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1.  Difference in Restricted Mean Survival Time for Cost-Effectiveness Analysis Using Individual Patient Data Meta-Analysis: Evidence from a Case Study 
PLoS ONE  2016;11(3):e0150032.
Objective
In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). This study illustrates how different survival analysis methods can be used to estimate the rmstD for economic evaluation using individual patient data (IPD) meta-analysis. Our aim was to study if/how the choice of a method impacts on cost-effectiveness results.
Methods
We used IPD from the Meta-Analysis of Radiotherapy in Lung Cancer concerning 2,000 patients with locally advanced non-small cell lung cancer, included in ten trials. We considered methods either used in the field of meta-analysis or in economic evaluation but never applied to assess the rmstD for economic evaluation using IPD meta-analysis. Methods were classified into two approaches. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. With the second approach, the rmstD is based on the aggregation of the rmstDs estimated in each trial.
Results
The average incremental cost-effectiveness ratio (ICER) and acceptability curves were sensitive to the method used to estimate the rmstD. The estimated rmstDs ranged from 1.7 month to 2.5 months, and mean ICERs ranged from € 24,299 to € 34,934 per life-year gained depending on the chosen method. At a ceiling ratio of € 25,000 per life year-gained, the probability of the experimental treatment being cost-effective ranged from 31% to 68%.
Conclusions
This case study suggests that the method chosen to estimate the rmstD from IPD meta-analysis is likely to influence the results of cost-effectiveness analyses.
doi:10.1371/journal.pone.0150032
PMCID: PMC4784740  PMID: 26960150
2.  Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection 
Journal of Clinical Oncology  2015;33(30):3439-3446.
Purpose
The classification for invasive lung adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and WHO is based on the predominant histologic pattern—lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MIP), or solid (SOL)—present in the tumor. This classification has not been tested in multi-institutional cohorts or clinical trials or tested for its predictive value regarding survival from adjuvant chemotherapy (ACT).
Patients and Methods
Of 1,766 patients in the IALT, JBR.10, CALGB 9633 (Alliance), and ANITA ACT trials included in the LACE-Bio study, 725 had adenocarcinoma. Histologies were reclassified according to the new classification and then collapsed into three groups (LEP, ACN/PAP, and MIP/SOL). Primary end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs were estimated through multivariable Cox models stratified by trial. Prognostic value was estimated in the observation arm and predictive value by a treatment effect interaction with histologic subgroups. Significance level was set at .01 for pooled analysis.
Results
A total of 575 patients were included in this analysis. OS was not prognostically different between histologic subgroups, but univariable DFS and SDFS were worse for MIP/SOL compared with LEP or ACN/PAP subgroup (P < .01); this remained marginally significant after adjustment. MIP/SOL patients (but not ACN/PAP) derived DFS and SDFS but not OS benefit from ACT (OS: HR, 0.71; 95% CI, 0.51 to 0.99; interaction P = .18; DFS: HR, 0.60; 95% CI, 0.44 to 0.82; interaction P = < .01; and SDFS: HR, 0.59; 95% CI, 0.42 to 0.81; interaction P = .01).
Conclusion
The new lung adenocarcinoma classification based on predominant histologic pattern was not predictive for ACT benefit for OS, but it seems predictive for disease-specific outcomes.
doi:10.1200/JCO.2014.58.8335
PMCID: PMC4606061  PMID: 25918286
3.  Bias and precision of methods for estimating the difference in restricted mean survival time from an individual patient data meta-analysis 
Background
The difference in restricted mean survival time (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ rmstD\left({t}^{\ast}\right) $$\end{document}rmstDt∗), the area between two survival curves up to time horizon \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {t}^{\ast } $$\end{document}t∗, is often used in cost-effectiveness analyses to estimate the treatment effect in randomized controlled trials. A challenge in individual patient data (IPD) meta-analyses is to account for the trial effect. We aimed at comparing different methods to estimate the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ rmstD\left({t}^{\ast}\right) $$\end{document}rmstDt∗ from an IPD meta-analysis.
