The strengths and limitations of meta-analyses based on aggregate data

BACKGROUND: Properly performed systematic reviews and meta-analyses are thought by many to represent among the highest level of evidence addressing important clinical issues. Few would disagree that meta-analyses based on individual patient data (IPD) offer several advantages and represent the standard to which all other systematic reviews should be compared. METHODS: All cancer-related meta-analyses cited in Medline were classified as based on aggregate or individual patient data. A review was then undertaken of all reports comparing the comparative strengths and limitations of meta-analyses using either aggregate or individual patient data. RESULTS: The majority of published meta-analyses are based on summary or aggregate patient data (APD). Reasons suggested for this include the considerable resources, years of study and often, broad international cooperation required for IPD meta-analyses. Many of the most important features of systematic reviews including formal meta-analyses are addressed by both IPD and APD meta-analyses. The need for defining an explicit and relevant clinical question, exhaustively searching for the totality of evidence, meticulous and unbiased data transfer or extraction, assessment of between study heterogeneity and the use of appropriate statistical methods for estimating summary effect measures are essentially the same for the two approaches. CONCLUSION: IPD offers advantages and, when feasible, should be considered the best opportunity to summarize the results of multiple studies. However, the resources, time and cooperation required for such studies will continue to limit their use in many important areas of clinical medicine which can be meaningfully and cost-effectively approached by properly performed APD meta-analyses. APD meta-analyses continue to be the mainstay of systematic reviews utilized by the US Preventive Services Task Force, the Cochrane Collaboration and many professional societies to support clinical practice guidelines

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update 2014

More information, including Data and Methodology Supplements, slidesets, and clinicaltools and resources,is available atwww.asco.org/ guidelines/vte. Patient information is available at www.cancer.net. Visit www.asco.org/guidelineswiki to provide comments on the guideline or to submit new evidencePurpose To provide current recommendations about the prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. Methods PubMed and the Cochrane Library were searched for randomized controlled trials, systematic reviews, meta-analyses, and clinical practice guidelines from November 2012 through July 2014. An update committee reviewed the identified abstracts. Results Of the 53 publications identified and reviewed, none prompted a change in the 2013 recommendations. Recommendations Most hospitalized patients with active cancer require thromboprophylaxis throughout hospitalization. Routine thromboprophylaxis is not recommended for patients with cancer in the outpatient setting. It may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low–molecular weight heparin (LMWH) or low-dose aspirin. Patients undergoing major surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Extending prophylaxis up to 4 weeks should be considered in those undergoing major abdominal or pelvic surgery with high-risk features. LMWH is recommended for the initial 5 to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term secondary prophylaxis (at least 6 months). Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer. Anticoagulation should not be used to extend survival of patients with cancer in the absence of other indications. Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should educate patients about the signs and symptoms of VTE.Amgen (Inst)LEO PharmaBristol-Myers SquibbAcerta (Inst)Infinity (Inst)Onyx Pharmaceuticals (Inst)Janssen Oncology (Inst)Gilead Sciences (Inst)Spectrum Pharmaceuticals (Inst)Celgene (Inst)TG Therapeutics (Inst)Genentech/Roche (Inst)Pharmacyclics (Inst)Eisai IncBayer (Inst)Boehringer Ingelheim (Inst)Eisai IncBaxter Biosciences (Inst

Cost-Effectiveness of Primary versus Secondary Prophylaxis with Pegfilgrastim in Women with Early-Stage Breast Cancer Receiving Chemotherapy

AbstractObjectiveProphylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the risk of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy. We estimated the incremental cost-effectiveness of G-CSF pegfilgrastim primary (starting in cycle 1 and continuing in subsequent cycles of chemotherapy) versus secondary (only after an FN event) prophylaxis in women with early-stage breast cancer receiving myelosuppressive chemotherapy with a ≥20% FN risk.MethodsA decision-analytic model was constructed from a health insurer's perspective with a lifetime study horizon. The model considers direct medical costs and outcomes related to reduced FN and potential survival benefits because of reduced FN-related mortality. Inputs for the model were obtained from the medical literature. Sensitivity analyses were conducted across plausible ranges in parameter values.ResultsThe incremental cost-effectiveness ratio (ICER) of pegfilgrastim as primary versus secondary prophylaxis was $48,000/FN episode avoided. Adding survival benefit from avoiding FN mortality yielded an ICER of$110,000/life-year gained (LYG) or $116,000/quality-adjusted life-year (QALY) gained. The most influential factors included FN case-fatality, FN relative risk reduction from primary prophylaxis, and age at diagnosis.ConclusionsCompared with secondary prophylaxis, the cost-effectiveness of pegfilgrastim as primary prophylaxis may be equivalent or superior to other commonly used supportive care interventions for women with breast cancer. Further assessment of the direct impact of G-CSF on short- and long-term survival is needed to substantiate these findings

