High-dose folinic acid and 5-fluorouracil bolus and continuous infusion in advanced colorectal cancer

Gramont, Aimery de; Krulik, M; Cady, J; Lagadec, B; Maisani, Jean-Eric; Loiseau, J.P.; Grangé, Jean‐Didier; Gonzalez-Canali, Gustavo; Demuynck, B.; Louvet, Christophe; Seroka, J.; Dray, Claude; Debray, J

doi:10.1016/0277-5379(88)90341-0

Cited by 123 publications

(49 citation statements)

References 8 publications

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“…Patients who progressed were offered alternative treatment. Patients whose catheters became occluded or unusable because of other complications were commenced on an intravenous De Gramont regimen: FA (200 mg m 2) as a 2-h infusion, 5-FU (400 mg m-2) bolus, 5-FU (600 mg m-2) infused over 22 h, repeated on day 2 (De Gramont et al, 1988). Survival analysis (Kaplan-Meier) was used to predict median survival and times to progression.…”

Section: Methodsmentioning

confidence: 99%

A phase II study of regional 2-weekly 5-fluorouracil infusion with intravenous folinic acid in the treatment of colorectal liver metastases

Howell

McArdle²,

Kerr³

et al. 1997

Br J Cancer

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Summary Forty patients with unresectable colorectal metastases confined to the liver were evaluated in a phase 11 study. 5-Fluorouracil (5-FU) was delivered via a surgically placed hepatic artery catheter. Patients received folinic acid (200 mg m-2) intravenously over 2 h followed by a loading dose of intra-arterial 5-FU (400 mg m-2) over 15 min, then 5-FU (1600 mg m-2) by intra-arterial infusion over the following 22 h. This was repeated on day 2 and the whole schedule was repeated every 2 weeks. Response was assessed after six treatments. The median follow-up was 17 months. Overall response rate was 46% with 8% complete response. Estimated median survival is 19 months. Site of progression was the liver alone in 55%, liver and lung in another 16% and 29% in other sites. Eight patients experienced grade 3 or 4 toxicity. The response rate of this regimen compares favourably with reported trials of intra-arterial FUDR, and our schedule is currently being compared with a similar schedule of intravenous 5-FU and folinic acid in a randomized Medical Research Council trial (CR05).Keywords: colorectal cancer; liver metastases; chemotherapy; infusion intra-arterial Colorectal cancer is the second most common cause of cancer deaths in the UK. Approximately half of the patients undergoing apparently curative resection will die within 5 years because of recurrent disease, mostly with liver metastases; in 30% of these patients the liver will be the only site affected. Few patients are suitable for surgical treatment, most having multiple metastases affecting both lobes. Unfortunately, the results of conventional systemic chemotherapy have been disappointing. For example, single-agent 5-flourouracil (5-FU) has a response rate of approximately 10% (Blijham et al, 1996). Furthermore, although the addition of folinic acid (FA) to 5-FU has resulted in higher response rates, there remains doubt as to whether this translates into a survival benefit (Advanced Colorectal Cancer Meta-analysis Project, 1992).As most cytotoxic drugs have a steep dose-response curve, it is a basic pharmacokinetic principle that if one can increase drug delivery to a tumour then increased response rates can be achieved (Gamelin et al, 1995). An alternative approach to the therapy of liver metastases is therefore to deliver the drug intra-arterially. In the case of patients with liver metastases the arterial route of delivery is particularly appropriate as it has been shown that established liver metastases over 1 cm in diameter are mainly supplied by the hepatic artery (Breedis, 1954).We report our experience of an intra-arterial 5-FU-based regimen in patients with unresectable colorectal liver metastases. In this study, we combined three factors that, on the basis of pharmacological studies, have been shown to offer a therapeutic advantage, namely intra-arterial administration, infusional rather Received 17 February 1997 Revised 9 April 1997 Accepted 29April 1997 Correspondence to: JD Howell than bolus 5-FU therapy and modulation of 5-FU by high-dose ...