Methods
We compared four methods: the area between Kaplan-Meier curves (experimental vs. control arm) ignoring the trial effect (Naïve Kaplan-Meier); the area between Peto curves computed at quintiles of event times (Peto-quintile); the weighted average of the areas between either trial-specific Kaplan-Meier curves (Pooled Kaplan-Meier) or trial-specific exponential curves (Pooled Exponential). In a simulation study, we varied the between-trial heterogeneity for the baseline hazard and for the treatment effect (possibly correlated), the overall treatment effect, the time horizon \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {t}^{\ast } $$\end{document}t∗, the number of trials and of patients, the use of fixed or DerSimonian-Laird random effects model, and the proportionality of hazards. We compared the methods in terms of bias, empirical and average standard errors. We used IPD from the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) and its updated version MAC-NPC2 for illustration that included respectively 1,975 and 5,028 patients in 11 and 23 comparisons.
Results
The Naïve Kaplan-Meier method was unbiased, whereas the Pooled Exponential and, to a much lesser extent, the Pooled Kaplan-Meier methods showed a bias with non-proportional hazards. The Peto-quintile method underestimated the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ rmstD\left({t}^{\ast}\right) $$\end{document}rmstDt∗, except with non-proportional hazards at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {t}^{\ast } $$\end{document}t∗= 5 years. In the presence of treatment effect heterogeneity, all methods except the Pooled Kaplan-Meier and the Pooled Exponential with DerSimonian-Laird random effects underestimated the standard error of the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ rmstD\left({t}^{\ast}\right) $$\end{document}rmstDt∗. Overall, the Pooled Kaplan-Meier method with DerSimonian-Laird random effects formed the best compromise in terms of bias and variance. The \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ rmstD\left({t}^{\ast },=,10,\kern0.5em ,\mathrm{years}\right) $$\end{document}rmstDt∗=10years estimated with the Pooled Kaplan-Meier method was 0.49 years (95 % CI: [−0.06;1.03], p = 0.08) when comparing radiotherapy plus chemotherapy vs. radiotherapy alone in the MAC-NPC and 0.59 years (95 % CI: [0.34;0.84], p < 0.0001) in the MAC-NPC2.
Conclusions
We recommend the Pooled Kaplan-Meier method with DerSimonian-Laird random effects to estimate the difference in restricted mean survival time from an individual-patient data meta-analysis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12874-016-0137-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12874-016-0137-z
PMCID: PMC4812643  PMID: 27025706
Restricted mean survival time; Survival benefit; Meta-analysis; Multicenter clinical trial; Survival analysis; Simulation study
4.  Hyperfractionated or Accelerated Radiotherapy in Lung Cancer: An Individual Patient Data Meta-Analysis 
Journal of Clinical Oncology  2012;30(22):2788-2797.
Purpose
In lung cancer, randomized trials assessing hyperfractionated or accelerated radiotherapy seem to yield conflicting results regarding the effects on overall (OS) or progression-free survival (PFS). The Meta-Analysis of Radiotherapy in Lung Cancer Collaborative Group decided to address the role of modified radiotherapy fractionation.
Material and Methods
We performed an individual patient data meta-analysis in patients with nonmetastatic lung cancer, which included trials comparing modified radiotherapy with conventional radiotherapy.
Results
In non–small-cell lung cancer (NSCLC; 10 trials, 2,000 patients), modified fractionation improved OS as compared with conventional schedules (hazard ratio [HR] = 0.88, 95% CI, 0.80 to 0.97; P = .009), resulting in an absolute benefit of 2.5% (8.3% to 10.8%) at 5 years. No evidence of heterogeneity between trials was found. There was no evidence of a benefit on PFS (HR = 0.94; 95% CI, 0.86 to 1.03; P = .19). Modified radiotherapy reduced deaths resulting from lung cancer (HR = 0.89; 95% CI, 0.81 to 0.98; P = .02), and there was a nonsignificant reduction of non–lung cancer deaths (HR = 0.87; 95% CI, 0.66 to 1.15; P = .33). In small-cell lung cancer (SCLC; two trials, 685 patients), similar results were found: OS, HR = 0.87, 95% CI, 0.74 to 1.02, P = .08; PFS, HR = 0.88, 95% CI, 0.75 to 1.03, P = .11. In both NSCLC and SCLC, the use of modified radiotherapy increased the risk of acute esophageal toxicity (odds ratio [OR] = 2.44 in NSCLC and OR = 2.41 in SCLC; P < .001) but did not have an impact on the risk of other acute toxicities.
Conclusion
Patients with nonmetastatic NSCLC derived a significant OS benefit from accelerated or hyperfractionated radiotherapy; a similar but nonsignificant trend was observed for SCLC. As expected, there was increased acute esophageal toxicity.
doi:10.1200/JCO.2012.41.6677
PMCID: PMC4934452  PMID: 22753901
5.  Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis 
Journal of Clinical Oncology  2014;32(10):1031-1039.