Use of re-randomized data in meta-analysis

BACKGROUND: Outcomes collected in randomized clinical trials are observations of random variables that should be independent and identically distributed. However, in some trials, the patients are randomized more than once thus violating both of these assumptions. The probability of an event is not always the same when a patient is re-randomized; there is probably a non-zero covariance coming from observations on the same patient. This is of particular importance to the meta-analysts. METHODS: We developed a method to estimate the relative error in the risk differences with and without re-randomization of the patients. The relative error can be estimated by an expression depending on the percentage of the patients who were re-randomized, multipliers (how many times more likely it is to repeat an event) for the probability of reoccurrences, and the ratio of the total events reported and the initial number of patients entering the trial. RESULTS: We illustrate our methods using two randomized trials testing growth factors in febrile neutropenia. We showed that under some circumstances the relative error of taking into account re-randomized patients was sufficiently small to allow using the results in the meta-analysis. Our findings indicate that if the study in question is of similar size to other studies included in the meta-analysis, the error introduced by re-randomization will only minimally affect meta-analytic summary point estimate. We also show that in our model the risk ratio remains constant during the re-randomization, and therefore, if a meta-analyst is concerned about the effect of re-randomization on the meta-analysis, one way to sidestep the issue and still obtain reliable results is to use risk ratio as the measure of interest. CONCLUSION: Our method should be helpful in the understanding of the results of clinical trials and particularly helpful to the meta-analysts to assess if re-randomized patient data can be used in their analyses

Cost‐effectiveness analysis of low‐dose direct oral anticoagulant (DOAC) for the prevention of cancer‐associated thrombosis in the United States

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154607/1/cncr32724.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154607/2/cncr32724_am.pd

Use of Erythropoietin in Cancer Patients: Assessment of Oncologists’ Practice Patterns in the United States and Other Countries

PURPOSE: To assess physician use of erythropoietin in cancer patients before publication of the American Society of Clinical Oncology/American Society of Hematology guidelines. METHODS: Questionnaires about erythropoietin use in practice and 12 hypothetical clinical scenarios involving patients with cancer were mailed to 2000 oncologists/hematologists in the United States and 19 other countries. Response rates were 30% in the United States and 25% internationally. Data on erythropoietin use for ovarian cancer were obtained from one clinical trial. Multivariate regression models assessed predictors of erythropoietin prescription. RESULTS: Most physicians selected a hemoglobin level ≤10 g/dL as an upper threshold for erythropoietin use (36% to 51% of U.S. physicians and 21% to 32% of foreign physicians). Frequent erythropoietin use (defined as use in at least 10% of cancer patients) was higher in the United States than elsewhere (adjusted odds ratio [OR]=5.8; 95% confidence interval [CI]: 2.5 to 13.4). Among U.S. physicians, those who said they used erythropoietin frequently were more likely to be in fee-for-service than managed care settings (OR=2.2; 95% CI: 1.3 to 3.7). Those who reported never using erythropoietin practiced in countries that had lower annual per capita health care expenditures, lower proportions of privately funded health care, and a national health service (P \u3c0.05 for all comparisons). Of 235 ovarian cancer patients who received topotecan, 38% (45/118) of U.S. patients and 2% (2/117) of European patients who developed grade 1 anemia (hemoglobin level between 10 and 12 g/dL) were treated with erythropoietin (P\u3c0.01). CONCLUSION: Financial considerations and a hemoglobin level \u3c10 g/dL appear to influence erythropoietin use in the United States, whereas financial considerations alone determine erythropoietin use abroad

Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growthfactor receptor 2-positive breast cancer

Background: We assessed long-term cardiac safety and efficacy in patients with human epidermal growth factor receptor 2epositive early breast cancer treated with a trastuzumab biosimilar (SB3) or its reference product, trastuzumab (TRZ), in a phase 3 study. Methods: Patients who completed the phase 3 study could be enrolled in this extension study. The outcomes included the incidence of symptomatic congestive heart failure (CHF), asymptomatic significant left ventricular ejection fraction (LVEF) decrease, incidence of other cardiac events, event-free survival (EFS), and overall survival. In post hoc analysis, the Cox proportional hazards regression model was used to assess factors associated with EFS. Results: A total of 367 patients were enrolled in the study (SB3, n Z 186; TRZ, n Z 181). The median follow-up duration from the main study enrolment was 40.8 and 40.5 months for SB3 and TRZ, respectively. During the two-year follow-up after adjuvant therapy, incidence of asymptomatic significant LVEF decrease was rare (SB3, n Z 1; TRZ, n Z 2), with all patients recovering with LVEF - 50%, and no cases of symptomatic CHF or other cardiac events were reported. At 3 years, the EFS was 91.9% with SB3 and 85.2% with TRZ. The number of patients with events was 17 (9.1%) with SB3 and 31 (17.1%) with TRZ [hazard ratio: 0.47, 95% confidence interval: 0.26e0.87]. Antibody-dependent cell-mediated cytotoxicity (ADCC) activity and the breast pathologic complete response rate were the factors associated with EFS. Conclusion: Cardiotoxicity was rare in this extension study. EFS was higher with SB3 versus TRZ, with post hoc analysis suggesting that a downward drift in ADCC activity was a contributing factor. Clinical trial registration numbers: NCT02771795 (EudraCT 2015-005663-17)

American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136493/1/caac21319_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136493/2/caac21319-sup-0001-suppinfo1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136493/3/caac21319.pd