Mark T Holdsworth

Nilutamide: An Antiandrogen for the Treatment of Prostate Cancer

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of nilutamide and to compare this agent with the currently marketed nonsteroidal antiandrogens (i.e., bicalutamide, flutamide) by critically analyzing the published literature. DATA SOURCES: MEDLINE (1980–1995) and CANCERLIT (1991–1995) were searched for English-language publications using the terms nilutamide, bicalutamide, and flutamide alone, and either nilutamide or androgen antagonists in combination with prostatic neoplasms. STUDY SELECTION AND DATA EXTRACTION: All articles with subject matter on nilutamide, bicalutamide, and flutamide were considered for inclusion. For studies published in more than one journal, the first publication was used unless a subsequent publication included additional or follow-up data, in which case the latter publication was cited instead. DATA SYNTHESIS: Nilutamide was effective in combination with orchiectomy in improving responses in patients with advanced prostate cancer. However, patient survival was not improved in these trials, and improvements in bone pain did not usually result in improved performance status in these patients. The few trials of nilutamide monotherapy or nilutamide in combination with a luteinizing hormone-releasing hormone analog are too small to draw meaningful conclusions regarding its efficacy or its role in the treatment of advanced prostate cancer. No comparative trials of nilutamide with other antiandrogens and no analysis of the impact of nilutamide on patient quality of life are currently available. Nilutamide appears to produce a higher frequency of adverse effects than the other currently marketed nonsteroidal antiandrogens, bicalutamide and flutamide. CONCLUSIONS: Nilutamide does not appear to represent a major advance in the treatment of advanced prostate cancer and appears to be somewhat inferior to both flutamide and bicalutamide with regard to adverse effects. Nilutamide should not be considered the antiandrogen of choice in the treatment of advanced prostate cancer.

Survey ranking of emetogenic control in children receiving chemotherapy.

PURPOSE To determine the effect of standard antiemetic treatment in children receiving various combination chemotherapy regimens. METHODS A validated nausea/vomiting survey was administered to 78 patients receiving 13 different emetogenic chemotherapy regimens. Patients received antiemetic prophylaxis with ondansetron (0.3 mg/kg/day) alone for moderately emetogenic chemotherapy regimens or ondansetron (0.45 mg/kg/day) and methylprednisolone (4 mg/kg/day) for severely emetogenic chemotherapy regimens. A total of 324 different courses of chemotherapy were surveyed. Nausea and vomiting severity, duration, number of emetic episodes, appetite, daily activity interference, and rates of both complete and good antiemetic protection were determined for each chemotherapy protocol. Differences between genders and ages were analyzed. RESULTS Chemotherapy combinations containing platinum compounds were found to be highly emetogenic and nauseating despite antiemetic therapy with ondansetron plus a corticosteroid. In addition, complete antiemetic protection for the combination of vincristine, cyclophosphamide, and dactinomycin was poor. For most of the severely emetogenic chemotherapy protocols, patients experienced good protection from nausea and vomiting less than 60% of the time, despite the use of ondansetron plus methylprednisolone. Significant differences were found in rates of residual nausea and vomiting and failure of antiemetic protection among the severely emetogenic chemotherapy protocols despite identical antiemetic therapy. Good protection rates were higher for moderately emetogenic chemotherapy treated with ondansetron alone. CONCLUSIONS The currently recommended prophylactic therapy for pediatric patients receiving severely emetogenic chemotherapy fails to provide protection for many patients receiving commonly administered chemotherapy regimens and for most pediatric patients receiving platinum-containing chemotherapy combinations. New and refined antiemetic strategies are needed to improve efficacy in the pediatric population.

