Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma.

Abstract

Leucovorin potentiates the cytotoxicity of fluorouracil (5-FU) in experimental tumor systems and appears to enhance the effectiveness of 5-FU in patients with colon cancer. Twenty-two eligible patients (18 previously untreated) with advanced pancreatic adenocarcinoma were treated in a phase II trial of leucovorin 500 mg/m2/d for 6 days by continuous intravenous infusion with 5-FU 370 mg/m2/d by rapid intravenous injection on 5 consecutive days, beginning 24 hours after initiation of leucovorin infusion. Among the 20 assessable patients, there were no complete or partial regressions, although there was one minor response lasting 4 months. Three patients had stable disease for 5, 20, and 21 months, respectively. Median survival was 10 weeks. Toxicity was predominantly mucosal; stomatitis grade 2 or worse was seen in five patients, and diarrhea grade 2 or worse was seen in four. Hospitalization for toxicity was necessary in four previously untreated patients and three previously treated patients. The median WBC nadir was 4.6 (range, 1.4 to 9.6) x 10(3)/microL, and the median platelet nadir was 147.0 (range, 69.0 to 240.0) x 10(3)/microL. This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity. It should not be considered a standard treatment for patients with this disease.

Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis

“…5-FU and gemcitabine are used as first-line drugs for patients with advanced PDAC. The response rate of PDAC to 5-FU is around 20% (Cullinan et al, 1990;Crown et al, 1991). Gemcitabine -a novel pyrimidine analogue -provides a slightly improved clinical results and fewer side effects (Burris et al, 1997).…”

The Medical Management of Pancreatic Cancer: A Review

“…As 5-FU is a cell-cycle-specific agent with a short duration of action, investigators have attempted to improve the efficacy of this drug using infusional or chronomodulated administration or with the addition of folinic acid (FA). Unfortunately, there has been no clear evidence of additional clinical benefit with these strategies [24][25][26][27]. Therefore, manipulations that have been proven to improve the activity of 5-FU in other cancers remain of uncertain benefit in pancreatic cancer.…”

Metastatic Pancreatic Cancer: Emerging Strategies in Chemotherapy and Palliative Care

“…Biomodulation of 5-FU with leucovorin, N-(phosphonacetyl)-L-aspartic acid (PALA), or α-2b interferon has not improved upon these outcomes [70][71][72][73][74]. However, reviewing the survival outcomes associated with varying 5-FU doses and schedules, more prolonged infusion schedules are associated with median overall survival times of 6-8 months.…”