Purpose
Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain.
Patients and Methods
We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens.
Results
Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5′VNTR2R/3R and 3′UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10−6). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens.
Conclusion
A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value—better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.
doi:10.1200/JCO.2013.51.1857
PMCID: PMC4879695  PMID: 24590654
6.  Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data 
The Lancet Oncology  2013;14(7):619-626.
Summary
Background
The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels.
Methods
We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints.
Findings
In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2=0·83, 95% CI 0·83–0·83 in trials without radiotherapy, and 0·87, 0·87–0·87 in trials with radiotherapy) and excellent at trial level (R2=0·92, 95% CI 0·88–0·95 in trials without radiotherapy and 0·99, 0·98–1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77–0·85, dependent on the regimen being assessed) and trial level (R2 range 0·89–0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2=0·71, 95% CI 0·71–0·71 for concurrent chemotherapy and ρ2=0·61, 0·61–0·61 for modified vs standard radiotherapy) and trial-level correlations very good (R2=0·85, 95% CI 0·77–0·92 for concurrent chemotherapy and R2=0·95, 0·91–0·98 for modified vs standard radiotherapy).
Interpretation
We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted.
Funding
Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.
doi:10.1016/S1470-2045(13)70158-X
PMCID: PMC3732017  PMID: 23680111
7.  Pooled Analysis of the Prognostic and Predictive Effects of KRAS Mutation Status and KRAS Mutation Subtype in Early-Stage Resected Non–Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy 
Journal of Clinical Oncology  2013;31(17):2173-2181.
Purpose
We undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non–small-cell lung cancer (NSCLC).
Methods
KRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model.
Results
Among 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon-12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02).
Conclusion
KRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.
doi:10.1200/JCO.2012.48.1390
PMCID: PMC4881333  PMID: 23630215
9.  How individual participant data meta-analyses have influenced trial design, conduct, and analysis 
Journal of Clinical Epidemiology  2015;68(11):1325-1335.
Objectives
To demonstrate how individual participant data (IPD) meta-analyses have impacted directly on the design and conduct of trials and highlight other advantages IPD might offer.
Study Design and Setting
Potential examples of the impact of IPD meta-analyses on trials were identified at an international workshop, attended by individuals with experience in the conduct of IPD meta-analyses and knowledge of trials in their respective clinical areas. Experts in the field who did not attend were asked to provide any further examples. We then examined relevant trial protocols, publications, and Web sites to verify the impacts of the IPD meta-analyses. A subgroup of workshop attendees sought further examples and identified other aspects of trial design and conduct that may inform IPD meta-analyses.
Results
We identified 52 examples of IPD meta-analyses thought to have had a direct impact on the design or conduct of trials. After screening relevant trial protocols and publications, we identified 28 instances where IPD meta-analyses had clearly impacted on trials. They have influenced the selection of comparators and participants, sample size calculations, analysis and interpretation of subsequent trials, and the conduct and analysis of ongoing trials, sometimes in ways that would not possible with systematic reviews of aggregate data. We identified additional potential ways that IPD meta-analyses could be used to influence trials.
Conclusions
IPD meta-analysis could be better used to inform the design, conduct, analysis, and interpretation of trials.
doi:10.1016/j.jclinepi.2015.05.024
PMCID: PMC4635379  PMID: 26186982
Individual participant data (IPD); Systematic review; Meta-analysis; Trial conduct; Trial design; Trial analysis
10.  Disease-Free Survival as a Surrogate for Overall Survival in Adjuvant Trials of Gastric Cancer: A Meta-Analysis 
Background
In investigations of the effectiveness of surgery and adjuvant chemotherapy for gastric cancers, overall survival (OS) is considered the gold standard endpoint. However, the disadvantage of using OS as the endpoint is that it requires an extended follow-up period. We sought to investigate whether disease-free survival (DFS) is a valid surrogate for OS in trials of adjuvant chemotherapy for gastric cancer.
Methods
The GASTRIC group initiated a meta-analysis of individual patient data collected in randomized clinical trials comparing adjuvant chemotherapy vs surgery alone for patients with curatively resected gastric cancer. Surrogacy of DFS was assessed through the correlation between the endpoints as well as through the correlation between the treatment effects on the endpoints. External validation of the prediction based on DFS was also evaluated.
