Predicting steady-state endoxifen plasma concentrations in breast cancer patients by CYP2D6 genotyping or phenotyping. Which approach is more reliable?

In previous studies, steady-state Z-endoxifen plasma concentrations (ENDOss) correlated with relapse-free survival in women on tamoxifen (TAM) treatment for breast cancer. ENDOss also correlated significantly with CYP2D6 genotype (activity score) and CYP2D6 phenotype (dextromethorphan test). Our aim was to ascertain which method for assessing CYP2D6 activity is more reliable in predicting ENDOss. The study concerned 203 Caucasian women on tamoxifen-adjuvant therapy (20 mg q.d.). Before starting treatment, CYP2D6 was genotyped (and activity scores computed), and the urinary log(dextromethorphan/dextrorphan) ratio [log(DM/DX)] was calculated after 15 mg of oral dextromethorphan. Plasma concentrations of TAM, N-desmethyl-tamoxifen (ND-TAM), Z-4OH-tamoxifen (4OH-TAM) and ENDO were assayed 1, 4, and 8 months after first administering TAM. Multivariable regression analysis was used to identify the clinical and laboratory variables predicting log-transformed ENDOss (log-ENDOss). Genotype-derived CYP2D6 phenotypes (PM, IM, NM, EM) and log(DM/DX) correlated independently with log-ENDOss. Genotype-phenotype concordance was almost complete only for poor metabolizers, whereas it emerged that 34% of intermediate, normal, and ultrarapid metabolizers were classified differently based on log(DM/DX). Multivariable regression analysis selected log(DM/DX) as the best predictor, with patients' age, weak inhibitor use, and CYP2D6 phenotype decreasingly important: log-ENDOss = 0.162 - log(DM/DX) × 0.170 + age × 0.0063 - weak inhibitor use × 0.250 + IM × 0.105 + (NM + UM) × 0.210; (R2  = 0.51). In conclusion, log(DM/DX) seems superior to genotype-derived CYP2D6 phenotype in predicting ENDOss.

Pemetrexed as second-line chemotherapy for castration-resistant prostate cancer after docetaxel failure: results from a phase II study.

OBJECTIVE: Although there is no standard treatment after docetaxel failure in patients with castration-resistant prostate cancer (CRPC), second-line chemotherapy is increasingly required. Its mechanism of action and toxicity profile make pemetrexed suitable for testing in this setting. METHODS AND MATERIALS: Patients with docetaxel-resistant CRPC received pemetrexed 500 mg/m(2) every 3 weeks for 6 courses. The usual premedication with vitamin supplementation and dexamethasone prophylaxis was regularly administered. The primary objective was to quantify the biochemical response rate. RESULTS: The biochemical response rate was 10.5% (95% CI 1.3-33.1), with 2 patients showing a reduction in prostate specific antigen (PSA) of ≥50%. The null hypothesis that the PSA response rate would be less than 20% was therefore accepted, and patient accrual was stopped after the evaluation of the 19th patient. The 1-year overall survival rate was 61.5%, with a median survival of 14 months. A considerable proportion of the patients (36%) were withdrawn from the study because of hematologic and nonhematologic toxicity. CONCLUSIONS: Our experience with pemetrexed in CRPC patients appears discouraging in terms of activity and toxicity. No further studies of this drug should be performed in CRPC patients.

Impact of docetaxel-based chemotherapy on quality of life of patients with castration-resistant prostate cancer: results from a prospective phase II randomized trial.

UNLABELLED: What's known on the subject? and What does the study add? Data on quality of life during docetaxel treatment in castration resistant prostate cancer was mainly provided by SWOG and TAX327 trials. In the TAX327 trial biochemical response and pain predicted survival, whereas quality of life outcomes did not. In the present study, there were no statistically significant changes in the quality of life scales during treatment except in the case of patients receiving docetaxel and estramustine, who experienced a significant decrease in pain. Our data seem to suggest that patients with a better baseline quality of life (and consequently with fewer symptoms) are more likely to achieve a biochemical response. OBJECTIVES: • To assess quality of life (QoL) outcomes and pain changes in patients affected by castration-resistant prostate cancer enrolled in a phase II randomized trial of 3-week docetaxel (DOC)-based chemotherapy. • To provide further data to clarify the conflicting published data concerning the impact of DOC on the patients' QoL. PATIENTS AND METHODS: • QoL outcomes were assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 questionnaire. • Pain changes were evaluated by means of the Brief Pain Inventory at baseline and after every two DOC courses. • The patients completing at least two questionnaires (at baseline and before the third course) were considered evaluable. RESULTS: • In all, 59 patients were evaluable. • Asymptomatic patients and responders had a better baseline QoL than symptomatic patients and non-responders. • There were no statistically significant changes in the QLQ-C30 scales during treatment except in the case of patients receiving DOC and estramustine, who experienced a significant decrease in pain. • There was a progressive improvement in the mean intensity and interference scores of the Brief Pain Inventory. CONCLUSIONS: • Our data confirm that QoL is generally maintained during chemotherapy. • There is a substantial reduction in pain. • Our results also suggest that baseline QoL may predict treatment response.