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Section: Methodsmentioning

confidence: 99%

A phase II study of regional 2-weekly 5-fluorouracil infusion with intravenous folinic acid in the treatment of colorectal liver metastases

Howell

McArdle²,

Kerr³

et al. 1997

Br J Cancer

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“…It involves a 2-h infusion of LV (200 mg m 72 ), bolus injection of FU (400 mg m 72 ), then 22-h infusion of FU (600 mg m 72 ), with the same sequence repeated on the second day, repeated fortnightly (de Gramont et al, 1988). It was compared with the Mayo Clinic 5-day bolus FU/LV regimen in a 448-patient randomised trial, and showed a better response rate (32.6% vs 14.4%; P=0.0004), and median progression-free survival (27.6 vs 22 weeks; P50.0012) with significantly reduced rates of diarrhoea, mucositis and neutropenia; however, overall survival was not significantly improved (de Gramont et al, 1997).…”

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confidence: 99%

A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer

et al. 2002

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The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified 'Modified de Gramont' (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m 72 ), then ambulatory 46-h fluorouracil infusion (2000 -3600 mg m 72 , cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m 72 . Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m 72 bolus + 2800 mg m 72 46-h infusion. A lower dose of 400 mg m 72 bolus + 2400 mg m 72 infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC 0 -48 h ) at this lower dose is equivalent to dG. With OxMdG, grade 3 -4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea 51% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. 1988). It was compared with the Mayo Clinic 5-day bolus FU/LV regimen in a 448-patient randomised trial, and showed a better response rate (32.6% vs 14.4%; P=0.0004), and median progression-free survival (27.6 vs 22 weeks; P50.0012) with significantly reduced rates of diarrhoea, mucositis and neutropenia; however, overall survival was not significantly improved (de Gramont et al, 1997). Following this trial dG was adopted as a standard therapy option by many oncologists, especially in France and the UK.Its low toxicity profile makes dG a good basis for combination chemotherapy. Pivotal trials of the design 'dG+new agent' have been performed in first-line therapy of metastatic colorectal cancer using oxaliplatin or irinotecan (Douillard et al, 2000), in each case producing a high response rate and good safety profile. Similar trials are now ongoing in the adjuvant setting.Although dG can be administered on an ambulatory, out-patient basis, many units find it more convenient to admit patients. This, together with the high dose of LV, and a labour-intensive administration schedule, place high demands on healthcare resources (Ross et al, 1998). Furthermore, repeated hospital visits or admissions during dG may detract from the benefits of its low toxicity profile.Along with others (see Discussion), we reasoned that it would be possible to modify the dG regimen, reducing its ...

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“…We hypothesised that the standard streptozocin plus bolus 5FU chemotherapy regimen could be improved in terms of both cytotoxicity and patient tolerance by using an infusional 5FU regimen well established in colorectal cancer management (de Gramont et al, 1997). Therefore, we adapted the standard de Gramont regimen (also known as 'LV5FU2' (De Gramont et al, 1988) to include streptozocin when offering chemotherapy to patients with metastatic NETs. Here, we review the results of treating 15 patients with this regimen.…”

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confidence: 99%

Treatment of neuroendocrine tumours with infusional 5-fluorouracil, folinic acid and streptozocin

et al. 2003

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High-dose folinic acid and 5-fluorouracil bolus and continuous infusion in advanced colorectal cancer

Cited by 123 publications

References 8 publications

A phase II study of regional 2-weekly 5-fluorouracil infusion with intravenous folinic acid in the treatment of colorectal liver metastases

A phase II study of regional 2-weekly 5-fluorouracil infusion with intravenous folinic acid in the treatment of colorectal liver metastases

A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer

Treatment of neuroendocrine tumours with infusional 5-fluorouracil, folinic acid and streptozocin

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