Results
Individual patient data from 14 randomized clinical trials that included a total of 3288 patients were analyzed. The rank correlation coefficient between DFS and OS was 0.974 (95% confidence interval [CI] = 0.971 to 0.976). The coefficient of determination between the treatment effects on DFS and on OS was as high as 0.964 (95% CI = 0.926 to 1.000), and the surrogate threshold effect based on adjusted regression analysis was 0.92. In external validation, the six hazard ratios for OS predicted according to DFS were in very good agreement with those actually observed for OS.
Conclusions
DFS is an acceptable surrogate for OS in trials of cytotoxic agents for gastric cancer in the adjuvant setting.
doi:10.1093/jnci/djt270
PMCID: PMC4202244  PMID: 24108812
11.  Cross-validation analysis of the prognostic significance of mucin expression in patients with resected non-small cell lung cancer treated with adjuvant chemotherapy: results from IALT, JBR.10 and ANITA 
INTRODUCTION
CALGB 9633 was a randomized trial of observation versus adjuvant chemotherapy for patients with stage IB non-small cell lung cancer (NSCLC). In CALGB 9633, the presence of mucin in the primary tumor was associated with shorter disease-free survival (DFS; hazard ratio (HR)=1.9, p=0.002) and overall survival (OS; HR=1.9, p=0.004).
METHODS
To validate these results, mucin staining was performed on primary tumor specimens from 780 patients treated on IALT, 351 on JBR.10 and 150 on ANITA. The histochemical technique using mucicarmine was performed. The prognostic value of mucin for DFS and OS was tested in a Cox model stratified by trial and adjusted for clinical and pathological factors. A pooled analysis of all 4 trials was performed for the predictive value of mucin for benefit from adjuvant chemotherapy.
RESULTS
The cross-validation group had 48% squamous, 37% adenocarcinoma and 15% other NSCLC compared with 29%, 56%, and 15% respectively in CALGB. Among 1262 patients with assessable results, mucin was positive in IALT 24%, JBR.10 30%, ANITA 22% compared with 45% in CALGB. Histology was the only significant covariate (p<0.0001) in multivariate analysis with mucin seen more commonly in adenocarcinoma (56%) compared with squamous (5%) and other NSCLC (15%). Mucin was a borderline negative prognostic factor for DFS (HR=1.2 [1.0–1.5], p=0.06) but not significantly so for OS (HR=1.1 [0.9–1.4], p=0.25). Prognostic value did not vary according to histology: HR=1.3 [1.0–1.6] in adenocarcinoma vs. 1.6 [1.2–2.2] for DFS in other histology (interaction p=0.69). Mucin status was not predictive for benefit from adjuvant chemotherapy (test of interaction: DFS p=0.27; OS p=0.49).
CONCLUSIONS
Mucin was less frequent in the cross-validation group due to its higher percentage of squamous cell carcinomas. The negative impact of mucin was confirmed for DFS but not for OS. Mucin expression was not predictive of overall survival benefit from adjuvant chemotherapy.
doi:10.1016/j.lungcan.2013.06.015
PMCID: PMC3804220  PMID: 23920379
Non-small cell lung cancer; prognostic factors; mucin; predictive factors; adenocarcinoma
12.  ERCC1 Isoform Expression and DNA Repair in Non–Small-Cell Lung Cancer 
The New England journal of medicine  2013;368(12):1101-1110.
BACKGROUND
The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non–small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation.
METHODS
We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage.
RESULTS
We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance.
CONCLUSIONS
Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.)
doi:10.1056/NEJMoa1214271
PMCID: PMC4054818  PMID: 23514287
14.  Efficacy, Safety, and Biomarkers of Single-Agent Bevacizumab Therapy in Patients with Advanced Hepatocellular Carcinoma 
The Oncologist  2012;17(8):1063-1072.
The safety, efficacy, and potential biomarkers of activity of bevacizumab in patients with advanced hepatocellular carcinoma were assessed. Bevacizumab was active and well tolerated. The clinical value of circulating endothelial cells and interleukin-6 and -8 warrants further investigation.
Objective.
Hepatocellular carcinoma (HCC) is a highly vascularized tumor in which neoangiogenesis contributes to growth and metastasis. We assessed the safety, efficacy, and potential biomarkers of activity of bevacizumab in patients with advanced HCC.
Methods.
