Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial fluorouracil.

Kerr, David; Ledermann, Jonathan A.; McArdle, C. S.; Buckels, J. A. C.; Neoptolemos, John P.; Seymour, Michel; Doughty, JC; Budden, J.; Taylor, I.

doi:10.1200/jco.1995.13.12.2968

Cited by 32 publications

(11 citation statements)

References 16 publications

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“…In this way, we hoped to maximize response rates within the liver but also to suppress the development of extrahepatic metastases. It seemed likely that both of these objectives could be achieved; our previous pharmacokinetic and phase I studies showed that high doses of 5-FU could be safely infused intra-arterially and that this regimen produced equitoxic and similar steady-state plasma levels compared with conventional systemic infusional 5-FU (Kerr et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…The chemotherapy regimen was based on the results of a previous phase I pharmacokinetic study (Kerr et al, 1995). Folinic acid (200 mg m-2, 10 mg ml-') was infused intravenously over 2 h followed by an intra-arterial loading dose of 5-FU (400 mg m-2, 25 mg ml-1) over 15 min, then 5-FU (1600 mg m-2, 25 mg ml-', plus 4000 j of heparin per g of 5-FU) by intra-arterial infusion over 22 h. This was repeated on day 2 and the 48-h regimen was repeated every 2 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…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 than bolus 5-FU therapy and modulation of 5-FU by high-dose folinic acid (Kerr et al, 1995). The aim of this approach was firstly to achieve high drug levels within the hepatic metastases and secondly to deliberately allow the 5-FU to 'spill over' into the systemic circulation, in an attempt to maximize tumour response and also delay extrahepatic progression.…”

mentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Intravenous leucovorin 400 mg/m 2 over 2 h was followed by a loading dose of 400 mg/m 2 hepatic arterial 5-FU after which 5-FU 1.6 g/m 2 as an hepatic arterial infusion was given over 22 h daily for 2 days, every 2 weeks. A phase I and pharmacokinetic study showed that this regimen produced equitoxic and similar steady-state plasma levels as compared with systemic infusional 5-FU/leucovorin [44]. A subsequent phase II study resulted in a response rate of 46%, and only 29% of patients experienced extrahepatic progression as the first site of relapse [45].…”

Section: Results and Complications Of Hacmentioning

confidence: 99%

Hepatic Arterial Chemotherapy for Colorectal Cancer Metastatic to the Liver

et al. 2000

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In advanced colorectal cancer, liver metastases are a major problem. In patients with liver metastases as the major site of disease hepatic arterial chemotherapy is a valid alternative to systemic treatment. In this review about hepatic arterial chemotherapy we will discuss the theoretical and practical aspects, the results and complications, the selection of patients for hepatic arterial chemotherapy, and its future developments.

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“…Dose modification can be performed in accordance with systemic side effects. Since the first-pass hepatic extraction of 5-FU is between 19 and 51%, intra-arterial treatment produces not only high intrahepatic drug levels but also significant systemic levels as a result of nonmetabolized 5-FU that passes the liver [9,24,25].…”

Section: Discussionmentioning

confidence: 99%

A Pilot Study on Intensive Weekly 24-Hour Intra-Arterial Infusion with 5-Fluorouracil and Folinic Acid for Colorectal Liver Metastases

Lorenz

Staib-Sebler²,

Gog³

et al. 1997

Oncology

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Purpose: A pilot study was performed to evaluate the tolerance and efficacy of a hepatic arterial infusion (HAI) of 5-fluorouracil (5-FU) and folinic acid (FA) in patients with unresectable liver metastases from colorectal carcinoma. Patients and Methods: In 11 patients, 135 applications of high-dose HAI of 5-FU/FA were administered. All patients had been intra-arterially pretreated, and 2 of them had received an additional intravenous therapy. The chemotherapy regimen consisted of a weekly HAI of FA 500 mg/m² over 1 h, immediately followed by HAI of 5-FU over 24 h. Four patients received a 5-FU starting dose of 2,000 mg/m² and 7 patients of 2,400 mg/m². One course consisted of 12 weekly applications interrupted by 1 week after 6 applications and 4 weeks after 12 applications. Results: The applied regimen caused only mild side effects. Nausea and vomiting were the most frequently side effects with 36 episodes out of 135 applications (WHO grade ≥3: 2 episodes). Diarrhea was a minor problem occurring with 8 episodes (WHO grade ≥3: 1 episode). There was no evidence of myelosuppression, hand-foot syndrome, neurotoxicity, and biliary sclerosis. A partial remission was observed in 3 patients, and a disease stabilization in 2 patients while the disease progressed in 6 patients under high-dose HAI of 5-FU/FA. Conclusion: The present pilot study demonstrates that the weekly high-dose HAI of 5-FU/FA is well tolerated and associated with very mild toxicity. Because of the encouraging response rate in patients, whose disease progressed under the conventional intra-arterial therapy either with 5-FU/FA or 5-fluorodeoxyuridine, this regimen seems to be an effective second-line treatment and should be evaluated in nonpretreated patients in a phase II study.

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Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial fluorouracil.

Cited by 32 publications

References 16 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

Hepatic Arterial Chemotherapy for Colorectal Cancer Metastatic to the Liver

A Pilot Study on Intensive Weekly 24-Hour Intra-Arterial Infusion with 5-Fluorouracil and Folinic Acid for Colorectal Liver Metastases

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