Analysis of the time course and prognostic factors determining toxicity due to infused fluorouracil

Abstract

This study used a prospectively managed clinical database in order to identify 1470 patients with gastrointestinal cancers receiving protracted venous infusion (PVI) fluorouracil (5FU). It aimed to determine the time course of toxicity due to PVI 5FU and to analyse factors predicting toxicity. The initial development of stomatitis occurred more rapidly than diarrhoea or palmar plantar erythema (PPE). The percentage of patients with National Cancer Institute Common Toxicity Criteria (CTC) grade 2 or worse PPE peaked at 9% between weeks 8 and 17, whereas this peak occurred earlier for stomatitis and diarrhoea. The development of CTC grade 1 toxicity in the first 28 days after commencement of chemotherapy was classified as early grade 1 toxicity. Multivariate Cox regression analysis showed that female sex, better performance status, elevated bilirubin, early grade 1 PPE and early grade 1 diarrhoea were independent prognostic factors for the development of CTC grade 2 or worse PPE (Po0.01). Female sex, increased age, elevated alanine transaminase and urea and early grade 1 PPE were significant independent prognostic factors for the development of CTC grade 2 or worse stomatitis (Po0.01). Early CTC grade 1 diarrhoea predicted CTC grade 2 or worse diarrhoea (Po0.01). Older, female patients with good performance status and impaired liver and renal function who develop early grade 1 PPE alone or in combination with diarrhoea are at highest risk of subsequently developing grade 2 or worse PPE or stomatitis during treatment with PVI 5FU. Reduction of infused 5FU dose should be considered for these patients. Such an approach could both reduce severe toxicity owing to chemotherapy and minimise treatment delays, and should be evaluated prospectively.

Failure to complete adjuvant chemotherapy is associated with adverse survival in stage III colon cancer patients

“…The other major factor likely to result in failure to complete chemotherapy is toxicity. It is well-documented that bolus schedules of 5FU cause more severe leucopenia and stomatitis in elderly patients, particularly in females (Milano et al, 1992;Metaanalysis Group in Cancer, 1998;Zalcberg et al, 1998;Popescu et al, 1999;Tebbutt et al, 2000;Sloan et al, 2002;Chansky et al, 2005). In agreement with these findings, the present study found that females were less likely to complete adjuvant chemotherapy when adjusted for other variables (Table 6), and we postulate this is due to an increased incidence of toxicity.…”

“…Many of the toxicities that lead to the termination of 5FU chemotherapy culminate around the time of the third cycle (Tebbutt et al, 2000). Unfortunately, steady-state plasma 5FU levels do not correlate with toxicity (Jodrell et al, 2001) and hence pharmacokinetic monitoring is not used to identify patients who are at increased risk of toxicity (Tebbutt et al, 2000).…”

“…Unfortunately, steady-state plasma 5FU levels do not correlate with toxicity (Jodrell et al, 2001) and hence pharmacokinetic monitoring is not used to identify patients who are at increased risk of toxicity (Tebbutt et al, 2000). In randomised controlled trials, dose reductions are common after the first two cycles and 15 -30% of patients fail to complete chemotherapy (Wolmark et al, 1993;O'Connell et al, 1997;Poplin et al, 2005).…”

Elderly patients with fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer derive similar benefit without excessive toxicity when treated with irinotecan monotherapy

“…These results suggested that women might be intrinsically more sensitive to 5-FU. However, this gender difference in toxicity is not limited to bolus 5-FU/LV schedules, but also extends to infused 5-FU (Tebbutt et al, 2003). In our analysis, we evaluated whether there were gender differences in efficacy and developing toxicity to irinotecan.…”

Pharmacogenetics of Capecitabine in Advanced Breast Cancer Patients

“…In fact, in the event of marked DPD deficiency, one could anticipate intracellular metabolic imbalance with intracellular overexposure to locally produced 5-FU within normal proliferating cells. Women are at risk of severe toxicity under fluoropyrimidines (33). Prospective studies have shown that women exhibit lower DPD activity than men (24).…”