Literature-based Meta-analyses Research Articles

Invited Perspective: PFAS and the Childhood Obesity Phenotype-Challenges and Opportunities.

Invited Perspective: PFAS and the Childhood Obesity Phenotype-Challenges and Opportunities.

Abstract GS1-07: Effects of capecitabine as part of neo-/adjuvant chemotherapy. A meta-analysis of individual patient data from 12 randomized trials including 15,457 patients

Abstract Background: Despite the large number of patients with early breast cancer (EBC) that have been treated with capecitabine in randomized trials no individual patient data meta-analysis has yet been conducted. So far only two literature-based meta-analyses have been published including only five neoadjuvant studies and two adjuvant trials, respectively. Whereas the first did not report an improvement in response to neoadjuvant therapy, the latter found an improvement in disease-free survival (DFS) in the capecitabine arm. Methods: In order to select trials the following criteria were used at www.clinicaltrials.gov: Use of capecitabine in EBC as adjuvant or neoadjuvant therapy; randomized; N>100 patients; recruitment completed and outcomes available. This yielded the following trials: GeparTrio, GeparQuattro, GAIN, ICE, ICE II, FinXX, Alliance/CALGB 49907, Roche / US Oncology 01062, NSABP-B40, ABCSG-24, CREATE-X, GEICAM 2003/10, GEICAM 2003/11_CIBOMA 2004/01. Data were available for all these trials and 15,457 patients were included in this individual patient data based meta-analysis. The primary objective was to examine the effect of capecitabine on disease-free survival (DFS). Secondary objectives were to examine effects on distant DFS (DDFS), overall survival (OS), pathological complete response (for neoadjuvant studies) and whether there was an interaction of occurrence of capecitabine-specific toxicity (mucositis, diarrhea, hand-foot syndrome) and treatment effect. Bi- and multivariable frailty-based Cox proportional hazards models including log-normal distributed random effects of study were used to report hazard ratios with 95% CI between the groups of patients treated with or without capecitabine for DFS, DDFS and OS. Results: Individual data from 15,457 patients was collected. Of these 7,980 received capecitabine during the course of their treatment and 7,477 patients were treated in the control arms. Median age at diagnosis was 54 years in both groups. Most patients were diagnosed with stage 2 tumors (55.9%) and the majority presented with nodal involvement (74.0%). Estrogen and progesterone receptor positivity was observed in 66.0% and 56.9%, respectively, and 15.1% of patients were diagnosed as HER2-positive. 2,816 patients (18.2%) received neoadjuvant treatment and 12,641 (81.8%) an adjuvant chemotherapy regimen. Cox regression analyses of all included patients revealed that the addition of capecitabine did not alter DFS significantly compared to treatment without capecitabine (HR 0.952; 95% CI 0.895-1.012; p-value 0.115). There was also no effect on DFS if studies were selected in which capecitabine was given instead of another drug (HR 1.035; 95% CI 0.945-1.134; p=0.455). However, capecitabine in addition to systemic treatment lead to a small but significant improvement of DFS (HR 0.888; 95% CI 0.817-0.965; p=0.005). Results concerning other endpoints will be presented at the meeting. Conclusion: Capecitabine did not alter DFS in this meta-analysis of 15,457 patients with early breast cancer from 12 prospective randomized trials, but as addition to systemic treatment DFS was improved. Subgroup analyses are needed for final interpretation and will be presented at the meeting. Citation Format: Marion van Mackelenbergh, Fenja Seither, Volker Möbus, Joyce O'Shaugnessy, Miguel Martin, Heikki Joenssuu, Michael Untch, Ulrike Nitz, Juan J Miralles, Masakazu Toi, Harry D Bear, Hymann Muss, Toralf Reimer, Valentina Nekljudova, Sibylle Loibl. Effects of capecitabine as part of neo-/adjuvant chemotherapy. A meta-analysis of individual patient data from 12 randomized trials including 15,457 patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-07.

