Charles L. Bennett

Thrombotic Thrombocytopenic Purpura Associated with Clopidogrel

BACKGROUND The antiplatelet drug clopidogrel is a new thienopyridine derivative whose mechanism of action and chemical structure are similar to those of ticlopidine. The estimated incidence of ticlopidine-associated thrombotic thrombocytopenic purpura is 1 per 1600 to 5000 patients treated, whereas no clopidogrel-associated cases were observed among 20,000 closely monitored patients treated in phase 3 clinical trials and cohort studies. Because of the association between ticlopidine use and thrombotic thrombocytopenic purpura and other adverse effects, clopidogrel has largely replaced ticlopidine in clinical practice. More than 3 million patients have received clopidogrel. We report the clinical and laboratory findings in 11 patients in whom thrombotic thrombocytopenic purpura developed during or soon after treatment with clopidogrel. METHODS The 11 patients were identified by active surveillance by the medical directors of blood banks (3 patients), hematologists (6), and the manufacturer of clopidogrel (2). RESULTS Ten of the 11 patients received clopidogrel for 14 days or less before the onset of thrombotic thrombocytopenic purpura. Although 10 of the 11 patients had a response to plasma exchange, 2 required 20 or more exchanges before clinical improvement occurred, and 2 had relapses while not receiving clopidogrel. One patient died despite undergoing plasma exchange soon after diagnosis. CONCLUSIONS Thrombotic thrombocytopenic purpura can occur after the initiation of clopidogrel therapy, often within the first two weeks of treatment. Physicians should be aware of the possibility of this syndrome when initiating clopidogrel treatment.

Platelet Transfusion for Patients With Cancer: Clinical Practice Guidelines of the American Society of Clinical Oncology*

OBJECTIVE To determine the most effective, evidence-based approach to the use of platelet transfusions in patients with cancer. OUTCOMES Outcomes of interest included prevention of morbidity and mortality from hemorrhage, effects on survival, quality of life, toxicity reduction, and cost-effectiveness. EVIDENCE A complete MedLine search was performed of the past 20 years of the medical literature. Keywords included platelet transfusion, alloimmunization, hemorrhage, threshold and thrombocytopenia. The search was broadened by articles from the bibliographies of selected articles. VALUES Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly related to one of the primary outcomes in a randomized design. BENEFITS/HARMS/COST: The possible consequences of different approaches to the use of platelet transfusion were considered in evaluating a preference for one or another technique producing similar outcomes. Cost alone was not a determining factor. RECOMMENDATIONS Appendix A summarizes the recommendations concerning the choice of particular platelet preparations, the use of prophylactic platelet transfusions, indications for transfusion in selected clinical situations, and the diagnosis, prevention, and management of refractoriness to platelet transfusion. VALIDATION Five outside reviewers, the ASCO Health Services Research Committee, and the ASCO Board reviewed this document. SPONSOR American Society of Clinical Oncology

Single-Therapy Androgen Suppression in Men with Advanced Prostate Cancer: A Systematic Review and Meta-Analysis

