) and eight FOLFOX4 patients (5.2%) who were deemed to be ineligible, had major treatment violations, or canceled treatment.
Efficacy With a median follow-up time of 40 months, 87.5% of patients have experienced disease progression. Time to disease progression differed significantly between patients receiving rIFL (median, 5.5 months) and patients receiving FOLFOX4 (median, 9.7 months; P < .0001; hazard ratio = 0.55; 95% CI, 0.43 to 0.70; Fig 1). In the sensitivity analysis, in which patients whose initial treatment ceased without progression were censored at the completion of protocol-specified therapy, these results remained significant (median time to disease progression, 5.6 and 10.1 months on rIFL and FOLFOX4, respectively; hazard ratio = 0.42; P < .0001).
The median survival time for patients receiving rIFL was 16.4 months compared with 19.0 months for patients receiving FOLFOX4 (P = .026; hazard ratio = 0.76; 95% CI, 0.60 to 0.97; Fig 2). The RR of patients receiving FOLFOX4 (48%) was higher than the RR of patients receiving rIFL (32%; P = .006).
Time to treatment discontinuation did not differ significantly between rIFL and FOLFOX4 (Fig 3). The reason for treatment discontinuation did differ between arms. Among patients receiving rIFL, 71.8% ceased treatment because of disease progression or death compared with 36.2% of patients receiving FOLFOX4 (P < .0001).
Adverse Events The rates of grade 3 or higher toxicity are listed in Table 3. Patients treated with rIFL had similar rates of diarrhea, vomiting, nausea, febrile neutropenia, and dehydration and significantly lower rates of paresthesias and neutropenia compared with patients treated with FOLFOX4. The onset of grade 3 paresthesias in patients receiving FOLFOX4 occurred after a median of 11 2-week treatment cycles. The death rates within the first 60 days of treatment were 3.3% (95% CI, 1.1% to 7.7%) for patients receiving rIFL, and 2.0% (95% CI, 0.4% to 5.7%) for patients receiving FOLFOX4.
Second-Line Therapy Treatments administered after first-line therapy are listed in Table 4. A high proportion of patients on both arms of the study received second-line therapy (74% on rIFL and 75% on FOLFOX4). The proportion of patients receiving any second-line therapy before progression was similar across arms (40% on rIFL v 29% on FOLFOX4). Fifty-eight percent of patients who were initially treated with rIFL received a second-line regimen containing oxaliplatin, and 55% of patients who were initially treated with FOLFOX4 received a second-line regimen containing irinotecan.
Dose-Intensity of rIFL Compared With IFL In the prior stage of N9741, the full-dose IFL regimen was used. We compared the dose-intensity of irinotecan delivered in the patients treated with rIFL to the dose-intensity previously reported in patients who were treated with IFL (Table 5). Many patients required a dose reduction of full-dose IFL, such that 85.5% of the intended dose was delivered during the first cycle, whereas 93.8% of the planned dose of rIFL was delivered at the first cycle (P = .012). The absolute doses of irinotecan also differed in cycle 2, with a median delivered dose of 375 mg/m2 of rIFL versus 425 mg/m2 of full-dose IFL (P < .001). At cycles 3 and 6, there was no significant difference observed between the absolute doses of the drugs administered in IFL and rIFL because the doses for patients on full-dose IFL had been reduced to levels similar to the protocol-specified rIFL doses. Results for FU administration are similar in the full-dose IFL and rIFL cohorts (data not shown).
This study set out to reduce the toxicity associated with IFL, particularly the severe toxicity that affected a minority of patients during the first cycle of therapy and which contributed to the deaths of some of those patients. It was hoped that, by reducing toxicity, the regimen could be safely administered while retaining or even augmenting its activity. We met our goal of permitting a safe comparison of the rIFL and FOLFOX4 regimens. In this segment of the study, as in the previously reported segment, FOLFOX4 proved to be the superior regimen for all three outcome measures. Treatment with FOLFOX4 led to a statistically significantly improved RR, time to disease progression, and overall survival compared with rIFL. Comparatively, the adverse event profile for rIFL was reduced to the point where the grade 3 to 4 toxicity rates were not significantly different, with the exception of significantly more paresthesias and more neutropenia in the FOLFOX4-treated patients. Sensory neuropathy was treatment limiting in patients benefiting from FOLFOX4 treatment because it generally occurred after eight to 10 cycles. Several issues must be considered in integrating this trial's data with data from other studies to define optimal treatment for this disease. As in the prior stage of this trial using full-dose IFL, the rIFL regimen delivered FU via bolus injection; the FOLFOX4 arm infused FU over 2 days. IFL was chosen because it was the regimen most often used by North American oncologists of the two irinotecan and FU regimens approved by the US Food and Drug Administration to be the standards for comparison for future chemotherapy regimens in advanced colorectal cancer. Previous studies have demonstrated diminished toxicity with FU infusion compared with bolus administration, with a modest 1-month improvement in median survival time.8,16 The current study does not allow isolation of independent contributions of oxaliplatin versus irinotecan and infused versus bolus FU. Tournigand et al17 randomly assigned 226 patients to oxaliplatin or irinotecan, both with infused FU plus leucovorin. Patients received both regimens in opposite sequence in a cross-over design. The primary end point was time to progression after receiving both regimens. No statistically significant difference in time to progression or overall survival was observed between the treatment strategies. Second-line chemotherapy likely contributed to overall survival. At the time of this segment of the trial, both