In this phase II trial, eligible patients received bevacizumab, 5 mg/kg or 10 mg/kg every 2 weeks. The disease-control rate at 16 weeks (16W-DCR) was the primary endpoint. Circulating endothelial cells (CECs) and plasma cytokines and angiogenic factors (CAFs) were measured at baseline and throughout treatment.
Results.
The 16W-DCR was 42% (95% confidence interval, 27%–57%). Six of the 43 patients who received bevacizumab achieved a partial response (objective response rate [ORR], 14%). Grade 3–4 asthenia, hemorrhage, and aminotransferase elevation occurred in five (12%), three (7%), and three (7%) patients, respectively. During treatment, placental growth factor markedly increased, whereas vascular endothelial growth factor (VEGF)-A dramatically decreased (p < .0001); soluble VEGF receptor-2 (p < .0001) and CECs (p = .03) transiently increased on day 3. High and increased CEC counts at day 15 were associated with the ORR (p = .04) and the 16W-DCR (p = .02), respectively. Lower interleukin (IL)-8 levels at baseline (p = .01) and throughout treatment (p ≤ .04) were associated with the 16W-DCR. High baseline IL-8 and IL-6 levels predicted shorter progression-free and overall survival times (p ≤ .04).
Conclusion.
Bevacizumab is active and well tolerated in patients with advanced HCC. The clinical value of CECs, IL-6, and IL-8 warrants further investigation.
doi:10.1634/theoncologist.2011-0465
PMCID: PMC3425524  PMID: 22707516
Hepatocellular carcinoma; Bevacizumab; Circulating endothelial cells; Prognosis; Biomarker
15.  A Pooled Exploratory Analysis of the Effect of Tumor Size and KRAS Mutations on Survival Benefit from Adjuvant Platinum-Based Chemotherapy in Node Negative Non-Small Cell Lung Cancer 
Introduction
Staging of node negative (N0) non-small cell lung cancer is modified in the 7th edition TNM classification. Here, we pool data from JBR.10 and CALGB-9633 to explore the prognostic and predictive effects of the new T-size descriptors and KRAS mutation status.
Methods
Node negative patients were reclassified as T2a (>3-≤5cm), T2b (>5-≤7cm), T3 (>7cm) or T≤3 cm (≤3cm but other T2 characteristics).
Results
Of 538 eligible patients, 288 (53.5%) were T2a, 111 (21%) T2b, 62 (11.5%) T3, while 77 (14%) T≤3cm were excluded to avoid confounding. KRAS mutations were detected in 104/390 (27%) patients. T-size was prognostic for disease-free survival (DFS; p=0.03), but borderline for overall survival (OS; p=0.10), on multivariable analysis. Significant interaction between the prognostic value of KRAS and tumor size was observed for OS (p=0.01), but not DFS (p=0.10). There was a non-significant trend (p=0.24) for increased chemotherapy effect on OS with advancing T-size (HR T2a 0.90, [0.63-1.30]; T2b 0.69, [0.38-1.24]; and T3 0.57, [0.28-1.17]). The HR for chemotherapy effect on OS in T2a patients with KRAS wild-type tumors was 0.81 (p=0.36), while a trend for detrimental effect was observed in those with mutant tumors (HR 2.11; p=0.09; interaction p=0.05). Similar trends were observed in T2b-T3 patients with wild-type (HR 0.86; p=0.62), and KRAS mutant tumors (HR 1.16; p=0.74; interaction p=0.58).
Conclusion
Chemotherapy effect appears to increase with tumor size. However, this small study could not identify subgroups of patients who did or did not derive significant benefit from adjuvant chemotherapy based on T-size or KRAS status.
doi:10.1097/JTO.0b013e31824fe9e6
PMCID: PMC3638870  PMID: 22588152
16.  Prediction of survival benefits from progression-free survival benefits in advanced non-small-cell lung cancer: evidence from a meta-analysis of 2334 patients from 5 randomised trials 
BMJ Open  2013;3(3):e001802.
Objectives
To investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in advanced non-small-cell lung cancer (NSCLC).
Design
Meta-analysis of individual patient data from randomised trials.
Setting
Five randomised controlled trials comparing docetaxel-based chemotherapy with vinorelbine-based chemotherapy for the first-line treatment of NSCLC.
Participants
2331 patients with advanced NSCLC.
Primary and secondary outcome measures
Surrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. The surrogate threshold effect was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS.
