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This article focuses on the necessary psychometric properties of a patient-reported outcomes (PROs) measure. Topics include the importance of reliability and validity, psychometric approaches used to provide reliability and validity estimates, the kinds of evidence needed to indicate that a PRO has a sufficient level of reliability and validity, contexts that may affect psychometric properties, methods available to evaluate PRO instruments when the context varies, and types of reliability and validity testing that are appropriate during different phases of clinical trials. Points discussed include the perspective that the psychometric properties of reliability and validity are on a continuum in which the more evidence one has, the greater confidence there is in the value of the PRO data. Construct validity is the type of validity most frequently used with PRO instruments as few "gold standards" exist to allow the use of criterion validity and content validity by itself only provides beginning evidence of validity. Several guidelines are recommended for establishing sufficient evidence of reliability and validity. For clinical trials, a minimum reliability threshold of 0.70 is recommended. Sample sizes for testing should include at least 200 cases and results should be replicated in at least one additional sample. At least one full report on the development of the instrument and one on the use of the instrument are deemed necessary to evaluate the PRO psychometric properties. Psychometric testing ideally occurs before the initiation of Phase III trials. When testing does not occur prior to a Phase III trial, considerable risk is posed in relation to the ability to substantiate the use of the PRO data. Various qualitative (e.g., focus groups, behavioral coding, cognitive interviews) and quantitative approaches (e.g., differential item functioning testing) are useful in evaluating the reliability and validity of PRO instruments.

A B S T R A C T PurposeThis phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4). Patients and MethodsPatients were randomly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or lomustine (100 to 130 mg/m 2 , day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025. ResultsEnrollment was terminated at 266 patients (enzastaurin, n ϭ 174; lomustine, n ϭ 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] ϭ 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR ϭ 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P ϭ .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR ϭ 1.12; P ϭ .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P Յ .001). ConclusionEnzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.

Eli Lilly and Company.

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PurposeTo identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer.Materials and MethodsWe pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters.ResultsOf 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64–0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor.ConclusionsThe identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies.

HRQoL parameters are independent prognostic factors for outcome in advanced bladder cancer; their prognostic importance needs further evaluation.

Compared with observation and other agents used and/or reimbursed for maintenance therapy in advanced NSCLC, Pem may be considered cost-effective, particularly in patients with nonsquamous cell histology. This analysis is the first to evaluate the cost-effectiveness of maintenance therapy in advanced NSCLC and emphasizes the importance of histology in identifying the appropriate patient for Pem maintenance therapy.