Phase I-II study of the addition of alpha-2a interferon to 5-fluorouracil/leucovorin. Pharmacokinetic interaction of alpha-2a interferon and leucovorin.
5-Fluorouracil (5-FU) activity has been improved by the use of leucovorin (LV) or alpha-2a interferon (alpha-IF). We investigated the feasibility and activity of addition of alpha-IF to a 5-FU/LV regimen. A phase I study with 26 patients (14 previously untreated, 12 previously treated) with disseminated cancer was conducted. 15 patients were treated with 5-FU/LV and 11 with 5-FU/LV/alpha-IF. The 5-FU/LV regimen consisted of escalating doses of 5-FU bolus intravenously on days 2 and 3, combined with repeated oral LV on days 1, 2 and 3. Treatment was every 2 weeks. In the 5-FU/LV/alpha-IF schedule, 18 x 10(6) U alpha-IF subcutaneously daily was added on days 1, 2 and 3. The phase I study was followed by a phase II study of 5-FU/LV/alpha-IF at the established 5-FU dose in 29 previously untreated patients with disseminated colorectal cancer. The optimal 5-FU dose in both parts of the phase I study was 750 mg/m2/day. Mucositis, diarrhea and leucopenia were dose limiting. Although alpha-IF added its own toxicity (fever, flu-like symptoms, fatigue), it did not decrease the optimal dose of 5-FU. In the phase II study 28 patients were evaluable for response: three complete responses and 12 partial responses were observed (response rate 54%, 95% confidence interval, 34 to 72%). Pharmacokinetics of oral LV was performed in patients treated with and without alpha-IF: significantly higher serum levels of LV and 5-methyltetrahydrofolate were found after alpha-IF addition. Influence of alpha-IF on gastrointestinal absorption or renal clearance could be excluded. In conclusion, this 5-FU/LV/alpha-IF combination seems active in metastatic colorectal cancer. The pharmacokinetic interaction between alpha-IF and LV may play a role in the activity of this regimen. Controlled studies are necessary to establish the value of addition of alpha-IF to 5-FU/LV regimens.
Department of Internal Medicine, University Hospital, Groningen, The Netherlands.
H A
HA
Sinnige
J
J
Buter
E G
EG
de Vries
D R
DR
Uges
H W
HW
Roenhorst
R C
RC
Verschueren
D T
DT
Sleijfer
P H
PH
Willemse
N H
NH
Mulder
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D002955:Leucovorin / Q000008:administration & dosage / Q000493:pharmacokinetics; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged
D016898:Interferon-alpha; D002955:Leucovorin; D005472:Fluorouracil