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Competing risks data often exist within a center in multi-center randomized clinical trials where the treatment effects or baseline risks may vary among centers. In this paper, we propose a subdistribution hazard regression model with multivariate frailty to investigate heterogeneity in treatment effects among centers from multi-center clinical trials. For inference, we develop a hierarchical likelihood (or h-likelihood) method, which obviates the need for an intractable integration over the frailty terms. We show that the profile likelihood function derived from the h-likelihood is identical to the partial likelihood, and hence it can be extended to the weighted partial likelihood for the subdistribution hazard frailty models. The proposed method is illustrated with a dataset from a multi-center clinical trial on breast cancer as well as with a simulation study. We also demonstrate how to present heterogeneity in treatment effects among centers by using a confidence interval for the frailty for each individual center and how to perform a statistical test for such heterogeneity using a restricted h-likelihood. [ABSTRACT FROM AUTHOR]

The frailty model, an extension of the proportional hazards model, is often used to model clustered survival data. However, some extension of the ordinary frailty model is required when there exist competing risks within a cluster. Under competing risks, the underlying processes affecting the events of interest and competing events could be different but correlated. In this paper, the hierarchical likelihood method is proposed to infer the cause-specific hazard frailty model for clustered competing risks data. The hierarchical likelihood incorporates fixed effects as well as random effects into an extended likelihood function, so that the method does not require intensive numerical methods to find the marginal distribution. Simulation studies are performed to assess the behavior of the estimators for the regression coefficients and the correlation structure among the bivariate frailty distribution for competing events. The proposed method is illustrated with a breast cancer dataset. [ABSTRACT FROM AUTHOR]

The double-blind, prospective, National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) showed a 50% reduction in the risk of breast cancer for tamoxifen versus placebo, yet many women at risk of breast cancer do not adhere to the 5-year course. This first report of the rich BCPT drug adherence data examines predictors of adherence. Between June, 1992 and September, 1997 13,338 women at high risk of breast cancer were randomly assigned to 20 mg/d tamoxifen versus placebo; we analyzed the 11,064 enrolled more than 3 years before trial unblinding. Primary endpoint was full drug adherence (100% of assigned pills per staff report, excluding protocol-required discontinuation) at 1 and 36 months; secondary was adequate adherence (76%-100%). Protocol-specified multivariable logistic regression tested lifestyle factors, controlling for demographic and medical predictors. About 13% were current smokers; 60% were overweight/obese; 46% had moderate/heavy physical activity; 21%, 66%, 13% drank 0, 0-1, 1+ drinks per day, respectively; 91% were adequately adherent at 1 month; and 79% were at 3 years. Alcohol use was associated with reduced full adherence at 1 month (P = 0.016; OR = 0.79 1+ vs. 0), as was college education (P <0.001; OR = 0.78 vs. high school); age (P < 0.001; OR = 1.4 age 60+) and per capita household annual income (P < 0.001; OR = 1.2 per $30,000) with increased adherence. Current smoking (P = 0.003; OR = 0.75), age (P = 0.024, OR = 1.1), college education (P = 0.037; OR = 1.4), tamoxifen assignment (P = 0.031; OR = 0.84), and breast cancer risk (P <.001; OR = 1.5 high vs. low) predicted adequate adherence at 36 months. There were no significant associations with obesity or physical activity. Alcohol use and smoking might indicate a need for greater adherence support., (©2011 AACR.)

Purpose: Sentinel lymph node resection (SNR) may reduce morbidity while providing the same clinical utility as conventional axillary dissection (AD). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 is a randomized phase III trial comparing SNR immediately followed by AD (SNAD) to SNR and subsequent AD if SN is positive. We report the definitive patient-reported outcomes (PRO) comparisons., Patients and Methods: Eligible patients had clinically node-negative, operable invasive breast cancer. The PRO substudy included all SN-negative participants enrolled May 2001 to February 2004 at community institutions in the United States (n = 749; 78% age > or = 50; 87% clinical tumor size < or = 2.0 cm; 84% lumpectomy; 87% white). They completed questionnaires presurgery, 1 and 2 to 3 weeks postoperatively, and every 6 months through year 3. Arm symptoms, arm use avoidance, activity limitations, and quality of life (QOL) were compared with intent-to-treat two-sample t-tests and repeated measures analyses., Results: Arm symptoms were significantly more bothersome for SNAD compared with SNR patients at 6 months (mean, 4.8 v 3.0; P < .001) and at 12 months (3.6 v 2.5; P = .006). Longitudinally, SNAD patients were more likely to experience ipsilateral arm and breast symptoms, restricted work and social activity, and impaired QOL (P < or = .002 all items). From 12 to 36 months, fewer than 15% of either SNAD or SNR patients reported moderate or greater severity of any given symptom or activity limitation., Conclusion: Arm morbidity was greater with SNAD than with SNR. Despite considerable fears about complications from AD for breast cancer, this study demonstrates that initial problems with either surgery resolve over time.