Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer.

Buroker, T.; O'Connell, M. J.; Wieand, Harry S.; Krook, James E.; Gerstner, James B.; Mailliard, James A.; Schaefer, P; Levitt, Ralph; Kardinal, Carl G.; Gesme, Dean H.

doi:10.1200/jco.1994.12.1.14

Cited by 290 publications

(106 citation statements)

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“…We have corroborated this figure for the p53 knockout mouse (Bach, 2003). The higher dose of 200 mg kg À1 5-FU is equivalent to 600 mg m À2 in this mouse, the exact concentration of 5-FU employed for weekly combination schedules with folinic acid in humans (Buroker et al, 1994). PDTC (250 mg kg À1 ) was the maximum tolerated as a single dose in previous experiments utilising the BDF1 mouse (Bach et al, 2000), whereas 200 mg kg À1 NAC approximates to the clinical dose used in humans (Prescott et al, 1989).…”

Section: Animalssupporting

confidence: 75%

Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut

et al. 2006

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Pyrrolidinedithiocarbamate (PDTC) enhanced the activity of 5-fluorouracil (5-FU) in a colorectal cancer xenograft model. Pyrrolidinedithiocarbamate also reduced gastrointestinal toxicity associated with 5-FU therapy in large but not small bowel. We sought to clarify the basis of this differential enteric toxicity. Apoptosis and mitosis were assessed on a cell positional basis in small and large intestinal crypts of p53 wild-type ( þ / þ ) and p53 null (À/À) mice 6, 12, 24, 36, 48 and 72 h after the administration of high (200 mg kg À1 ) or low (40 mg kg À1 ) dose 5-FU7250 mg kg À1 PDTC. Regimens were chosen to model a single human dose and a weekly schedule. The effects of another antioxidant N-acetylcysteine (NAC) were also investigated. Large intestinal crypts affect apoptosis purely by p53-dependent mechanisms, whereas small intestinal crypts are able to initiate both p53-dependent and -independent pathways following treatment with 5-FU. Pyrrolidinedithiocarbamate and NAC antagonised p53-dependent but potentiated p53-independent apoptotic activity. Consequently, the proportion of surviving clonogens increased in the large but not in the small intestine. Regional availability of p53-dependent and -independent apoptotic pathways in small and large intestine together with separate modulation of these pathways by antioxidants explains the different regional enterotoxicity following 5-FU therapy.

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Section: Animalssupporting

confidence: 75%

Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut

et al. 2006

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“…Twenty-®ve per cent of patients in the present study required hospitalisation for drug-related adverse events, compared with 21% patients who received the Mayo Clinic regimen of 5-FU/LV in a recent study [26]. In the present study diarrhoea was a causal event in 15/27 (56%) of patients requiring hospitalisation for adverse events.…”

Section: Discussionmentioning

confidence: 40%

Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU)

Cutsem¹,

Cunningham

Huinink

et al. 1999

European Journal of Cancer

101

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The aim of this prospective study was to assess the eYcacy, clinical bene®t and safety of in patients with stringently-de®ned 5-¯uorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m 2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18±53 +). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from ®rst administration of CPT-11 was 10.4 months or 45 weeks (range: 3±66 + weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade ! 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m 2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical bene®t. The toxicity pro®le of CPT-11 is becoming better understood and has been considerably improved. #

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“…Despite their widespread acceptance, combinations of 5-FU and LV require complex and inconvenient dosing schedules and are associated with significant toxicity (Lokich et al, 1989;Poon et al, 1989;Buroker et al, 1994;Bleiberg, 1997). In view of the limitations of these therapies, there is a need for the development of new anti-cancer agents with greater or equivalent efficacy, improved tolerability and more acceptable administration schedules.…”

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confidence: 99%

Mature results from three large controlled studies with raltitrexed ('Tomudex')

Cunningham

1998

Br J Cancer

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Summary Since the publication of the results of phase I dose-finding studies, an extensive phase 11 and III clinical study programme has been undertaken to study the clinical efficacy and tolerability of the quinazoline folate analogue raltitrexed ('Tomudex'), a novel direct and specific inhibitor of thymidylate synthase. Two international phase III trials, studies 3 and 12, have compared raltitrexed 3 mg m-2 with 5-fluorouracil (5-FU) plus low-dose leucovorin (LV) (Mayo regimen) or high-dose LV (Machover regimen) respectively. A North American study (study 10) was originally set up to compare two raltitrexed dosage arms (3.0 and 4.0 mg m-2) with 5-FU and low-dose LV, but the 4.0 mg m-2 arm was discontinued prematurely because of excessive toxicity. Minimum follow-up times for studies 3, 10 and 12 were 15.5, 12 and 9 months, respectively (for data other than survival), with corresponding survival follow-up times of 26, 12 and 17 months. Objective response rates were similar for raltitrexed and 5-FU + LV, and palliative improvements were seen to a similar extent with both treatments in all phase III studies. Survival was statistically similar for raltitrexed and 5-FU + LV in both studies 3 and 12. Raltitrexed was, however, associated with inferior survival to 5-FU + low-dose LV in study 10, but there appears to be evidence that this was linked to an unconscious effect on investigator behaviour of early toxicity problems in this trial, in that patients appeared to be withdrawn from raltitrexed treatment without progression or protocolled toxicity. Moreover, it appeared that 5-FU + LV patients were continued on treatment after disease progression.5-FU-based therapy was associated with a higher incidence of mucositis than raltitrexed in all studies, with the attainment of statistical significance in studies 3 and 12. Elevations in hepatic transaminase levels were seen with raltitrexed, but these are thought to be of no clinical significance. Overall, much greater levels of toxicity were seen with 5-FU + LV than with raltitrexed in early treatment cycles. In addition, retrospective UK audit data have shown the monthly cost of raltitrexed therapy to be similar to that of Mayo and continuous infusion 5-FU regimens, and appreciably lower than that of the de Gramont regimen of 5-FU (bolus + 22-h infusion) + high-dose LV. Thus, raltitrexed is an effective alternative to 5-FU-based therapy in patients with advanced colorectal cancer, with an acceptable and, unlike 5-FU, predictable toxicity profile. In particular, patients receiving raltitrexed may benefit from the minimization or avoidance of mucositis, and both patients and healthcare providers may find the convenient administration schedule of the drug advantageous.

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Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer.

Cited by 290 publications

References 0 publications

Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut

Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut

Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU)

Mature results from three large controlled studies with raltitrexed ('Tomudex')

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