Androgen ablation delays clinical progression and palliates symptoms of metastatic disease in men with advanced prostate cancer (1-4). The earliest method was orchiectomy, and diethylstilbestrol (DES) subsequently became the first reversible method (5-7). Newer alternatives include luteinizing hormone-releasing hormone (LHRH) agonists, such as leuprolide, goserelin, and buserelin (8-10), and nonsteroidal antiandrogens, such as flutamide, nilutamide, and bicalutamide (11-13). Cyproterone acetate is the only steroidal antiandrogen still used for primary hormonal therapy (14-16). Many randomized, controlled trials have compared two or more of these options for monotherapy in men with advanced prostate cancer. Additional trials have tested the efficacy of antiandrogens combined with orchiectomy or LHRH agonists, an approach that is often called combined or maximal androgen blockade. Previous meta-analyses have compared monotherapy with combined androgen blockade (17-19). To date, no systematic review or meta-analysis has evaluated the evidence on effectiveness of monotherapies. Systematic reviews offer structured analysis of results of primary investigations by using strategies to limit bias and random error. They efficiently integrate otherwise unmanageable amounts of information to support clinical decision making. When it is feasible, quantitative meta-analysis can increase power and precision and enhance estimates of treatment effects and exposure risks. Meta-analysis also allows evaluation of consistency of findings or exploration of differences in outcomes, according to predefined subpopulations or factors regarding study quality. As part of a comprehensive review of the evidence on the relative effectiveness and cost-effectiveness of methods of androgen suppression as primary treatment for advanced prostate cancer (20), we conducted a systematic review and meta-analysis of randomized, controlled trials that compared different monotherapies. We establish that DES is equivalent to orchiectomy as a comparator for treatments of advanced prostate cancer and summarize our findings on four questions: 1) How effective is an LHRH agonist compared with orchiectomy or DES? 2) How effective is an antiandrogen compared with orchiectomy, DES, or an LHRH agonist? 3) Do the LHRH agonists differ in effectiveness? and 4) Do the antiandrogens differ in effectiveness? Although we sought to compare the adverse effects and quality-of-life effects of these treatments, scant evidence was available. Methods Our review was prospectively designed to define study objectives, search strategy, study selection criteria and methods for determining study eligibility, data elements to be abstracted and methods for abstraction, and methods for assessment of study quality. Two independent reviewers completed each step in this protocol and resolved disagreements by consensus. Disagreements were infrequent and were usually resolved by reconciliation of an oversight. When survival rates were estimated from figures in publications, disagreements were always less than 5% of the measured value, and the consensus estimate was the midpoint. All efficacy studies were randomized, controlled trials. Reviewers assessed the study quality dimensions that have been shown to be sources of bias (21): adequacy of randomization method, use of blinding and adequacy of concealment of allocation, and documentation of withdrawals and whether results were analyzed in an intention-to-treat fashion. Except for blinding and intention-to-treat analysis, published reports usually provided insufficient information to permit valid assessments of these quality dimensions. Therefore, studies that blinded patients and investigators to group assignment and used an intention-to-treat analysis of overall survival or progression-related outcomes were classified as higher-quality studies for sensitivity analysis. Blinding was considered not applicable when orchiectomy was one of the study arms. Literature Search and Study Selection We searched the MEDLINE, Cancerlit, EMBASE, and Cochrane Library databases from 1966 to March 1998 and Current Contents through 24 August 1998 for all articles that included at least one of the following terms in their titles, abstracts, or keyword lists: leuprolide (Lupron, TAP Pharmaceuticals Inc., Deerfield, Illinois), goserelin (Zoladex, Zeneca Pharmaceuticals, Wilmington, Delaware), buserelin (Suprefact, Hoechst Marion Roussel, Kansas City, Missouri), flutamide (Eulexin, Schering Corp., Kenilworth, New Jersey), nilutamide (Anandron, Roussel-Uclaf Laboratory, Romainville, France, and Nilandron, Hoechst Marion Roussel), bicalutamide (Casodex, Zeneca Pharmaceuticals, Wilmington, Delaware), cyproterone acetate (Androcur, Schering Corp.), diethylstilbestrol (DES), and orchiectomy (castration or orchidectomy). Search results were limited to studies on humans indexed under the Medical Subject Heading prostatic neoplasms. Randomized, controlled trials were identified by using the search strategy of the United Kingdom Cochrane Center (22). A total of 1477 references were retrieved and checked against the Cochrane Controlled Trials Register, the Cochrane Collaboration CENTRAL register, and trials cited in two recent meta-analyses. No additional trials were identified. Our study selection criteria limited reports of efficacy outcomes to randomized, controlled trials that compared 1) monotherapy with an LHRH agonist and monotherapy with orchiectomy or DES or 2) monotherapy with an antiandrogen and monotherapy with orchiectomy, DES, or an LHRH agonist. To facilitate comparison of results across trials that used different controls, studies that directly compared orchiectomy with DES were also included. Randomized, controlled trials that compared only different doses of the same agent were excluded. For adverse events, phase II studies that reported withdrawals from therapy were included. All studies reporting on quality of life were included. The patient population of interest was men with advanced prostate cancer, including regional or disseminated metastases (stage D1 or D2 disease [any T, N1 to N3, M0 or any T, any N, M1]) and minimally advanced disease (stage C disease [T3 or T4, N0 or NX, M0]). We also looked for outcomes that were analyzed by such patient prognostic factors as tumor grade, extent of disease, and performance status. Outcomes of interest were overall cancer-specific and progression-free survival, time to treatment failure, adverse effects, and quality of life. Where available, data on patient preferences were included. Adverse Events We encountered well-described difficulties (23, 24) in capturing infrequent events from small trials and inconsistencies among trials in measuring and reporting adverse events. Summarized here is the most reliable index of serious adverse events: the rate of withdrawal from therapy. A summary of adverse events by category (for example, cardiovascular, endocrine) is included in the full evidence report (20). Meta-Analysis We used the general approach to meta-analysis of trials in prostate cancer described by Caubet and colleagues (17), with additional guidance from Whitehead and Whitehead (25). To combine evidence from studies with several different treatment arms, it was necessary to go beyond standard meta-analysis techniques (26). The solution to the problem entails defining variables that describe the possible interventions. The poor survival rates for metastatic prostate cancer have implied a large value for the hazard rate (rate of death across time). We made the same assumption that is used in standard meta-analysisthat is, we assumed that the effect measure (hazard ratio in this case) remains constant across studies. Because several different treatments are now available, we assumed that all of the hazard ratios among the various treatments remain constant. The model is a generalization of the random-effects model described by DerSimonian and Laird (27). It is essentially the same model used by EGRET (28), except that it is applied to continuous outcomes instead of dichotomous outcomes. The model is a generalization that includes both fixed-effects and random-effects terms. The fixed-effects terms are the individual study intercepts. The random-effects terms are the slopes for the treatment effects. Estimates of all variables, including the extra variation, are obtained by maximum likelihood. On the basis of the preceding assumptions, our objective was to estimate the hazard rate for each arm of each study or to estimate the proportional hazards term and its standard error. We obtained estimates from other statistics for studies that did not provide this information directly. Caubet and colleagues (17) suggested a technique for estimating the log-hazard ratio from the chi-square value of the log-rank test. Where Kaplan-Meier curves were given, it was usually possible to estimate individual hazards, as described in the comprehensive evidence review (20). To use this meta-analysis method, we constructed a table of hazard rates for each arm of each study. The meta-analysis was done with software developed at the Duke Clinical Research Institute, Durham, North Carolina. Sensitivity analyses were used to test for heterogeneity of methods (including the effect of including studies of lower methodologic quality), participants, and interventions. An initial analysis determined whether the results of orchiectomy and DES were comparable and whether it was valid to pool studies in which the control groups used either of these monotherapies. Separate analyses also compared the available monotherapies and categories of monotherapies. All meta-analysis results were reported as hazard ratios relative to orchiectomy. Data Synthesis Overview of the Evidence Base The literature search identified 24 controlled trials that, collectively, randomly assigned more than 6600 patients to treatment with different monotherapies for