The Efficacy and Safety of Anti-epidermal Growth Factor Receptor Monoclonal Antibodies in Nasopharyngeal Carcinoma: Literature-based Meta-analyses.

Background: Anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), such as cetuximab and nimotuzumab have been used in the treatment of nasopharyngeal carcinoma (NPC), yet their efficacy and safety are undetermined.Materials and Methods: We performed two meta-analyses based on systematic searches of PubMed, EMBASE, the Cochrane Library and SinoMed: comparison 1 (standard therapy plus mAbs vs. standard therapy) and comparison 2 (radiotherapy plus concurrent mAbs vs. concurrent chemoradiotherapy) to explore the treatment value of anti-EGFR mAbs in NPC. Primary outcomes were overall survival (OS) and disease-free survival (DFS); secondary outcomes, locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and grade 3 and above acute adverse events.Results: Four randomized controlled trials and thirteen observational studies were eligible. Comparison 1 (twelve studies): adding mAbs to standard therapy (radiotherapy or chemoradiotherapy) significantly improved OS (HR, 0.51; 95% CI, 0.39-0.66) and DFS (HR, 0.68; 95% CI, 0.54-0.86), but increased the frequency of skin rashes and mucositis. Comparison 2 (six studies): OS (HR, 1.17; 95% CI, 0.81-1.70) and DFS (HR, 1.16; 95% CI, 0.86-1.57) were not significantly different when mAbs replaced conventional cytotoxic chemotherapy concurrently with radiotherapy, with fewer hematological, gastrointestinal and renal toxicities and more skin rashes in the mAb group.Conclusion: We recommend anti-EGFR mAbs enhance—but should not replace—current treatment paradigms for locoregionally advanced NPC. Further evidence from phase III clinical trials is required.

Gene-environment interaction for polymorphisms in ataxia telangiectasia-mutated gene and radiation exposure in carcinogenesis: results from two literature-based meta-analyses of 27120 participants.

PurposeWe conducted two meta-analyses of ATM genetic polymorphisms and cancer risk in individuals with or without radiation exposure to determine whether there was a joint effect between the ATM gene and radiation exposure in carcinogenesis.Resultsrs1801516, which was the only ATM polymorphism investigated by more than 3 studies of radiation exposure, was eligible for the present study. The meta-analysis of 23333 individuals without radiation exposure from 24 studies showed no association between the rs1801516 polymorphism and cancer risk, without heterogeneity across studies. The meta-analysis of 3787 individuals with radiation exposure from 6 studies showed a significant association between the rs1801516 polymorphism and a decreased cancer risk, with heterogeneity across studies. There was a borderline-significant difference between the ORs of the two meta-analyses (P = 0.066), and the difference was significant when only Caucasians were included (P = 0.011).Materials and methodsPublications were identified by searching PubMed, EMBASE, Web of Science, and CNKI databases. Odds ratios (ORs) were calculated to estimate the association between ATM genetic polymorphisms and cancer risk. Tests of interaction were used to compare differences between the ORs of the two meta-analyses.ConclusionsOur meta-analyses confirmed the presence of a gene-environment interaction between the rs1801516 polymorphism and radiation exposure in carcinogenesis, whereas no association was found between the rs1801516 polymorphism and cancer risk for individuals without radiation exposure. The heterogeneity observed in the meta-analysis of individuals with radiation exposure might be due to gene-ethnicity or gene-gene interactions. Further studies are needed to elucidate sources of the heterogeneity.

Primary tumour standardised uptake value is prognostic in nonsmall cell lung cancer: a multivariate pooled analysis of individual data.

