Doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma: a phase II study of the Genitourinary Group of the French Federation of Cancer Centers.

PURPOSE: We assessed the efficacy and toxicity of a chemotherapy regimen combining doxorubicin and ifosfamide in patients with metastatic sarcomatoid renal cell carcinoma. MATERIALS AND METHODS: Of the 25 patients included in a prospective multicenter phase II trial 23 were evaluable for efficacy and toxicity studies after pathological review. RESULTS: A median of 3 cycles per patient (range 1 to 8) was administered. No objective response was observed. Median time to progression was 2.2 months and median overall survival was 3.9 months. A single patient died of toxicity. CONCLUSIONS: The results do not support the standard use of doxorubicin/ifosfamide chemotherapy in patients with metastatic sarcomatoid renal cell carcinoma.

Age-related difference in tamoxifen disposition.

PURPOSE: To investigate the pharmacokinetic aspects of tamoxifen, such as the pharmacokinetic-pharmacodynamic (toxicity and clinical response) relationship and the influence of hepatic dysfunction, age, treatment duration, and associated chemotherapy on tamoxifen pharmacokinetics. PATIENTS AND METHODS: Three hundred sixteen patients with breast cancer (247 postmenopausal women) were investigated. Mean age was 58 years (age range, 29 to 85 years). One hundred seventeen patients received tamoxifen as single therapy (adjuvant, 60; neoadjuvant, 17; metastatic, 40); 292 of 316 received 30 mg daily. We obtained 794 blood samples at steady state. Tamoxifen and metabolites, N-desmethyltamoxifen, N-desdimethyltamoxifen, primary alcohol, and 4-hydroxytamoxifen were measured by HPLC. RESULTS: Serum concentrations of tamoxifen and metabolites showed a wide asymmetrical distribution. Median and extremes were 347 nmol/L (not detectable [ND] to 1677) for tamoxifen, 572 nmol/L (ND to 3132) for N-desmethyltamoxifen, 109 nmol/L (ND to 795) for N-desdimethyltamoxifen, and 59 nmol/L (ND to 390) for primary alcohol. 4-Hydroxytamoxifen was detectable in 9.5% of the samples (ND to 162 nmol/L). Neither the absolute nor the relative concentrations of each compound showed significant variations during treatment. Chemotherapy concomitant with tamoxifen slightly increased the tamoxifen blood concentration. Hepatic dysfunction had no obvious effect on drug concentrations, an exception being a slight reduction in the relative proportion of tamoxifen. The influence of age revealed that concentrations of tamoxifen and metabolites increased significantly with age: women younger than 40 years had a tamoxifen plus metabolite median concentration of 802 nmol/L compared with 2428 nmol/L for women older than 80 years. In the 28 patients in whom tamoxifen-related side effects developed, the proportion of demethylated metabolites was higher than that in patients in whom toxicity did not develop. There was no difference in drug concentrations between responding and nonresponding patients. CONCLUSION: Despite the tremendous interpatient variability in drug concentrations, the present data show that tamoxifen and metabolite concentrations significantly increase with age.