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 Talcott's 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.

Erythropoietin or darbepoetin for patients with cancer.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoiesis stimulating agents (ESAs) and red blood cell transfusions. OBJECTIVES: To assess the effects of ESAs to either prevent or treat anaemia in cancer patients. SEARCH METHODS: This is an update of a Cochrane review first published in 2004. We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE and other databases. Searches were done for the periods 01/1985 to 12/2001 for the first review, 1/2002 to 04/2005 for the first update and to November 2011 for the current update. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials on managing anaemia in cancer patients receiving or not receiving anti-cancer therapy that compared the use of ESAs (plus transfusion if needed). DATA COLLECTION AND ANALYSIS: Several review authors assessed trial quality and extracted data. One review author assessed quality assessment and extracted data, a second review author checked for correctness. MAIN RESULTS: This update of the systematic review includes a total of 91 trials with 20,102 participants. Use of ESAs significantly reduced the relative risk of red blood cell transfusions (risk ratio (RR) 0.65; 95% confidence interval (CI) 0.62 to 0.68, 70 trials, N = 16,093). On average, participants in the ESAs group received one unit of blood less than the control group (mean difference (MD) -0.98; 95% CI -1.17 to -0.78, 19 trials, N = 4,715). Haematological response was observed more often in participants receiving ESAs (RR 3.93; 95% CI 3.10 to 3.71, 31 trials, N = 6,413). There was suggestive evidence that ESAs may improve Quality of Life (QoL). There was strong evidence that ESAs increase mortality during active study period (hazard ratio (HR) 1.17; 95% CI 1.06 to 1.29, 70 trials, N = 15,935) and some evidence that ESAs decrease overall survival (HR 1.05; 95% CI 1.00 to 1.11, 78 trials, N = 19,003). The risk ratio for thromboembolic complications was increased in patients receiving ESAs compared to controls (RR 1.52, 95% CI 1.34 to 1.74; 57 trials, N = 15,498). ESAs may also increase the risk for hypertension (fixed-effect model: RR 1.30; 95% CI 1.08 to 1.56; random-effects model: RR 1.12; 95% CI 0.94 to 1.33, 31 trials, N = 7,228) and thrombocytopenia/haemorrhage (RR 1.21; 95% CI 1.04 to 1.42; 21 trials, N = 4,507). There was insufficient evidence to support an effect of ESA on tumour response (fixed-effect RR 1.02; 95% CI 0.98 to 1.06, 15 trials, N = 5,012). AUTHORS' CONCLUSIONS: ESAs reduce the need for red blood cell transfusions but increase the risk for thromboembolic events and deaths. There is suggestive evidence that ESAs may improve QoL. Whether and how ESAs affects tumour control remains uncertain. The increased risk of death and thromboembolic events should be balanced against the potential benefits of ESA treatment taking into account each patient's clinical circumstances and preferences. More data are needed for the effect of these drugs on quality of life and tumour progression. Further research is needed to clarify cellular and molecular mechanisms and pathways of the effects of ESAs on thrombogenesis and their potential effects on tumour growth.

ASCO Clinical Practice Guideline on Uses of Serum Tumor Markers in Adult Males With Germ Cell Tumors.

An examination of serum tumor markers for monitoring or surveillance for each histologic germ cell tumor subtype: seminoma and nonseminomatous germ cell tumors.

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/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.

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.

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.

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.

This guideline update addresses two clinical questions: (1) What are the defining features of patients with a malignancy who are appropriate candidates for ESA treatment? (2) For patients who are appropriate candidates for treatment with ESAs, what are the optimal approaches to ESA therapy?

