UFT in Elderly Patients with Colorectal Cancer

Cancer is a disease of aging; at present 70% of cases occur in patients aged over 65 (1). In general, however, there are few studies of elderly patients, and in most clinical trials, age over 72 has been exclusion criteria. Thus, elderly patients have not been analyzed in research, and patients between 65 and 72 have never been analyzed separately. There are data regarding the treatment for leukemia and lymphoma in the National Cancer Data Base (2) showing that survival by stage is worse in elderly patients and suggesting age-dependent biological differences in the cancer itself. Studies of the elderly are necessary so we can analyze these possibilities. Among the reasons for low or nonexistent participation by the elderly in clinical trials is the belief that older patients do not tolerate chemotherapy and the existence of concomitant medical conditions that may preclude certain treatments. Co-morbidities need to be considered as an objective reason for avoiding aggressive treatments. In the elderly population, 55% have three additional pathologies and 37% have one or two, while only 8% have cancer alone (3). The pharmacokinetic changes associated with aging are also important. Volume of distribution is altered by increasing lipid-soluble drugs and decreasing water-soluble drugs; anemia and hypoalbuminemia increase the toxicity of the agents related to albumine or eritrocites; renal excretion can also decrease, thus increasing toxicity (4). For these reasons, patients over 70 are often insufficiently staged and treated (5). Survival decreases with age among patients with colorectal cancer (CRC); 5-yr overall survival is 47% in patients under 60 and 30% in patients over 60 (6). Furthermore, in women older than 75, CRC is the second cause of cancer deaths (2). It is clear that the cost of cancer care will have a major impact on our aging society. All of these factors prompted us to search for an alternative treatment that could be suitable for elderly patients with advanced CRC. The intravenous modulated bolus fluorouracil-based (5-FU) regimen has been the standard treatment for advanced CRC in the last 10 yr. The Meta-Analysis Group in Cancer showed an overall response rate of 19–23% and median survival of 10.7–11.5 mo (7,8) with this regimen, and we have obtained 19–26% and 10.6–14.3 mo (9,10). An alternative to this regimen is the administration of 5-FU by continuous infusion (CI). Several studies have reported increased response rates with 5-FU CI; this could be related to higher dose intensity and to the short serum half-life of 5-FU, which does not exceed 11 min, a short period of time for cell exposure. Two comparative trials (11,12) have demonstrated the superiority of 5-FU CI in terms of response rate, toxicity, and time to progression compared to 5-FU bolus. Moreover, a meta-analysis of randomized trials comparing 5-FU CI with 5-FU bolus has shown that there is a small but significant improvement in survival (13). Using a 48-h high-dose 5-FU CI (2–3.5 g/m2 48 h/wk) the TTD Spanish Group (Spanish Group for Treatment of Gastrointestinal Tumors) has obtained interesting results, with a response rate of 29-38% and 12–14 mo of median survival in patients with advanced CRC (14–16). Nevertheless, 5-FU CI needs a subcutaneous port, a portable infusional pump, frequent hospital visits, and frequent complete blood counts, all of which make the treatment difficult in older patients. Several studies in Japan have demonstrated the activity of oral fluoropyrimidine UFT (tegafur plus uracil) in advanced CRC (17–19). In Europe, Malik et al. obtained a response rate of 16.6% using UFT alone (20). Recently in the United States and Europe, folinic acid modulation of UFT has shown good results with response rates of 42% and 39% (21–22). The continuous oral administration of UFT simulates protracted 5-FU CI, making this oral therapy a possible substitute for intravenous chemotherapy.