American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin in Adult Patients With Cancer

PURPOSE To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. METHODS An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. RESULTS The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. RECOMMENDATIONS For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.

IL-1β and TNF-α in prostatic secretions are indicators in the evaluation of men with chronic prostatitis

Purpose: Chronic Prostatitis, or Chronic Pelvic Pain Syndrome [CPPS], is a common disorder characterized by pelvic pain and varying degrees of inflammation in expressed prostatic secretions (EPS). In search of markers to more clearly define CPPS, we compared proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels in EPS from men with CPPS, to healthy men and men with Benign Prostatic Hyperplasia (BPH).Methods: 78 men: controls (n = 16), BPH (n = 14), CPPS IIIA [≥10 white blood cells per high power field (WBC/hpf) in EPS] (n = 18), CPPS IIIB [<10 WBC/hpf in EPS] (n = 20), and asymptomatic inflammatory prostatitis (AIP) (n = 10) were evaluated for EPS WBC, and IL-1β and TNF-α by ELISA.Results: IL-1β and TNF-α levels in EPS were usually detectable in men with CPPS IIIA (89% and 45%, respectively) or AIP (90%; 100%), but less often in controls (31%; 17%), BPH (57%; 15%), and CPPS IIIB (35%; 15%) respectively. IL-1β and TNF-α levels were higher in CPPS IIIA versus CPPS IIIB,...

