5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer

We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m2), modulated by MTX (24 h earlier, 200 mg/m2) were alternated with a 3-week continuous infusion of FU (200 mg/m2daily), modulated by LV (20 mg/m2weekly bolus). Mito, 7 mg/m2, was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28–46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III–IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents. © 2001 Cancer Research Campaign http://www.bjcancer.co

Cisplatin pharmacokinetics in elderly patients

The treatment of elderly patients with cancer may be difficult because of the narrow therapeutic index of antineoplastic drugs, the decline in the performance of organs and functions, and frequent comorbidity. In these patients, therapeutic drug monitoring may be useful in optimizing chemotherapy. Six patients older than 70 years with a variety of solid tumors received a total of 21 cycles of cisplatin (DDP)-based chemotherapy program (DDP dose, 50\u201365 mg/m2). Total and ultrafilterable platinum (Pt) were determined in plasma and urine during the first cycle of the therapy by means of atomic absorption spectroscopy. Pharmacokinetic parameters were analyzed with use of a two-compartment open model. The treatment was generally well tolerated. The most important side effects were a significant increase in serum creatinine level (from 0.98 to 1.23 mg/dl) and a decrease in creatinine clearance (from 44.4 to 38.9 ml/min) in comparison with pretreatment values. The mean decrease in hemoglobin levels was slight. The values of the main pharmacokinetic parameters of total Pt agreed well with the data obtained with other adult patients. Total and ultrafilterable Pt had a short distribution phase (t1/2\u3b1 = 0.35 and 0.54 h, respectively) followed by a prolonged elimination phase (t,1/2\u3b2 = 63.08 and 58.91 h, respectively). A reduced ability to clear ultrafilterable Pt (ClT = 123.52 ml h-1 kg-1) was evident and, as a result, the area under the curve increased (15.47 mg h L-1). The limited number of patients and the concomitant use of other agents prevent any firm conclusions. However, the documented impaired clearance of ultrafilterable Pt suggests that it may be safer in the elderly to use DDP at lower doses than in the adult and that this is associated with optimal drug exposure. \ua9 1994 Raven press, Ltd., New York

Prognostic significance of estrogen receptors in 405 primary breast cancers: a comparison of immunohistochemical and biochemical methods

Over the last few years, estrogen receptor determination by means of immunohistochemistry has been extensively used. The aim of this study was to compare this technique with estrogen receptor determination by means of dextran-coated charcoal, and to evaluate whether one of the two methods is more predictive of prognosis. Estrogen receptors were determined by means of both the dextran-coated charcoal method and immunohistochemistry in 405 patients with primary breast cancer; age, pathological tumor size, nodal status, and progesteron receptors by dextran-coated charcoal method were also recorded. The disease-free and overall survival probabilities were estimated using the product-limit method; Cox's proportional hazard model was used to evaluate the prognostic role of estrogen receptors as determined by the two methods. There appears to be a close association between estrogen receptor determination by the two methods (81.5% of concordant results) and their prognostic role was similar, even when the patients were divided into different groups (on the basis of their estrogen receptor status) and adjustments for the effect of other prognostic variables were taken into account. Our study shows that the two methods can be used indifferently to evaluate estrogen receptor status as a prognostic factor in breast cancer patients