Results
The median follow-up of patients still alive was 23.4 months. Median OS was 10 months and median PFS was 5.5 months. The treatment effects on PFS and OS were correlated, whether using centres (R²=0.62, 95% CI 0.52 to 0.72) or prognostic strata (R²=0.72, 95% CI 0.60 to 0.84) as units of analysis. The surrogate threshold effect was a PFS hazard ratio (HR) of 0.49 using centres or 0.53 using prognostic strata.
Conclusions
These analyses provide only modest support for considering PFS as an acceptable surrogate for OS in patients with advanced NSCLC. Only treatments that have a major impact on PFS (risk reduction of at least 50%) would be expected to also have a significant effect on OS. Whether these results also apply to targeted therapies is an open question that requires independent evaluation.
doi:10.1136/bmjopen-2012-001802
PMCID: PMC3612819  PMID: 23485717
Clinical Pharmacology
17.  MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma 
Cancer research  2010;70(21):8288-8298.
This study determined whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted to date of adjuvant chemotherapy in patients with radically resected non-small cell lung carcinoma (NSCLC). Expression of miR-21, miR-29b, miR-34a/b/c, miR-155 and let-7a was determined by quantitative real-time PCR in paraffin embedded formalin fixed tumor specimens from 639 IALT patients. Prognostic and predictive value of microRNA expression for survival were studied using a Cox model, which included every factor used in the stratified randomization, clinicopathological prognostic factors and other factors statistically related to microRNA expression. Investigation of the expression pattern of microRNAs in situ was performed. We also analyzed association of TP53 mutation status and miR-34a/b/c expression, EGFR and KRAS mutation status and miR-21 and Let-7a expression, respectively. Finally, association of p16 and miR-29b expression was assessed. Overall, no significant association was found between any of the tested microRNAs and survival, with the exception of miR-21 where a deleterious prognostic effect of lowered expression was suggested. Otherwise, no single or combinatorial microRNA expression profile predicted response to adjuvant cisplatin-based chemotherapy. Together, our results indicate that the miRNA expression patterns examined were neither predictive nor prognostic in a large patient cohort of radically resected NSCLC randomized to receive adjuvant cisplatin-based chemotherapy versus follow-up only.
doi:10.1158/0008-5472.CAN-10-1348
PMCID: PMC2970724  PMID: 20978195
non–small cell lung cancer; adjuvant chemotherapy; randomized trial; biomarker; drug resistance; microRNA
18.  Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: a FNCLCC-ACCORD/0201 randomized phase II trial's pre-planned analysis and case report of a 5.5-year disease-free survival 
Background
To explore possible improvement in the treatment of locally advanced pancreatic carcinoma (LAPC) we performed a randomized, non-comparative phase II study evaluating docetaxel - plus either daily continuous 5 FU or weekly cisplatin concurrent to radiotherapy. We report here the results of the docetaxel plus 5 FU regimen stopped according to the interim analysis. The docetaxel plus cisplatin arm was continued.
Methods
Forty (40) chemotherapy-naive patients with unresectable LAPC were randomly assigned (1:1) to either continuous fluorouracil (5-FU) 200 mg/m2/day (protracted IV) and docetaxel (DCT) 20 mg/m2/week or DCT 20 mg/m2 and cisplatin (CDDP) 20 mg/m2, plus concurrent radiotherapy for a period of 6 weeks. The radiation dose to the primary tumor was 54 Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate (NPR). Secondary endpoints were tolerance, objective response rate, and overall survival. Accrual was to be stopped if at 6 months more than 13 disease progressions were observed in 20 patients.
Results
Eighteen (18) progressions occurred at 6 months in the 5-FU-DCT arm. Six-month NPR was 10% (95%CI: 0-23). Six and 12-month survivals were 85% (95%CI: 64-95) and 40% (95%CI: 22-61); median overall survival was 10.1 months. Median progression-free survival was 4.3 months. We report the case of one patient who was amenable to surgery and has been in complete response (CR) for 5.5 years. Toxicities grade ≥ 3 were reported in 75% of patients; no treatment-related death occurred. Severe toxicities were mainly vomiting (35%), abdominal pain (10%) and fatigue (10%).
Conclusions
Combination of 5-FU, docetaxel and radiotherapy has inadequate efficacy in the treatment of LAPC despite good tolerance for the 5-FU-DCT regimen.
Trial Registration
ClinicalTrials.gov: NCT00112697
doi:10.1186/1748-717X-6-124
PMCID: PMC3191360  PMID: 21943032

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