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) as Adjunct Therapy in Relapsed Hodgkin Disease

OBJECTIVE To determine the clinical and economic effects of granulocyte macrophage colony-stimulating factor (GM-CSF) as adjunct therapy in relapsed or refractory Hodgkin disease. DESIGN A randomized, double-blind, phase III clinical trial. SETTING A tertiary referral center. PATIENTS Twenty-four patients (twelve of whom were controls) treated with high-dose chemotherapy and autologous bone marrow transplantation. MAIN RESULTS The 12 patients treated with GM-CSF, when compared with placebo recipients, had shorter periods of neutropenia (median duration of an absolute neutrophil count of less than 1000 cells/mm3, 16 days compared with 27 days; P = 0.02), shorter periods of platelet-transfusion dependency (median duration, 13.5 days compared with 21 days; P = 0.03), and shorter hospitalizations (median hospital stay, 32 days compared with 40.5 days; P = 0.004). Other clinical outcomes, such as frequency and severity of toxicities, development of pneumonia or infection, in-hospital death, and response rate were similar in the two groups. Actuarial long-term disease-free survival was 64% for patients treated with GM-CSF and 58% for patients who received placebo after 32 months of follow-up (P = 0.15). The group treated with GM-CSF had lower total charges after infusion of autologous marrow than the placebo group (median in-hospital charges,

Estimating the Cost of Cancer: Results on the Basis of Claims Data Analyses for Cancer Patients Diagnosed With Seven Types of Cancer During 1999 to 2000

39,800 compared with

American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer

62,500; P = 0.005) because of lower post-infusion charges for room and board, antibiotic therapy, transfusions, laboratory tests, and physical therapy visits. CONCLUSIONS Administration of GM-CSF was associated with acceleration of myeloid and platelet recovery and was cost effective in the treatment of patients with relapsed Hodgkin disease who received intensive chemotherapy.

Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline

PURPOSE Cancer accounts for 60.9 billion dollars in direct medical costs and 15.5 billion dollars for indirect morbidity costs. These estimates are derived primarily from national surveys or Federal databases. We derive estimates of the costs of cancer using administrative databases, which include claims and employment-related information on individuals insured by private or Medicare supplemental health plans. METHODS A retrospective matched-cohort control analysis was performed using 1998 to 2000 databases with information on insurance claims, benefits, and health productivity for 3 million privately insured employees, their dependents, and early retirees. Study patients had new diagnoses of one of seven types of cancer (n = 12,709). Controls without cancer were matched at a 3:1 ratio by demographics. A variable follow-up length was used (maximum of 2 years). Direct costs included health care costs for patients and deductibles and copayments for caregivers. Indirect costs of work absence and short-term disability (STD) were calculated for a subgroup of cancer patients and caregivers. RESULTS Mean monthly health care costs ranged from 2,187 dollars for prostate cancer to 7,616 dollars for pancreatic cancer, most often driven by hospitalization. Costs for controls were 329 dollars per month. Indirect morbidity costs to employees with cancer averaged 945 dollars, a result of a mean monthly loss of 2.0 workdays and 5.0 STD days. CONCLUSION The economic burden of cancer is substantial. It is feasible to derive tumor-specific estimates of direct and indirect costs for large numbers of cancer patients using administrative databases. Policy makers charged with providing annual cost-of-cancer estimates should incorporate data obtained from a broad range of sources.

Epoetin-associated pure red cell aplasia: past, present, and future considerations.

PURPOSE To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. METHODS An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. RESULTS The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. RECOMMENDATIONS For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.