Estramustine plus docetaxel as second-line therapy in patients with hormone-refractory prostate cancer resistant to docetaxel alone.

OBJECTIVE: Although docetaxel (DOC) plus prednisone is currently the treatment of choice for hormone-refractory prostate cancer (HRPC), no standard therapy is available for those patients who progress during DOC treatment. The aim of this study was to evaluate whether the addition of estramustine (E) can overcome DOC resistance. METHODS: Patients who had not responded to DOC in a previous randomised phase II trial received a one-hour intravenous infusion of DOC 70 mg/m(2) on day 2 in combination with oral E 840 mg/day divided into three daily administrations on days 1-5. The primary endpoint was a >50% decrease in PSA; the secondary endpoints were biochemical progression-free survival, overall survival, the objective response rate, and toxicity. RESULTS: A biochemical response was observed in 52% of the 25 patients evaluable for response. The only grade 4 event was a cerebral stroke that occurred a few days after the administration of the first treatment course. Treatment discontinuation due to worsened compliance was observed in the patients who received a higher cumulative number of courses. CONCLUSIONS: Our findings suggest that the addition of E may be useful in selected HRPC patients resistant to DOC alone.

Docetaxel, with or without estramustine phosphate, as first-line chemotherapy for hormone-refractory prostate cancer: results of a multicentre, randomized phase II trial.

OBJECTIVE: To report the results of a randomized phase II trial of docetaxel with and without estramustine phosphate (EP) in patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Patients with progressive HRPC were randomized to receive docetaxel 70 mg/m(2) on day 1 (arm A), or docetaxel 70 mg/m(2) on day 2 plus oral EP three times daily, at a total daily dose of 840 mg, on days 1-5 (arm B). The primary objective of the trial was to evaluate the activity of the treatments in terms of the response in prostate-specific antigen (PSA) level. RESULTS: Forty-five of the 49 patients centrally randomized to arm A and 44 of the 46 in arm B were evaluable for activity. The PSA level decreased by > or =50% in 40% of the patients in arm A and in 75% of those in arm B. The median time to PSA progression was 20 weeks in arm A and 30 weeks in arm B. The patients in arm B had an improvement in pain over time. CONCLUSION: These data support the existence of a possible advantage in combining docetaxel and EP, which should be verified in a specific randomized phase III study.

Prospective clinical trials of biotherapies in solid tumors: a 5-year survey.

PURPOSE: To review the content and quality of prospective clinical trials of biotherapies in solid tumors. METHODS: Data were collected from the literature between 1990 and 2002 on general study characteristics, patient and disease factors, study methodology, and factors related to completeness of reporting. Quality of phase II studies was evaluated by an ad hoc questionnaire. Descriptive statistics, contingency tables, and the chi-square test were applied. RESULTS: A total of 334 studies were selected, of which about three quarters were multicenter, with 42.5% reporting phase I, 42.2% phase II or I/II, and 11.9% phase III or II/III studies. Only 13.7% were randomized, and a study design emphasizing statistical analysis was lacking in as many as one third. The assessment of biological endpoints was stated as the primary or secondary goal in half of these studies. Melanoma (17.1%), renal carcinoma (11.1%), gastrointestinal neoplasms (11.1%), and lymphomas (6.3%) were the most studied diseases. Immunotherapies accounted for 182 studies; the remaining 152 reported other biotherapies. Patients with (1) advanced disease (P = 0.003), (2) heavily pretreated neoplasms (P < 0.0001), (3) poor performance status (PS < 2) (P < 0.0001), were more frequently enrolled in studies of biotherapy. Biotherapies were less frequently evaluated in phase III studies (7/152) compared with immunotherapies (33/182) (P < 0.0001). A statistical study design was more frequently identified in biotherapy trials (127/152) compared with immunotherapy trials (98/182) (P < 0.0001). Biological endpoints were less frequently evaluated in phase III studies in both biotherapies (100% no vs 0% yes) and immunotherapies (81.8% no vs 18.2% yes) (P = 0.01, for biotherapies; P < 0.0001, for immunotherapies). Phase I immunotherapy studies more frequently applied biological or molecular criteria for patient selection (41.1%) than phase II (29.3%) and III (3.1%) studies (P < 0.0001). CONCLUSIONS: The very wide diversity in modalities of conducting and reporting clinical trials of biotherapies of solid tumors and the presence of some methodological pitfalls suggest that the methodological standards for conducting and publishing clinical trials in biotherapies should be improved to enhance the reliability of the body of published data.