Erythropoietin or Darbepoetin for patients with cancer--meta-analysis based on individual patient data.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients and may improve quality of life, but there are concerns that ESAs might increase mortality. OBJECTIVES: Our objectives were to examine the effect of ESAs and identify factors that modify the effects of ESAs on overall survival, progression free survival, thromboembolic and cardiovascular events as well as need for transfusions and other important safety and efficacy outcomes in cancer patients. SEARCH STRATEGY: We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials. Manufacturers of ESAs were contacted to identify additional trials. SELECTION CRITERIA: We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusions (as necessary) versus red blood cell transfusions (as necessary) alone, to prevent or treat anemia in adult or pediatric cancer patients with or without concurrent antineoplastic therapy. DATA COLLECTION AND ANALYSIS: We performed a meta-analysis of randomized controlled trials comparing epoetin alpha, epoetin beta or darbepoetin alpha plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anemia while or after receiving anti-cancer treatment. Patient-level data were obtained and analyzed by independent statisticians at two academic departments, using fixed-effects and random-effects meta-analysis. Analyses were according to the intention-to-treat principle. Primary endpoints were on study mortality and overall survival during the longest available follow-up, regardless of anticancer treatment, and in patients receiving chemotherapy. Tests for interactions were used to identify differences in effects of ESAs on mortality across pre-specified subgroups. The present review reports only the results for the primary endpoint. MAIN RESULTS: A total of 13933 cancer patients from 53 trials were analyzed, 1530 patients died on-study and 4993 overall. ESAs increased on study mortality (combined hazard ratio [cHR] 1.17; 95% CI 1.06-1.30) and worsened overall survival (cHR 1.06; 95% CI 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 and I(2) 7.1%, p=0.33, respectively). Thirty-eight trials enrolled 10441 patients receiving chemotherapy. The cHR for on study mortality was 1.10 (95% CI 0.98-1.24) and 1.04; 95% CI 0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients receiving different cancer treatments (P for interaction=0.42). AUTHORS' CONCLUSIONS: ESA treatment in cancer patients increased on study mortality and worsened overall survival. For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded.

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).

American Society of Clinical Oncology clinical practice guidelines: opportunities and challenges.

The American Society of Clinical Oncology (ASCO) published its first clinical practice guideline, which focused on the use of hematopoietic colony-stimulating factors, in 1994. Since then, ASCO has published 24 additional guidelines or technology assessments on a range of topics and is developing 11 additional guidelines. Guidelines are among ASCO's most valued products, according to membership surveys and data from the JCO.org Web site. However, the same data from ASCO members have highlighted a number of limitations to the guideline program. These relate to the timelines of guideline updates, difficulties locating guidelines and related products, and challenges to implementing ASCO guidelines in everyday clinical practice. This article outlines the concrete steps that the ASCO Health Services Committee (HSC) is taking to address these limitations, including the institution of a more aggressive guideline updating schedule, a transition from narrative to systematic literature reviews to support the practice recommendations, a new Board of Directors-approved policy to permit endorsement of other groups' guidelines, and a robust Clinical Tools and Resources program that offers a range of guideline dissemination and implementation aids. Additional work is underway to establish stronger and deeper collaborations with practicing oncologists to expand their role in the review, field testing, and implementation of guideline clinical tools and resources. Finally, the HSC is discussing evaluation of the guidelines program to maximize the impact of ASCO clinical practice guidelines on clinical decision making and, ultimately, the quality of cancer care.

HER2 testing to manage patients with breast cancer or other solid tumors.

OBJECTIVES: Systematic review of trastuzumab outcomes among breast cancer patients who have negative, equivocal, or discordant HER2 assay results; use of HER2 assay results to predict outcomes of chemotherapy or hormonal therapy regimen for breast cancer; use of serum HER2 to monitor treatment response or disease progression in breast cancer patients; and use of HER2 testing to manage patients with lung, ovarian, prostate, or head and neck tumors. Also, narrative review of concordance of HER2 assays. DATA SOURCES: We abstracted data from: three articles plus one conference abstract on negative, equivocal, or discordant HER2 results; 26 studies on selection of chemotherapy or hormonal therapy; 15 studies on serum HER2; and 26 studies on ovarian, lung, prostate, or head and neck tumors. Foreign-language studies were included. REVIEW METHODS: We sought randomized trials or single-arm series (prospective or retrospective) of identically treated patients that presented relevant outcome data associated with HER2 status. RESULTS: HER2 assay results are influenced by multiple biologic, technical, and performance factors. Many aspects of HER2 assays were standardized only recently, so inconsistencies confound the literature comparing different methods. The evidence is weak on outcomes of trastuzumab added to chemotherapy for HER2-equivocal, -discordant, or -negative patients. Evidence comparing chemotherapy outcomes in HER2-positive and HER2-negative patient subgroups may generate hypotheses, but is too weak to test hypotheses. Only a rigorous test can resolve whether HER2-positive patients (but not HER2-negative patients) benefit from an anthracycline regimen. Evidence is available only from uncontrolled series on whether HER2 status predicts complete pathologic response to neoadjuvant chemotherapy. Evidence also is weak regarding differences by HER2 status for outcomes of chemotherapy for advanced or metastatic disease; with most studies lacking statistical power. Data from studies of tamoxifen and aromatase inhibitors suggest that future studies should examine whether HER2 status predicts response to specific hormonal therapies among estrogen-receptor-positive patients. The evidence is weak on whether serum HER2 predicts outcome after treatment with any regimens in any setting, as is the evidence on use of serum or tissue HER2 testing for malignancies of lung, ovary, head and neck, or prostate. CONCLUSIONS: Overall, few studies directly investigated the key questions of this systematic review. Going forward, cancer therapy trial protocols should incorporate elements to facilitate robust analyses of the use of HER2 status and other biomarkers for managing treatment.

Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update.

PURPOSE: To update the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) recommendations for the use of epoetin. The guideline was expanded to address use of darbepoetin and thromboembolic risk associated with these agents. METHOD: An Update Committee ("Committee") reviewed and analyzed data published since 2002 through July 2007. MEDLINE and the Cochrane Collaboration Library databases were searched. RECOMMENDATIONS: For patients with chemotherapy-associated anemia, the Committee continues to recommend initiating an erythropoiesis-stimulating agent (ESA) as hemoglobin (Hb) approaches, or falls below, 10 g/dL, to increase Hb and decrease transfusions. ESA treatment continues to be recommended for patients with low-risk myelodysplasia for similar reasons. There is no evidence showing increased survival as a result of ESA treatment. Conclusive evidence is lacking that, absent clinical circumstances necessitating earlier treatment, initiating ESAs at Hb levels greater than 10 g/dL either spares more patients from transfusion or substantially improves their quality of life. Starting doses and dose modifications based on response or lack thereof should follow the package insert. Continuing ESAs beyond 6 to 8 weeks in the absence of response, assuming appropriate dose increase has been attempted in nonresponders as per US Food and Drug Administration-approved label, does not seem to be beneficial, and ESA therapy should be discontinued. The Committee recommends monitoring iron stores and supplementing iron intake for ESA-treated patients. ESAs should be used cautiously with chemotherapy, or in clinical states, associated with elevated risk for thromo-embolic complications. The Committee also cautions against ESA use for patients with cancer who are not receiving chemotherapy, since recent trials report increased thromboembolic risks and decreased survival under these circumstances.

Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update.

PURPOSE: To update the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) recommendations for the use of epoetin. The guideline was expanded to address use of darbepoetin and thromboembolic risk associated with these agents. METHOD: An Update Committee ("Committee") reviewed and analyzed data published since 2002 through July 2007. MEDLINE and the Cochrane Collaboration Library databases were searched. RECOMMENDATIONS: For patients with chemotherapy-associated anemia, the Committee continues to recommend initiating an erythropoiesis-stimulating agent (ESA) as hemoglobin (Hb) approaches, or falls below, 10 g/dL, to increase Hb and decrease transfusions. ESA treatment continues to be recommended for patients with low-risk myelodysplasia for similar reasons. There is no evidence showing increased survival as a result of ESA treatment. Conclusive evidence is lacking that, absent clinical circumstances necessitating earlier treatment, initiating ESAs at Hb levels greater than 10 g/dL either spares more patients from transfusion or substantially improves their quality of life. Starting doses and dose modifications based on response or lack thereof should follow the package insert. Continuing ESAs beyond 6 to 8 weeks in the absence of response, assuming appropriate dose increase has been attempted in nonresponders as per US Food and Drug Administration-approved labeling, does not seem to be beneficial, and ESA therapy should be discontinued. The Committee recommends monitoring iron stores and supplementing iron intake for ESA-treated patients. ESAs should be used cautiously with chemotherapy, or in clinical states, associated with elevated risk for thromboembolic complications. The Committee also cautions against ESA use for patients with cancer who are not receiving chemotherapy, since recent trials report increased thromboembolic risks and decreased survival under these circumstances.

Evidence for management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition).

PURPOSES: This systematic review addressed the following key questions on managing small cell lung cancer (SCLC): the sequence, timing, and dosing characteristics of primary thoracic radiotherapy (TRTx) for limited-stage disease; primary TRTx for extensive-stage disease; effect of prophylactic cranial irradiation (PCI); positron emission tomography (PET) for staging; treatment of mixed histology tumors; surgery; and second-line and subsequent-line treatment for relapsed/progressive disease. METHODS: The review methods were defined prospectively in a written protocol. We primarily sought randomized controlled trials that compared the interventions of interest. RESULTS: Robust evidence was lacking for all questions except PCI, for which a patient-level metaanalysis showed that PCI improves survival of SCLC patients who achieved complete response after primary therapy from 15.3 to 20.7% (p = 0.01). The case for concurrent over sequential radiation delivery rests largely on a single multicenter trial. Support for early concurrent therapy comes from one multicenter trial, but two other multicenter trials found no advantage. Metaanalysis did not find significant reductions in 2-year and 3-year mortality rates for early TRTx. Favorable results from a single-center trial on TRTx for extensive stage disease need replication in a multicenter setting. Relevant comparative studies were nonexistent for management of mixed histology disease and surgery for early limited SCLC. PET may be more sensitive in detecting extracranial disease than conventional staging modalities, but studies were of poor quality. CONCLUSIONS: PCI improves survival among those with a complete remission to primary therapy. A research agenda is needed to optimize the effectiveness of TRTx and its components.

Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients.

This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2005, on the effects of epoetin alfa and beta (i.e., epoetin) and darbepoetin alfa (i.e., darbepoetin). We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. The Cochrane Library, MEDLINE, EMBASE, and conference proceedings were searched. Effect estimates and 95% confidence intervals (CIs) were calculated with fixed-effects models. Treatment with epoetin or darbepoetin statistically significantly reduced the risk for red blood cell transfusions (relative risk [RR] = 0.64, 95% CI = 0.60 to 0.68; 42 trials and 6510 patients) and improved hematologic response (RR = 3.43, 95% CI = 3.07 to 3.84; 22 trials and 4307 patients). Treatment with epoetin or darbepoetin increased the risk of thrombo-embolic events (RR = 1.67, 95% CI = 1.35 to 2.06; 35 trials and 6769 patients). Uncertainties remain as to whether and how epoetin or darbepoetin affects overall survival (hazard ratio = 1.08, 95% CI = 0.99 to 1.18; 42 trials and 8167 patients). Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thrombo-embolic events.

The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review.

Evidence supporting the role of hematopoietic stem cell transplantation (SCT) in the therapy of acute lymphoblastic leukemia in adults (> or =15 years) is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published medical literature and for grading the quality and strength of the evidence, and the strength of the treatment recommendations. Treatment recommendations based on the evidence are presented and were reached unanimously by a panel of acute lymphoblastic leukemia experts. The priority areas of needed future research for adult acute lymphoblastic leukemia are: definition of patients at high risk in first complete remission, beyond Philadelphia chromosome positive; outcomes of SCT in older (>50 years) adults; determination if reduced intensity versus myeloablative conditioning regimens yield an equivalent graft-versus-leukemia effect with reduced toxicity; monitoring of minimal residual disease to achieve disease control before SCT; and the use of cord blood and other alternative sources of stem cells for use in adult SCT recipients.

Management of small cell lung cancer.

OBJECTIVES: This is a systematic review of evidence on issues in managing small cell lung cancer (SCLC). Key questions addressed are: the sequence, timing, and dosing characteristics of primary thoracic radiotherapy (TRTx) for limited-stage disease; primary TRTx for extensive-stage disease; effect of prophylactic cranial irradiation (PCI); positron emission tomography (PET) for staging; treatment of mixed histology tumors; surgery; and second- and subsequent-line treatment for relapsed/progressive disease. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Register REVIEW METHODS: The review methods were defined prospectively in a written protocol. We sought randomized controlled trials that compared the interventions of interest. Where randomized trials were limited or nonexistent, we sought additional studies. We performed meta-analysis of studies that compared early and late TRTx. RESULTS: The strongest evidence available for this report is a patient-level meta-analysis showing that PCI improves survival of SCLC patients who achieved complete response following primary therapy from 15.3 percent to 20.7 percent (p=0.01). No other question yielded evidence so robust. The case for concurrent over sequential radiation delivery rests largely on a single multicenter trial. Support for early concurrent therapy comes from one multicenter trial, but two other multicenter trials found no advantage. Our meta-analysis did not find significant reductions in 2- and 3-year mortality for early TRTx. Favorable results from a single-center trial on TRTx for extensive stage disease need replication in a multicenter setting. For other questions (i.e., management of mixed histology disease; surgery for early limited SCLC), relevant comparative studies were nonexistent. PET may be more sensitive in detecting disease outside the brain than conventional staging modalities, but studies were of poor quality and reliable estimates of performance are not possible. CONCLUSIONS: PCI improves survival among those with a complete response to primary therapy. A research agenda is needed to optimize the effectiveness of TRTx and its components. PET for staging may be useful, but its role awaits clarification by rigorous studies. No relevant evidence was available to address management of mixed histology disease or surgery for early limited SCLC.