oxaliplatin and irinotecan were marketed and readily available in the United States in the second-line setting; thus, an equal number of patients on each arm were treated with the drug that they had not received in the first-line setting. In this portion of the study and also in the prior segment of the study, availability of second-line therapy did not explain the increased RR and time to tumor progression observed with FOLFOX4 compared with rIFL or IFL. The increase in time to progression remained statistically significant in sensitivity analyses in which patients were censored for progression when initial treatment was discontinued. The equal balance of exposure to oxaliplatin or irinotecan in the second-line setting in this segment of the trial addresses one important issue left unresolved by the previously reported three-arm portion of the study. That issue relates to the effect of second-line therapy on overall survival. In the prior report, some felt that the imbalance in the availability of second-line agents biased the outcome in favor of FOLFOX4.18 In this segment of the trial, an equal number of patients in each arm received second-line therapy with the agent that they had not previously received. The benefits of FOLFOX over rIFL were preserved. In conclusion, this study has demonstrated improved RR, time to disease progression, and overall survival for patients treated with FOLFOX4 compared with rIFL. The improvement in efficacy, coupled with a favorable toxicity profile for FOLFOX4 over IFL in the prior segment of this trial, led to US Food and Drug Administration approval of FOLFOX4 as indicated for patients with previously untreated metastatic colorectal cancer. Since the time of that report, FOLFOX4 has replaced IFL as the most commonly used combination chemotherapy in patients with metastatic colorectal cancer in the United States, and this experience has been widely generalized worldwide. In this segment of the trial, we achieved the goal of improving the safety of IFL but confirm that it is not the regimen of choice in this setting. Regimens that deliver infused FU with leucovorin plus irinotecan, such as folinic acid, FU, and irinotecan (FOLFIRI), have been shown to provide similar outcomes to FOLFOX with a reduced toxicity profile compared with IFL. Additionally, since the time that this trial was conducted, the results of a study in which IFL was administered with bevacizumab have been reported.19 The standard of care in the United States for most patients has now shifted to incorporate antiangiogenic therapy with multiagent chemotherapy.20
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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,900 (C)
We thank the patients who enrolled onto the trial, the investigators who enrolled them, and the North Central Cancer Treatment Group Operations and Statistical Office personnel, including Jeannine A. Hadley, Carol A. Leonard, Linda G. Healy, and Erin M. Green.
Supported by National Institutes of Health Grants No. CA25224, CA32102, CA38926, CA21115, and CA77202; Pharmacia Corporation (now Pfizer); and Sanofi-Synthelabo (now sanofi-aventis). Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. CA Cancer J Clin 52:23-47, 2002 2. Hsiang YH, Hertzberg R, Hecht S, et al: Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14873-14878, 1985 3. 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 4. 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] 5. Raymond E, Faivre S, Woynarowski JM, et al: Oxaliplatin: Mechanism of action and antineoplastic activity. Semin Oncol 25:4-12, 1998[Medline] 6. Woynarowski JM, Chapman WG, Napier C, et al: Sequence- and region-specificity of oxaliplatin adducts in naked and cellular DNA. Mol Pharmacol 54:770-777, 1998 7. Rixe O, Ortuzar W, Alvarez M, et al: Oxaliplatin, tetraplatin, cisplatin, and carboplatin: Spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute's Anticancer Drug Screen panel. Biochem Pharmacol 52:1855-1865, 1996[CrossRef][Medline] 8. de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815, 1997 9. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 10. Goldberg RM, Sargent DJ, Morton RF, et al: Early detection of toxicity and adjustment of ongoing clinical trials: The history and performance of the North Central Cancer Treatment Group's real-time toxicity monitoring program. J Clin Oncol 20:4591-4596, 2002 11. Morton RF, Goldberg RM, Sargent DJ, et al: Oxaliplatin (OXAL) or CPT-11 combined with 5FU/leucovorin (LV) in advanced colorectal cancer (CRC): An NCCTG/CALGB study. Proc Am Soc Clin Oncol 20:125a, 2001 (abstr 495) 12. Sargent DJ, Niedzwiecki D, O'Connell MJ, et al: Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 345:144-145, 2001 13. O'Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 35:549-556, 1979[CrossRef][Medline] 14. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 15. Cox DR: Regression models and life tables. J R Stat Soc B 34:187-220, 1972 16. Meta-Analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301-308, 1998 17. Tournigand C, Louvet C, Quinax E, et al: FOLFIRI followed by FOLFOX or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004 18. Saltz LB: Metastatic colorectal cancer: Is there one standard approach? Oncology (Williston Park) 19:1147-1154, 2005[Medline] 19. 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 20. Kelly H, Goldberg RM: Systemic therapy for metastatic colorectal cancer: Current options, current evidence. J Clin Oncol 23:4553-4560, 2005 Submitted February 15, 2006; accepted March 17, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests were used to compare toxicity and confirmed RRs. P < .025 was considered statistically significant for the primary comparison of time to progression between the control and experimental arms; for all other comparisons, P < .05 was considered statistically significant. All randomly assigned patients are included for efficacy analyses according to intent-to-treat principles; patients who canceled treatment were excluded from toxicity analyses. 
