A phase II study of continuous infusion 5‐fluorouracil and leucovorin with weekly cisplatin in metastatic colorectal carcinoma

Jean L Grem, Nanette McAtee, Frank Balis, Robert Murphy, David Venzon, Barnett Kramer, Barry Goldspiel, Martin Begley, Carmen J. Allegra

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background. Prolonged infusional 5‐fluorouracil (5‐FU) and bolus 5‐FU modulated by leucovorin are associated with higher response rates than bolus 5‐FU alone. Cisplatin enhances 5‐FU cytotoxicity in some preclinical models. Methods. The authors tested the feasibility of combining concurrent infusional leucovorin (500 mg/m2/d) with protracted infusional 5‐FU (200 mg/m2/d) and weekly bolus cisplatin (20 mg/m2) in 22 patients with metastatic colorectal cancer. Results. Four partial responses (PR) were noticed among 21 evaluable patients (19%). The median time to treatment failure and median survival were 6 months and 11 months, respectively. All but two patients required 5‐FU dose reduction after a median of 2 weeks because of mucositis. However, severe mucositis and diarrhea occurred in only 18% and 5% of the patients, respectively. Palmar‐plantar erythrodysesthesia of mild to moderate severity occurred in 55% of patients. Megaloblastic changes were evident in the peripheral blood during therapy, and may reflect prolonged DNA‐directed toxicity of 5‐FU. The median tolerated dose level of 5‐FU was 113 mg/m2/d (range, 64–150 mg/m2/d). Mean steadystate plasma concentrations (Cpss) of 5‐FU appeared to increase linearly from 0.19 μM to 0.39 μM over the dose range 64 to 200 mg/m2/d. Patients with grade 2 gastrointestinal toxicity had significantly higher 5‐FU Cpss than patients with grade 0 or 1 toxicity. Conclusions. The early onset of toxicity with this regimen of protracted infusional 5‐FU/high‐dose leucovorin and weekly cisplatin required marked attenuation of the 5‐FU dose intensity, and the results were no better than that expected with infusional 5‐FU alone.

Original languageEnglish (US)
Pages (from-to)663-668
Number of pages6
JournalCancer
Volume72
Issue number3
DOIs
StatePublished - Jan 1 1993

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Leucovorin
Cisplatin
Colorectal Neoplasms
Mucositis
Treatment Failure
Diarrhea
Survival

Keywords

  • 5‐fluorouracil
  • biochemical modulation
  • colorectal cancer
  • pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase II study of continuous infusion 5‐fluorouracil and leucovorin with weekly cisplatin in metastatic colorectal carcinoma. / Grem, Jean L; McAtee, Nanette; Balis, Frank; Murphy, Robert; Venzon, David; Kramer, Barnett; Goldspiel, Barry; Begley, Martin; Allegra, Carmen J.

In: Cancer, Vol. 72, No. 3, 01.01.1993, p. 663-668.

Research output: Contribution to journalArticle

Grem, Jean L ; McAtee, Nanette ; Balis, Frank ; Murphy, Robert ; Venzon, David ; Kramer, Barnett ; Goldspiel, Barry ; Begley, Martin ; Allegra, Carmen J. / A phase II study of continuous infusion 5‐fluorouracil and leucovorin with weekly cisplatin in metastatic colorectal carcinoma. In: Cancer. 1993 ; Vol. 72, No. 3. pp. 663-668.
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T1 - A phase II study of continuous infusion 5‐fluorouracil and leucovorin with weekly cisplatin in metastatic colorectal carcinoma

AU - Grem, Jean L

AU - McAtee, Nanette

AU - Balis, Frank

AU - Murphy, Robert

AU - Venzon, David

AU - Kramer, Barnett

AU - Goldspiel, Barry

AU - Begley, Martin

AU - Allegra, Carmen J.

PY - 1993/1/1

Y1 - 1993/1/1

N2 - Background. Prolonged infusional 5‐fluorouracil (5‐FU) and bolus 5‐FU modulated by leucovorin are associated with higher response rates than bolus 5‐FU alone. Cisplatin enhances 5‐FU cytotoxicity in some preclinical models. Methods. The authors tested the feasibility of combining concurrent infusional leucovorin (500 mg/m2/d) with protracted infusional 5‐FU (200 mg/m2/d) and weekly bolus cisplatin (20 mg/m2) in 22 patients with metastatic colorectal cancer. Results. Four partial responses (PR) were noticed among 21 evaluable patients (19%). The median time to treatment failure and median survival were 6 months and 11 months, respectively. All but two patients required 5‐FU dose reduction after a median of 2 weeks because of mucositis. However, severe mucositis and diarrhea occurred in only 18% and 5% of the patients, respectively. Palmar‐plantar erythrodysesthesia of mild to moderate severity occurred in 55% of patients. Megaloblastic changes were evident in the peripheral blood during therapy, and may reflect prolonged DNA‐directed toxicity of 5‐FU. The median tolerated dose level of 5‐FU was 113 mg/m2/d (range, 64–150 mg/m2/d). Mean steadystate plasma concentrations (Cpss) of 5‐FU appeared to increase linearly from 0.19 μM to 0.39 μM over the dose range 64 to 200 mg/m2/d. Patients with grade 2 gastrointestinal toxicity had significantly higher 5‐FU Cpss than patients with grade 0 or 1 toxicity. Conclusions. The early onset of toxicity with this regimen of protracted infusional 5‐FU/high‐dose leucovorin and weekly cisplatin required marked attenuation of the 5‐FU dose intensity, and the results were no better than that expected with infusional 5‐FU alone.

AB - Background. Prolonged infusional 5‐fluorouracil (5‐FU) and bolus 5‐FU modulated by leucovorin are associated with higher response rates than bolus 5‐FU alone. Cisplatin enhances 5‐FU cytotoxicity in some preclinical models. Methods. The authors tested the feasibility of combining concurrent infusional leucovorin (500 mg/m2/d) with protracted infusional 5‐FU (200 mg/m2/d) and weekly bolus cisplatin (20 mg/m2) in 22 patients with metastatic colorectal cancer. Results. Four partial responses (PR) were noticed among 21 evaluable patients (19%). The median time to treatment failure and median survival were 6 months and 11 months, respectively. All but two patients required 5‐FU dose reduction after a median of 2 weeks because of mucositis. However, severe mucositis and diarrhea occurred in only 18% and 5% of the patients, respectively. Palmar‐plantar erythrodysesthesia of mild to moderate severity occurred in 55% of patients. Megaloblastic changes were evident in the peripheral blood during therapy, and may reflect prolonged DNA‐directed toxicity of 5‐FU. The median tolerated dose level of 5‐FU was 113 mg/m2/d (range, 64–150 mg/m2/d). Mean steadystate plasma concentrations (Cpss) of 5‐FU appeared to increase linearly from 0.19 μM to 0.39 μM over the dose range 64 to 200 mg/m2/d. Patients with grade 2 gastrointestinal toxicity had significantly higher 5‐FU Cpss than patients with grade 0 or 1 toxicity. Conclusions. The early onset of toxicity with this regimen of protracted infusional 5‐FU/high‐dose leucovorin and weekly cisplatin required marked attenuation of the 5‐FU dose intensity, and the results were no better than that expected with infusional 5‐FU alone.

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