(18)F-fluoro-2-deoxy-d-glucose positron emission tomography (PET) complements conventional imaging for diagnosing and staging lung cancer. Two literature-based meta-analyses suggest that maximum standardised uptake value (SUVmax) on PET has univariate prognostic value in nonsmall cell lung cancer (NSCLC). We analysed individual data pooled from 12 studies to assess the independent prognostic value of binary SUVmax for overall survival.After searching the published literature and identifying unpublished data, study coordinators were contacted and requested to provide data on individual patients. Cox regression models stratified for study were used.Data were collected for 1526 patients (median age 64 years, 60% male, 34% squamous cell carcinoma, 47% adenocarcinoma, 58% stage I-II). The combined univariate hazard ratio for SUVmax was 1.43 (95% CI 1.22-1.66) and nearly identical if the SUV threshold was calculated stratifying for histology. Multivariate analysis of patients with stage I-III disease identified age, stage, tumour size and receipt of surgery as independent prognostic factors; adding SUV (HR 1.58, 95% CI 1.27-1.96) improved the model significantly. The only detected interaction was between SUV and stage IV disease.SUV seems to have independent prognostic value in stage I-III NSCLC, for squamous cell carcinoma and for adenocarcinoma.

Prediction of Clinical Irrelevance of PK Differences in Atorvastatin Using PK/PD Models Derived From Literature-Based Meta-Analyses

To support the development of a fixed-dose combination (FDC) of ezetimibe and atorvastatin for the treatment of dyslipidemia, bioequivalence (BE) studies were conducted across a combined dose range (10/10, 10/20, 10/40, and 10/80 mg of ezetimibe/atorvastatin). In the BE trials, all parameters met traditional BE bounds except for atorvastatin peak plasma concentration (Cmax) at two intermediate doses. Literature-based metadata analysis predicted that the observed difference in Cmax between an ezetimibe+atorvastatin FDC and coadministration of these agents translates directly into a non–clinically significant change of <1.2% absolute difference in the percentage lowering of low-density-lipoprotein cholesterol . Both FDC doses were confirmed to be clinically equivalent to coadministration in the subsequent clinical equivalence trials. These data suggest that modeling of dose–response relationships may be useful in predicting clinical equivalence, lowering cost/timelines through effective powering of studies, and predicting the effectiveness of new dosage formulations without the need for additional clinical efficacy trials in regulatory settings.

P1-07-07: Assessing Two Methods of Meta-Analysis in Studies of Patients with Breast Cancer: Individual Patient Data-Based (IPD) Versus Literature Based Abstracted Data (AD) in 5 Meta-Analyses Including over 28,000 Patients. Are There Results Differences of Concern?

Abstract Background: Meta-analyses are widely used to provide high level evidence to resolve controversies. Differences of opinion continue concerning the two most frequently used methods (IPD and AD) and their roles in providing reliable recommendations for Evidence-Based Medicine. Some regard the IDP method as being more accurate, yet it is time-consuming, expensive, and can be troubled by getting data from all investigators. We tested whether overall conclusions would differ between the two methods when using the same studies for comparison. To overcome limitations related to simple correlation analysis, and: 1) to weigh the agreement between these 2 approaches (Bland-Altman [BA], Lancet 1986), and 2) to evaluate the eventual predictive role of the data coming from AD over IPD, an analysis with multiple methods was performed. Methods: 5 meta-analyses in breast cancer examining 9 outcomes which had been subjected to IPD meta-analysis were selected. Literature-based AD meta-analyses were then conducted. Hazard Ratios (HR) and Risk Ratios (RRs) with 95% confidence intervals (CI) were extracted or derived from original meta-analyses. At least 90% of patients’ reports were required for the IDP analysis. Methods agreement was analyzed according to the BA method, as difference or ratios, and a comparison with the Variance-Ratio test (F-test), and the Concordance Correlation Coefficient (CCC) was done. Correlations between IPD/AD-ratios were estimated using a linear regression model with Pearson (r) and R2 coefficients (parametric) and Spearman's Rho/Kendall's Tau coefficient (non-parametric), to derive a predictive estimation on IPD when adopting AD. MedCalc® Software was used. Results: 9 outcomes in 5 meta-analyses (28,358 patients) were analyzed, as seen in the table. Graphical comparison between the deviation from the ‘line of identity’ identified with the B-A method did not show meaningful differences between AD and IPD (mean difference −0.01535, 95% CI −0.0315, 0.0008; mean ratio 0.9816, 95% CI 0.9625, 1.0008). No significant difference in the Variance (F-test 1.01, p=0.98), and a high concordance (CCC 0.9775, 95% CI 0.91, 0.99) were found. A highly significant correlation by both parametric and non-parametric tests allowed derivation of a linear regression equation able to predict estimation IPD results from AD data; R2 0.97, p&amp;lt;0.001. Conclusions: When analyzing the results of studies (AD) or patient results from those same studies (IDP) we found: 1) No significant or meaningful differences between the 2 meta-analysis methods; and 2) Data from the AD analyses are able to predict those from IPD, without significant risk of overestimation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-07-07.