Economic impact with home delivery of chemotherapy to pediatric oncology patients

Objective To examine the economic impact of a home chemotherapy program (HCP) for pediatric oncology patients. Rationale Factors that led to initiation of an HCP included availability of specially trained nurses and programmable ambulatory infusion devices at local home care agencies, routine central venous catheter placement, inpatient bed space shortages, and the availability of ondansetron. Setting Chemotherapy delivery in the home setting from June 1991 through June 1994. Design Charge data and nausea and vomiting severity data were collected for patients treated through the HCP. Methods Economic impact was calculated by incorporating and summing all charge categories associated with hospital admission for chemotherapy (HAC) versus delivery by the HCP. All data were adjusted for 1993 dollars, and reflect charges for the average patient size (1 m2). Charge data for each chemotherapy protocol delivered in the home were analyzed by calculating the differences between HAC and HCP charges using the following formula: charge difference (HAC - HCP) per protocol times the number of courses. Total economic impact was calculated by summing the differences in charges for each protocol. Results A total of 262 chemotherapy courses were given to 44 patients (mean age 9.5 ± 5.1 y) through the HCP, which represented 1012 patient care days and 24 different chemotherapy protocols. Monetary savings from the HCP ranged from

Differences among raters evaluating the success of EMLA cream in alleviating procedure-related pain in children with cancer.

5180 per course of ifosfamide plus etoposide to

Comparative Methylprednisolone Pharmacokinetics in Renal Transplant Patients Receiving Double- or Triple-Drug Immunosuppression

367 per course for high-dose methotrexate. Total monetary savings from the HCP during the 3-year period was

Pharmacokinetics and clinical tolerance of intravenous and oral cyclosporine in the immediate postoperative period

640 793. Successful control of nausea and vomiting with a combination of ondansetron plus methylprednisolone was achieved in approximately 80% of the patients receiving highly emetogenic chemotherapy protocols. Conclusions HCP for pediatric oncology patients results in substantial monetary savings to payors. Effective control of nausea and vomiting can be accomplished at home in the majority of patients with an ondansetron-based antiemetic regimen.

Ethical Issues regarding Study Designs Used in Serotonin-Antagonist Drug Development

We evaluated the analgesic efficacy of EMLA cream after repeated bone marrow aspirations or lumbar punctures (LPs) in children with cancer, and compared the ratings among patients, their parents, physicians, and nurses. Data from LPs were analyzed at the last procedure without EMLA (T1) and the first and last procedures with EMLA (T2 and T3). Friedmans nonparametric analysis of variance was used for statistical analysis. A total of 272 procedures in 29 children were analyzed. For 179 procedures without EMLA, physicians rated pain lower than other raters, and for the 93 with EMLA physicians rated pain less than the children. Children rated pain at T2 lower than at T1 or T3. Physicians rated pain at T2 less than at T3. Both children and physicians rated pain at T3 as not different from that at T1. No differences were noted at these time points for other raters in LP distress ratings, or in bone marrow aspiration pain or distress ratings. Thus EMLA was associated with decreased pain ratings for LPs, but this effect was not sustainable with repeated procedures. The cream alone should not be relied on to control pain of bone marrow aspiration or repeated LPs in children. Physicians underestimated pain, which may have implications for undertreatment in this patient population.

Comparison of Cyclosporine Assay Methodology in the Immediate Postoperative Period of Renal Transplantation

