Serum vitamin B12 and folate status with chemotherapy 161 studies performed in the US yielded a lower grade of toxicity. The reason for that was assumed to be folate supplementation in flour (7). Therefore Alimta is given together with folate and vitamin B12 supplementation (8). In a randomized, prospective, phase III trial (Nordic VI), irinotecan (Campto†*topoisomerase 1 blocker) in combination with either bolus 5 Fluorouracil (5-FU)/leucovorin or bolus/infused 5- FU/leucovorin was compared in patients with meta- static colorectal cancer (9). These two schedules (FLIRI versus Lv5FU2-IRI) resulted in the same progression-free survival and overall survival, being the primary end-points, although the Lv5FU2-IRI schedule resulted in slightly more objective re- sponses and slightly less toxicity. We have retro- spectively analysed the patients from the two largest hospitals in the study for various clinical and other predictors of toxicity. The aim of this study was to compare serum cobalamin, folate, and homocysteine values of ACRC patients before and during chemotherapy treatment, to detect any possible deficiency and to relate that to outcome and toxicity in a retrospective analysis. Material and methods Patients From June 2001 to March 2004, 567 patients with non-resectable metastatic disease from histologically confirmed colorectal adenocarcinoma were inclu- ded in a Nordic multi-centre study, the Nordic VI study. At two major hospitals, Uppsala and Stock- holm, Sweden, 93 patients were included for serum sampling of cobalamin, folate, and homocysteine. This sub-study with B12, folate, and homocysteine status among ACRC patients was compared with a previously performed study on healthy volunteers in the same county with median age of 77 years (10). No prior chemotherapy other than adjuvant 5-FU-based chemotherapy completed at least 6 months before the study entry was allowed. All patients should have measurable disease according to the response evaluation criteria in solid tumours (RECIST) (11), age between 19 and 76 years, WHO performance status of 0 to 2, and adequate labora- tory values. The upper serum bilirubin level should be B1.25 the upper normal limit (UNL) (1.5 if liver metastases). The study was approved by the ethical com- mittees at each site. All patients provided infor- med consent for the clinical study and for this sub-study. Table I. Patient characteristics. Age, years Colon Rectum Sex WHO Primary tumour resected Adjuvant treatment Haemoglobin, g/L Objective response Median (range) Male Female 0 1 2 Yes No Missing data Yes No Mean (range) Median Complete remission Partial remission Stable disease Progressive disease Not evaluable 63 (42 76) 57 36 59 34 72 18 3 72 17 4 13 80 127 (94 158) 128 5 36 35 12 5 Treatment The patients were treated in a multi-centre phase III study comparing two different fluorouracil (5-FU) schedules in combination with irinotecan. The patients were randomly assigned to receive irinote- can with the Nordic 5FU/Leucovorin (FLv) sche- dule (12) or the Lv5FU2 schedule (13). The FLIRI regimen (14) consisted of irinotecan (Campto†) 180 mg/m2 (initially 210 mg/m2) as a 60-minute intravenous (i.v.) infusion on day 1, followed im- mediately by 5-FU 500 mg/m2 as a bolus (B5 min) injection, followed 30 40 minutes later by Folinic acid (FA) 60 mg/m2 i.v. bolus. The 5-FU/FA administrations were repeated on day 2. The Lv5FU2-IRI regimen (15) consisted of irinotecan 180 mg/m2 on day 1, followed by FA 200 mg/m2 as a 2-hour infusion, a 5-FU bolus of 400 mg/m2, followed by a 600 mg/m2 22-hour infusion. The 5- FU/FA administrations were repeated on day 2. All treatments were repeated every 2 weeks until disease progression or unacceptable toxicity. A 20% reduc- tion in dose of irinotecan and 5-FU was made in case of grade 3 4 haematological and non-haemato- logical toxicities. A second 20% reduction was also allowed if toxicities remained. Treatments were delayed for up to 2 weeks if the haematological and gastrointestinal toxicities had not resumed for grade 1 at the time of next cycle. Concomitant medication included subcutaneous atropine 0.25 mg, administered for cholinergic symp- toms, oral loperamide 2 mg for diarrhoea, and, in case of fever or severe neutropenia, a prophylactic broad- spectrum oral antibiotic (ciprofloxacin) was to be administered. Patients with febrile neutropenia were hospitalized to receive i.v. antibiotics. The patients