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

To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. 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. 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.

A1166C genetic variation of the angiotensin II type I receptor gene and susceptibility to coronary heart disease: Collaborative of 53 studies with 20,435 cases and 23,674 controls

Objective Angiotensin II induces vasoconstriction and vascular smooth muscle growth via stimulation of the angiotensin II type I receptor (AGTR1). Some studies have reported an association between a genetic variant (A1166C) in the 3′ un-translated region of AGTR1 and increased risk of coronary heart disease (CHD), but other have yielded apparently conflicting results. Methods Literature-based meta-analyses were performed on 48 papers including 53 studies published before June 2008 in relation to the A1166C polymorphism (NCBI, dbSNP: rs5186) of the AGTR1, involving a total of 20,435 CHD cases and 23,674 controls. We also explored potential sources of heterogeneity and conducted appropriate stratified analyses. Results In a combined analysis, the per-allele odds ratio (OR) for CHD of the A1166C polymorphism was 1.11 (95% confidence interval: 1.03–1.19), but there is an indication of publication bias and heterogeneity among the 53 studies. Sample size and study quality were significant sources of heterogeneity among studies of the A1166C polymorphism with possibly overestimates in studies of smaller sample-size and poor-quality. When the analyses were restricted to 11 larger studies (≥500 cases), and to 8 high-quality studies (quality score: ≥11 points), the summary per-allele odds ratios were 0.992 (95% confidence interval, 0.944–1.042) and 0.990 (95% confidence interval, 0.915–1.072), respectively. Conclusions An overall weak association between the A1166C polymorphism and CHD is observed but this is likely to be due to publication bias and heterogeneity between studies. There were no significant associations among the larger sample-size and high-quality studies which are less prone to selective publication and have greater power to detect a true association.

Understanding differences in results from literature-based and individual patient meta-analyses: An example from meta-analyses of observational data

Background Meta-analyses are increasingly used to summarise observational data however a literature meta-analysis (LMA) may give different results to the corresponding individual patient meta-analysis (IPMA). This study compares the published results of equivalent LMAs and IPMAs, highlighting factors that can affect the results and therefore impact on clinical interpretation of meta-analyses. Method Univariate results from published meta-analyses of prospective observational outcome data were compared, as were the number of studies, patients and length of follow-up. The absolute difference in survival was calculated. The association between severe diastolic dysfunction (RFP) and death post acute myocardial infarction (AMI) and in chronic heart failure (HF) were used as clinical examples. Results The IPMA hazard ratio was lower that the LMA odds ratio: AMI hazard ratio 2.67 (95% confidence interval 2.23 to 3.20), odds ratio 4.10 (3.38 to 4.99); HF hazard ratio 2.42 (2.06 to 2.83), odds ratio 4.36 (3.60 to 5.04). The IPMAs contained most of the studies from the LMAs as well as additional unpublished data, and a longer length of follow-up was available in the IPMAs (AMI 3.7 vs 2.6 yr, HF 4.0 vs 1.5 yr). Restricting analysis to the same studies in both the LMA and IPMA resulted in a similar difference in effect sizes between methods to those found in the published analyses. Conclusions The result of a meta-analysis is affected by whether study level or individual patient data have been used, and the variant of analysis that is required. Awareness and consideration of these factors is important for clinical interpretation of meta-analyses.

