Original Paper Haematological and Non-haematological Toxicity After 5-Fluorouracil and Leucovorin in Patients with Advanced Colorectal Cancer is Signi®cantly Associated with Gender, Increasing Age and Cycle Number J. Zalcberg, 1 D. Kerr, 2 L. Seymour 3 and M. Palmer 3 for the Tomudex 2 International Study Group 1 Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, Melbourne 8006, Victoria, Australia; 2 Department of Medical Oncology, Queen Elizabeth Hospital, Birmingham; and 3 Zeneca Pharmaceuticals, Maccles®eld, U.K. 5-Fluorouracil (5-FU) has been widely used for over 30 years. Recently, investigators have described interactions between toxicity with 5-FU and age and gender. Pharmacokinetics of infusional 5-FU are known to be gender dependent, with drug clearance being lower in females. The full impact of age and gender on both toxicity and response has not been fully explored and is worthy of further investigation. 439 patients were entered into a phase III trial comparing a novel thymidylate synthase (TS) inhibitor Tomudex 2 (raltitrexed, formerly ZD1694) with 5-FU and leucovorin (LV) for the treatment of advanced colorectal cancer. Approximately 20±24% of patients in each treatment group were aged 70 years or older and 41% of the patients were female. In a multiple regression analysis, female patients receiving 5-FU + LV experienced signi®cantly more grade 3/4 leucopenia, whilst those receiving ralti- trexed had more rises in transaminase levels. Grade 3/4 leucopenia and mucositis were signi®cantly correlated with age (especially > 70 years) only in patients receiving 5-FU + LV. Patients receiving 5-FU + LV were signi®cantly more at risk of experiencing grade 3/4 haematological and non- haematological toxicity in the ®rst three cycles than patients receiving raltitrexed. Female gender and increased age predict for increased grade 3/4 toxicity in patients receiving modulated 5-FU. Further studies with modulated 5-FU which utilise a modi®ed dose reduction schema for female patients, or patients aged 70 years or over, may be appropriate. # 1998 Elsevier Science Ltd. All rights reserved. Key words: gender, age, toxicity, modulated 5-FU Eur J Cancer, Vol. 34, No. 12, pp. 1871±1875, 1998 INTRODUCTION Cancer is a disease of the elderly; with the continuing ageing of Western populations, the median age of patients treated for cancer is likely to increase further. However, despite the frequency of malignancies in patients considered elderly (i.e. over 70 years), systematic studies addressing age-related dose±response and toxicity issues are limited. This lack of speci®c clinical data may be compounded by the reluctance of physicians to treat elderly patients with advanced cancer, or to enter them into clinical trials, due to concerns for potential negative eVects of drug toxicity on quality of life (QoL) and general well being. Previous studies have demonstrated that dose intensity is an important predictor of outcome for a variety of diVerent tumour types and that patients treated with inadequate doses of chemotherapy are relatively disadvantaged [1±3]. Increas- ingly, therefore, older patients of good performance status are being treated with full doses of chemotherapy and many clinical trials no longer have an upper age limit. Knowledge and understanding of the age-related kinetics and toxicity of European Journal of Cancer, Vol. 34, No. 12, pp. 1871±1875, 1998 # 1998 Elsevier Science Ltd. All rights reserved Pergamon Printed in Great Britain PII: S0959-8049(98)00259-7 0959-8049/98/$Ðsee front matter 1871 Correspondence to J. Zalcberg. Tomudex 2 is a trademark, the property of Zeneca Limited. Received 29 Sep. 1997; revised and accepted 12 Jun. 1998.