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

Richard M. Goldberg, Daniel J. Sargent, Roscoe F. Morton, Charles S. Fuchs, Ramesk K Ramanathan, Stephen K. Williamson, Brian P. Findlay, Henry Clement Pitot, Steven Robert Alberts

Research output: Contribution to journalArticle

183 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3347-3353
Number of pages7
JournalJournal of Clinical Oncology
Volume24
Issue number21
DOIs
StatePublished - Jul 20 2006
Externally publishedYes

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oxaliplatin
irinotecan
Leucovorin
Fluorouracil
Colorectal Neoplasms
Randomized Controlled Trials
Survival
Clinical Trials Data Monitoring Committees
Therapeutics
Febrile Neutropenia
Neutropenia
Dehydration
Nausea
Vomiting
Diarrhea
Survival Rate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{154878031e8242f8b35318c4ddb6c0db,
title = "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",
abstract = "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.",
author = "Goldberg, {Richard M.} and Sargent, {Daniel J.} and Morton, {Roscoe F.} and Fuchs, {Charles S.} and Ramanathan, {Ramesk K} and Williamson, {Stephen K.} and Findlay, {Brian P.} and Pitot, {Henry Clement} and Alberts, {Steven Robert}",
year = "2006",
month = "7",
day = "20",
doi = "10.1200/JCO.2006.06.1317",
language = "English (US)",
volume = "24",
pages = "3347--3353",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "21",

}

TY - JOUR

T1 - 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

T2 - A North American intergroup trial

AU - Goldberg, Richard M.

AU - Sargent, Daniel J.

AU - Morton, Roscoe F.

AU - Fuchs, Charles S.

AU - Ramanathan, Ramesk K

AU - Williamson, Stephen K.

AU - Findlay, Brian P.

AU - Pitot, Henry Clement

AU - Alberts, Steven Robert

PY - 2006/7/20

Y1 - 2006/7/20

N2 - 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.

AB - 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.

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U2 - 10.1200/JCO.2006.06.1317

DO - 10.1200/JCO.2006.06.1317

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JF - Journal of Clinical Oncology

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ER -