Disease-free survival (DFS) as surrogate end-point for overall survival (OS) in early breast cancer (EBC): Correlation may be different according to drugs and/or strategies tested

6622 Background: DFS is considered an accepted end-point for adjuvant trials in EBC. Two are the implications in using surrogates: 1) the chance for a smaller sample size/shorter follow-up (for clinical trial design optimization) and 2) for pursuing the approval of new drugs/strategies by regulatory boards. Although this correlation is linked to the explored disease, it is likely that drugs acting with different mechanisms have a different impact on that. A validation in all settings, and a comparison between the correlation-coefficients given by different drugs' families/strategies is required. Methods: 4 different settings in EBC were selected: 1) the evaluation of a experimental chemotherapeutic (Chemo-setting); 2) the evaluation of a strategy (Strategy-setting); 3) the evaluation of an hormonal-drug (Hormonal-setting); 4) the evaluation of a targeted-agent (Targeted-setting). Literature-based meta-analyses were accomplished, and a linear- regression-model considering outcome rates was used for correlation, estimated with the Pearson, R2 (parametric) and Spearman (non-parametric) coefficients. The comparison of coefficients was accomplished with the normally distributed Fisher's transformation. Results: All randomized trials (RCTs) exploring the efficacy of the following drugs/strategies as EBC-adjuvant treatment were gathered: 1) Chemo-setting: taxanes; 2) Strategy-setting: dose-dense; 3) Hormonal-setting: aromatase inhibitors; 4) Targeted-setting: trastuzumab. Results are listed in the table. No significant differences between coefficients were found. Conclusions: Cooperative groups designing RCTs and regulatory boards should take into account that, although DFS is a good surrogate of OS in EBC, the strength of the correlation may be different in the same disease-setting, in accordance with the experimental drugs and/or strategies to be tested. Setting Pts (#RCTs) Pearson (p) R2 (p) Spearman (p) Chemo 17,067 (10) 0.74 (<0.001) 0.55 (<0.001) 0.63 (<0.001) Strategy 4,411 (3) 0.97 (<0.001) 0.95 (<0.001) 0.89 (0.02) Hormonal 26,707 (9) 0.78 (0.001) 0.60 (0.001) 0.77 (0.001) Targeted 10,205 (5) 0.82 (0.01) 0.65 (0.01) 0.65 (0.06) No significant financial relationships to disclose.

Restrictive Filling Pattern and Mortality: Comparison of Individual Patient Versus Literature Based Meta-Analyses

patients hadNIHSS <1, 1/5NIHSS= 15, 1/5NIHSS= 18. In conclusion, standard 24h Holter monitoring only detects 4.9%of patientswith newor paroxysmalAF admittedwith AIS in sinus rhythm. Increasing the period of monitoring to 48 h will detect 7.3% more cases of significant AF. There is no correlation between stroke site, severity and the incidence of new onset or paroxysmal AF. doi:10.1016/j.hlc.2008.05.205 205 Restrictive Filling Pattern and Mortality: Comparison of Individual PatientVersusLiteratureBasedMeta-Analyses Katrina Poppe1,2,3,4,5,6,∗, Rob Doughty1,2,3,4,5,6, C.M. Yu1,2,3,4,5,6, Miguel Quintana1,2,3,4,5,6, Jacob Moller 1,2,3,4,5,6, Allan Klein1,2,3,4,5,6, Greg Gamble1,2,3,4,5,6, Frank Dini 1,2,3,4,5,6, Gillian Whalley1,2,3,4,5,6 1 The University of Auckland, Auckland, New Zealand; 2 The Prince of Wales Hospital, Hong Kong, China; 3 The Karolinska Institute, Stockholm, Sweden; 4 HS Rigshospitalet, Copenhagen, Denmark; 5 The Cleveland Clinic, Cleveland, United States; 6 Santa Chiara Hospital, Pisa, Italy Purpose: The restrictive mitral filling pattern (RFP) is the most severe form of diastolic dysfunction. We have performed standard literature-based meta-analyses (LMA) a l a a t M t r i t u s R t t v 1 d

