Phase I pharmacological study of intra-arterially infused fotemustine for colorectal liver metastases.
Fotemustine was investigated in 17 patients with progressive hepatic metastases from colorectal carcinoma to define the maximally tolerated dose for a daily hepatic intra-arterial infusion (HAI) schedule. Haematotoxicity was delayed, dose-dependent and related to pretreatment, with thrombo- and leucocytopenia being dose-limiting. Local side-effects at the liver were mild. Infection (WHO grade III) occurred in 1 patient due to neutropenia. Other side-effects, particularly renal, pulmonal, neurological or cardiac toxicity, mucositis and diarrhoea, hair loss or allergic reactions did not occur. Pharmacokinetic analysis indicated a short plasma half-life (t1/2 = 25.8 +/- 11.5 min) and a high body clearance (CL = 2193 +/- 870 ml/min) with large inter- and intra-individual variations. Of 15 evaluable patients, one complete and three partial responses were observed (ORR = 27%; CI95% [4.5-49.5%]). All tumour remissions appeared at higher dose levels in previously untreated patients. Considering the absence of mucosal side-effects, such as mucositis/diarrhoea and of hepatic toxicity, this agent was well tolerated. The recommended intra-arterial dose for consecutive phase II trials is 125 mg/m2/day1-3.
Hartmann
J T
JT
Department of Haematology/Oncology/Immunology, Eberhard-Karls-University Medical Centre, Tübingen, Germany.
Schmoll
E
E
Bokemeyer
C
C
Fety
R
R
Lucas
C
C
Giroux
B
B
Schmoll
H J
HJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D009607:Nitrosourea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; C054368:fotemustine