5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer

Jodrell, Duncan I.; Stewart, Marlene; Aird, Rhona; Knowles, Gillian; Bowman, A.; Wall, Lucy; Cummings, Jeff; McLean, Catriona

doi:10.1054/bjoc.2000.1664

Cited by 36 publications

(23 citation statements)

References 11 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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Two recent North American studies have shown that completion of 5-fluorouracil (5FU)-based adjuvant chemotherapy is a major prognostic factor for the survival of elderly stage III colon cancer patients. The aim of the present study was to confirm this finding in a population-based series from Australia. The study cohort comprised 851 stage III colon cancer patients treated by surgery alone and 461 who initiated the Mayo chemotherapy regime. One-third of patients who initiated chemotherapy failed to complete more than three cycles of treatment. Independent predictors for failure to complete were treatment in district or rural hospitals, low socioeconomic index and treatment by a low-volume surgeon. Patients who failed to complete chemotherapy showed worse cancer-specific survival compared not only to those who completed treatment (HR ¼ 2.24; 95% confidence interval (CI) (1.66 -3.03), Po0.001) but also to those treated by surgery alone (HR ¼ 1.37; 95% CI (1.09 -1.72), P ¼ 0.008). The current and previous studies demonstrate the importance of completing adjuvant 5-FU-based chemotherapy for colon cancer. Further prospective studies are required to identify better the physiological and socioeconomic factors responsible for failure to complete chemotherapy so that appropriate improvements in health service delivery can be made.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…Pharmacokinetic evaluation provides a more direct information about whole-body 5FU catabolism, and small studies suggest that with infused 5FU, higher plasma levels of 5FU correlate with increased toxicity (Findlay et al, 1996;Gamelin et al, 1996). However, plasma 5FU levels have been found to show wide inter-and intrapatient variation and larger studies have failed to show any relation between steady-state plasma 5FU levels and 5FU toxicity (Jodrell et al, 2001). Thus, 5FU pharmacokinetic assessment is not routinely used for the prediction of patients at increased risk of toxicity.…”

Section: Prediction Of Toxicity Using Pharmacokinetic Monitoringmentioning

confidence: 99%

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

et al. 2003

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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.

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“…The 52 patients studied had consented to participate in a study of protracted venous infusional 5-fluorouracil (PVI-5FU) for metastatic CRC (Jodrell et al, 2001). None of these patients had previously received any chemotherapeutic agents.…”

Section: Casesmentioning

confidence: 99%

Nuclear thymidylate synthase expression, p53 expression and 5FU response in colorectal carcinoma

et al. 2001

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Summary Thymidylate synthase (TS) is a key enzyme in DNA synthesis and is inhibited by metabolites of the chemotherapeutic agent 5-fluorouracil (5FU). Nuclear expression of TS in human tissue in vivo has not been characterised and its clinicopathological correlates in malignancy are unknown. 52 cases of primary colorectal carcinoma (CRC) and 24 cases of matched metastatic carcinoma were studied immunohistochemically using the monoclonal antibody TS106. The degree of nuclear TS immunostaining correlated closely with levels of TS mRNA expression amongst 10 CRCs studied. Strong nuclear immunostaining was seen in normal basal crypt colonocytes and germinal centre cells, and in a varying proportion of adenocarcinoma cells. Amongst the primary carcinomas, higher TS nuclear expression was associated with prominent extracellular mucin production and right-sided location. Higher TS nuclear expression also showed a significant association with poorer response to protracted venous infusional 5FU therapy. There was no clear association between TS nuclear expression and Ki67 or p53 expression assessed immunohistochemically. There was a strong positive correlation between TS nuclear expression in primary and metastatic CRC but the latter generally showed higher expression than matched primary tumour tissue. These findings confirm the nuclear expression of TS protein in human cells in vivo and provide new insight into how such expression may relate to the behaviour of CRCs.

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5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer

Cited by 36 publications

References 11 publications

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

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

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

Nuclear thymidylate synthase expression, p53 expression and 5FU response in colorectal carcinoma

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