Randomized trials of combination chemotherapy (combo) versus monotherapy (mono) in relapsed ovarian carcinoma (ROC): A meta-analysis of published data

5524 Background: Results of recent randomized clinical trials (RCTs) support the use of combination chemotherapy in the management of ROC, more specifically in the platinum-sensitive setting. We performed a literature-based meta-analysis of RCTs comparing combination versus monotherapy in previously treated ROC to validate or refute conclusions of individual trials. Methods: This was a systematic review of the available literature identified from multiple databases using the terms ‘combination chemotherapy‘, ‘advanced ovarian cancer‘ and ‘randomized trial‘. Data were pooled for Meta-analysis using the Mantel Hanzsel Peto model. Event-based relative odds ratios (OR) with 95% confidence intervals (CI) were derived. Heterogeneity test was applied. Results: We identified and included 8 RCTs trials fulfilling the selection criteria, 6 phase III and 2 Phase II. Seven published trials and one ASCO poster presentation. One study was conducted exclusively in patients with platinum-resistant disease, five in platinum-sensitive disease only, and 2 in a mixed population. A total of 2312 patients were included in those 8 trials. Relevant endpoints of interest for this meta-analysis were: Overall Response Rate (ORR), Progression-Free Survival (PFS) at 2 years and Overall Survival (OS) at 2 years. Results are summarized in the table : Conclusion: Acknowledging all the drawbacks related to literature-based meta-analyses, combination chemotherapy seems to improve ORR, PFS and OS when compared to monotherapy in the mangement of ROC.

Restrictive Filling Pattern is a Powerful Predictor of Heart Failure Events Postacute Myocardial Infarction and in Established Heart Failure: A Literature-Based Meta-Analysis

Two recent literature-based meta-analyses revealed that restrictive filling pattern (RFP) was associated with a 4-fold increase in the risk of death in patients with heart failure (HF) and postacute myocardial infarction (AMI). This similar but unique analysis evaluated the link between RFP and morbidity. Prospective echocardiographic studies of patients post-AMI and with HF that reported HF morbidity were identified. Events (post-AMI: development of HF; HF: HF readmission) were compared between patients with and without RFP in both patient groups. Review Manager version 4.2.7 software was used for the analysis. Twelve post-AMI studies (1286 patients, 271 events) and 5 HF studies (647 patients, 176 events) were identified. RFP was associated with HF readmission in the HF patients (OR 2.96 [2.02-4.33] and development of HF post-AMI (OR 10.10 [7.02-14.51]). The event rate in the RFP group was the same regardless of disease category (49% post-AMI, 42% HF); however, RFP was less prevalent in the post-AMI group (22% versus 39%). This literature-based meta-analysis confirms that RFP is a powerful predictor of HF hospitalization in patients with HF and especially the development of HF post-AMI. This is an important prognostic sign and should be incorporated into routine clinical practice.