OBJECTIVE: To assess the pharmacokinetics of chronic methylprednisolone therapy in renal transplant patients receiving double-drug (methylprednisolone and azathioprine) and triple-drug (methylprednisolone, azathioprine, and cyclosporine) immunosuppression. DESIGN: Parallel, randomized trial. PATIENTS: Fourteen renal transplant recipients (aged 29–65 y) evaluated in a public, university-affiliated hospital clinic. INTERVENTIONS: All patients received their chronic oral dose of methylprednisolone via a 10–20-minute intravenous infusion. MAIN OUTCOME MEASURES: Serum methylprednisolone concentrations were determined by HPLC and were used to generate pharmacokinetic parameters for this drug. RESULTS: The mean daily methylprednisolone dosage was 19 ± 19 mg in the double-drug group and 9 ± 2 mg in the triple-drug group. Mean serum creatinine concentrations were 124 ± 44 and 124 ± 27 μmol/L, respectively. Mean methylprednisolone clearances were similar in both groups: 405 ± 205 (double-drug) and 373 ± 365 mL/h/kg (triple-drug) (p>0.05). Mean steady-state volume of distribution was 1.5 ± 0.8 L/kg in the double-drug group and 1.3 ± 0.8 L/kg in the triple-drug group (p>0.05). Plasma half-life ranged from 1.7 to 4.3 h (mean 2.7) in the double-drug group versus 1.4 to 3.4 h (mean 2.6) in the triple-drug group (p>0.05). CONCLUSIONS: These data indicate that cyclosporine had no definitive influence on methylprednisolone disposition. The results reveal a wide variation in methylprednisolone metabolism in renal transplant recipients receiving either a double- or triple-drug immunosuppressive regimen. Typically, methylprednisolone is prescribed according to a standardized dosing protocol that assumes minimal interpatient variation. Therefore, the pharmacokinetic variability noted in this study may have important clinical implications regarding the development of chronic toxicity (e.g., osteoporosis, hypothalamic-pituitary-adrenal suppression) and the attainment of successful immunosuppression.

State of Oncology Pharmacotherapy

The clinical tolerance and pharmacokinetics of cyclosporine during a prolonged intermittent intravenous infusion (3.5 mg/kg/day three times) followed by an 8 mg/kg daily oral dose was evaluated in eight renal transplant recipients in the immediate postoperative period. Cyclosporine was analyzed from whole blood samples by HPLC. Despite peak drug concentrations of 1463 ± 754 ng/ml during the infusion period, no adverse pulmonary effects were noted; renal function, urine output, and mean arterial pressure also appeared to have been unaffected. The mean trough cyclosporine concentration was 141 ± 50 ng/ml; however, two patients had trough values below sensitivity. Kinetic analysis after the third dose of intravenous cyclosporine revealed a mean total body clearance of 0.31 ± 0.1 L/min and a volume of distribution of 2.88 ± 1.1 L/kg, whereas the elimination half‐life was 12.8 ± 3.8 hours and the mean residence time was 9.5 ± 5.1 hours. After conversion to oral therapy the bioavailability ranged from 0.11 to 0.47, with a mean value of 0.27. Subsequently there was an unpredictable pattern of bioavailability within patients, with mean values of 0.27 ± 0.13 and 0.30 ± 0.25 during the second and third oral study periods, respectively. These data suggest that despite adjusting the intravenous cyclosporine dosage to account for acute changes in patient body weight, variable kinetics may result in subtherapeutic trough values, even when cyclosporine is administered by prolonged infusion. The clinical implications of fluctuating cyclosporine bioavailability and a potential alternative approach to dosing are discussed.

Book Review: Pain and its Relief without Addiction: Clinical Issues in the Use of Opioids and other AnalgesicsPain and Its Relief Without Addiction: Clinical Issues in the Use of Opioids and Other Analgesics By StimmelBarry MD. Published by The Haworth Press Inc., Binghamton, NY, 1997. ISBN 0-7890-0126-8. Paperbound, xv + 418 pp. (21.5 × 15.5 cm),

The time has come to develop new methods for the evaluation of antiemetic compounds. The well-established tenet that combination antiemetic therapy is superior to that achieved with any single agent for severely emetogenic cisplatin-containing chemotherapy does not warrant reevaluation with future cancer patients whenever a new antiemetic enters Phase II and III evaluation. New trials should instead focus on the more important issues of whether the new agent in combination offers comparable or superior efficacy to that achievable with the current standard antiemetic regimen for both acute and delayed nausea and vomiting. While proof of efficacy is crucial in drug trials, adequacy of patient care needs to be the first and foremost priority in any trial.