Jerome Seidenfeld

American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer

PURPOSE To develop evidence-based guidelines, based on a systematic review, for endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. METHODS A literature search identified relevant randomized trials. Databases searched included MEDLINE, PREMEDLINE, the Cochrane Collaboration Library, and those for the Annual Meetings of the American Society of Clinical Oncology (ASCO) and the San Antonio Breast Cancer Symposium (SABCS). The primary outcomes of interest were disease-free survival, overall survival, and time to contralateral breast cancer. Secondary outcomes included adverse events and quality of life. An expert panel reviewed the literature, especially 12 major trials, and developed updated recommendations. RESULTS An adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initial endocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AI after 5 years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with 5 years of tamoxifen alone. Data suggest that including an AI as primary monotherapy or as sequential treatment after 2 to 3 years of tamoxifen yields similar outcomes. Tamoxifen and AIs differ in their adverse effect profiles, and these differences may inform treatment preferences. CONCLUSION The Update Committee recommends that postmenopausal women with hormone receptor-positive breast cancer consider incorporating AI therapy at some point during adjuvant treatment, either as up-front therapy or as sequential treatment after tamoxifen. The optimal timing and duration of endocrine treatment remain unresolved. The Update Committee supports careful consideration of adverse effect profiles and patient preferences in deciding whether and when to incorporate AI therapy.

Use of Epoetin in Patients With Cancer: Evidence-Based Clinical Practice Guidelines of the American Society of Clinical Oncology and the American Society of Hematology

Anemia resulting from cancer or its treatment is an important clinical problem increasingly treated with the recombinant hematopoietic growth factor erythropoietin. To address uncertainties regarding indications and efficacy, the American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin (Hgb) concentration below 10 g/dL. Use of epoetin for patients with less severe anemia (Hgb level below 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances. Good evidence from clinical trials supports the use of subcutaneous epoetin thrice weekly (150 U/kg) for a minimum of 4 weeks. Less strong evidence supports an alternative weekly (40 000 U/wk) dosing regimen, based on common clinical practice. With either administration schedule, dose escalation should be considered for those not responding to the initial dose. In the absence of response, continuing epoetin beyond 6-8 weeks does not appear to be beneficial. Epoetin should be titrated once the hemoglobin concentration reaches 12 g/dL. Evidence from one randomized controlled trial supports use of epoetin for patients with anemia associated with low-risk myelodysplasia not receiving chemotherapy; however, there are no published high-quality studies to support its use for anemia in other hematologic malignancies in the absence of chemotherapy. Therefore, for anemic patients with hematologic malignancies it is recommended that physicians initiate conventional therapy and observe hematologic response before considering use of epoetin.

Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials.

BACKGROUND Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

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 2009 Clinical Evidence Review on Radiofrequency Ablation of Hepatic Metastases From Colorectal Cancer

PURPOSE To review the evidence about the efficacy and utility of radiofrequency ablation (RFA) for hepatic metastases from colorectal cancer (CRHM). METHODS The American Society of Clinical Oncology (ASCO) convened a panel to conduct and analyze a comprehensive systematic review of the RFA literature from Medline and the Cochrane Collaboration Library. RESULTS Because data were considered insufficient to form the basis of a practice guideline, ASCO has instead published a clinical evidence review. The evidence is from single-arm, retrospective, and prospective trials. No randomized controlled trials have been included. The following three clinical issues were considered by the panel: the efficacy of surgical hepatic resection versus RFA for resectable tumors; the utility of RFA for unresectable tumors; and RFA approaches (open, laparoscopic, or percutaneous). Evidence suggests that hepatic resection improves overall survival (OS), particularly for patients with resectable tumors without extrahepatic disease. Careful patient and tumor selection is discussed at length in the literature. RFA investigators report a wide variability in the 5-year survival rate (14% to 55%) and local tumor recurrence rate (3.6% to 60%). The reported mortality rate was low (0% to 2%), and the major complications rate was commonly reported to be between 6% and 9%. RFA is currently performed with all three approaches. CONCLUSION There is a compelling need for more research to determine the efficacy and utility of RFA to increase local recurrence-free, progression-free, and disease-free survival as well as OS for patients with CRHM. Clinical trials have established that hepatic resection can improve OS for patients with resectable CRHM.

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.

Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and on selection and treatment as outpatients of those with fever and neutropenia. METHODS A literature search identified relevant studies published in English. Primary outcomes included: development of fever and/or infections in afebrile neutropenic outpatients and recovery without complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia, defervescence without regimen change, time to defervescence, infectious complications, and recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicrobials. An Expert Panel developed guidelines based on extracted data and informal consensus. RESULTS Forty-seven articles from 43 studies met selection criteria. RECOMMENDATIONS Antibacterial and antifungal prophylaxis are only recommended for patients expected to have < 100 neutrophils/μL for > 7 days, unless other factors increase risks for complications or mortality to similar levels. Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully selected patients may be managed as outpatients after systematic assessment beginning with a validated risk index (eg, Multinational Association for Supportive Care in Cancer [MASCC] score or Talcotts rules). Patients with MASCC scores ≥ 21 or in Talcott group 4, and without other risk factors, can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of empirical antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours to determine suitability for outpatient management or be admitted to the hospital. An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin if penicillin allergic) is recommended as empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed.

Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma †‡

The current systematic review and meta‐analysis compared monotherapy and combined androgen blockade in the treatment of men with advanced prostate carcinoma. Outcomes of interest included overall, cancer specific, and progression‐free survival; time to treatment failure; adverse events; and quality of life.

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

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.

American Society of Clinical Oncology Clinical Practice Guideline on Uses of Serum Tumor Markers in Adult Males With Germ Cell Tumors

PURPOSE To provide recommendations on appropriate uses for serum markers of germ cell tumors (GCTs). METHODS Searches of MEDLINE and EMBASE identified relevant studies published in English. Primary outcomes included marker accuracy to predict the impact of decisions on outcomes. Secondary outcomes included proportions of patients with elevated markers and statistical tests of elevations as prognostic factors. An expert panel developed consensus guidelines based on data from 82 reports. RESULTS No studies directly compared outcomes of decisions with versus without marker assays. The search identified few prospective studies and no randomized controlled trials; most were retrospective series. Lacking data on primary outcomes, most Panel recommendations are based on secondary outcomes (relapse rates and time to relapse). RECOMMENDATIONS The Panel recommended against using markers to screen for GCTs, to decide whether orchiectomy is indicated, or to select treatment for patients with cancer of unknown primary. To stage patients with testicular nonseminomas, the Panel recommended measuring three markers (alpha-fetoprotein [AFP], human chorionic gonadotropin [hCG], and lactate dehydrogenase [LDH]) before and after orchiectomy and before chemotherapy for those with extragonadal nonseminomas. They also recommended measuring AFP and hCG shortly before retroperitoneal lymph node dissection and at the start of each chemotherapy cycle for nonseminoma, and periodically to monitor for relapse. The Panel recommended measuring postorchiectomy hCG and LDH for patients with seminoma and preorchiectomy elevations. They recommended against using markers to guide or monitor treatment for seminoma or to detect relapse in those treated for stage I. However, they recommended measuring hCG and AFP to monitor for relapse in patients treated for advanced seminoma.