Neoadjuvant chemotherapy in the treatment of nonsmall-cell lung cancer

To review the recent evidence regarding the potential benefit on the outcome of neoadjuvant chemotherapy in patients with early-stage nonsmall-cell lung cancer and compare this evidence with the theoretical advantages and disadvantages of the approach. The available evidence has mostly not yet been published in full manuscript form and should be interpreted cautiously. The observed gain in survival with neoadjuvant treatment is not consistent with expectations. Literature-based meta-analyses, however, estimate a gain in survival of at least 6% after 5 years. Neoadjuvant chemotherapy results in clinical downstaging in approximately 40-60% of the patients and pathological complete response rate in 5-10%. Neoadjuvant chemotherapy does not reduce the number of pneumonectomies. As expected, its compliance is better compared with adjuvant treatment. Neoadjuvant chemotherapy does not delay surgery or result in an increased hospital stay or rate of perioperative complications, when compared with immediate surgery. Neoadjuvant regimens should be platinum-based and at least three cycles of chemotherapy should be administered. Neoadjuvant chemotherapy in early-stage nonsmall-cell lung cancer should not yet be offered outside of clinical trials and will in the future have to be compared with adjuvant chemotherapy.

Restrictive Filling Pattern Is a Powerful Predictor of Progression of Heart Failure in Patients with Chronic Heart Failure and Post-Acute Myocardial Infarction: A Literature-Based Meta-Analysis

Background: Restrictive filling pattern (RFP) has been linked to prognosis in patients with chronic heart failure (CHF) and post-AMI. We recently showed in two literature-based meta-analyses (LMA) that the presence of RFP was associated with a 4-fold increase in the risk of death in both groups. This similar analysis evaluated the link between RFP and morbidity. Methods: We searched online databases for prospective studies of patients post-AMI and with CHF. HF events, defined as development of HF for patients post-AMI and HF readmission in patients with existing CHF, were compared between RFP and non-RFP.

Randomized trials of amifostine and radiotherapy: Effect on survival?

Amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) is a cytoprotective and radioprotective agent for normal tissues against the deleterious effects of chemotherapeutic agents and/or ionizing radiation. We have compiled a unique database for meta-analysis that aims to address the controversial concept of the tumor protection. The proposed meta-analysis on survival outcome, which is based on individual patient data, will be more useful than literature-based meta-analyses because of the superiority of reliable, longer follow-up patient data. It will be also possible to study the effect(s) of amifostine in different tumor types.

Individual Patient- versus Literature-Based Meta-analysis of Survival Data: Time to Event and Event Rate at a Particular Time Can Make a Difference, an Example Based on Head and Neck Cancer

The objective of this study is to compare the results of an individual patient-based and a literature-based meta-analysis in chemotherapy in head and neck cancer and to identify the sources of difference. For all head and neck cancer randomized controlled clinical trials comparing chemotherapy and loco-regional treatment with loco-regional treatment alone, both the literature data and the individual patient data are retrieved and meta-analyses performed and compared. Only survival data are used as outcome, although both time to death and mortality at specific time points are considered in different analyses. There are substantial differences between the individual patient-based and the literature-based meta-analyses. The most important reason for the differing results is that the individual patient-based meta-analysis is based on a time to event analysis, whereas the literature-based meta-analysis is based on mortality at a specific time point. Mortality can change substantially with follow-up time. The absolute survival differences in the case study, for instance, increase from 2.6% at 2 years to 5.6% at 5 years. Control Clin Trials 2001;22:538–547

Estimating number of events from the Kaplan-Meier curve for incorporation in a literature-based meta-analysis: what you don't see you can't get!

In literature-based meta-analyses of time-to-event data, the number of events in the treated and control groups together with the total number of patients randomized to the two treatment arms are often used as summary statistics. If interest is in mortality at a specified moment in time, the number of events can, in most cases, only be obtained from the Kaplan-Meier curve. The estimated number of events, however, is typically larger than the true number of events. The effect of this overestimation on the Mantel-Haenszel test and the odds ratio is studied in this paper. From these results, it can be concluded that the number of events should not be estimated from the Kaplan-Meier curves for meta-analytic purposes unless virtually no patients are lost to follow-up or censored and there are still many patients at risk in the two groups at the time at which the number of events is to be determined.