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Before biomarkers can be used in clinical trials or patients' management, the laboratory assays that measure their levels have to go through development and analytical validation. One of the most critical performance metrics for validation of any assay is related to the minimum amount of values that can be detected and any value below this limit is referred to as below the limit of detection (LOD). Most of the existing approaches that model such biomarkers, restricted by LOD, are parametric in nature. These parametric models, however, heavily depend on the distributional assumptions, and can result in loss of precision under the model or the distributional misspecifications. Using an example from a prostate cancer clinical trial, we show how a critical relationship between serum androgen biomarker and a prognostic factor of overall survival is completely missed by the widely used parametric Tobit model. Motivated by this example, we implement a semiparametric approach, through a pseudo‐value technique, that effectively captures the important relationship between the LOD restricted serum androgen and the prognostic factor. Our simulations show that the pseudo‐value based semiparametric model outperforms a commonly used parametric model for modeling below LOD biomarkers by having lower mean square errors of estimation. [ABSTRACT FROM AUTHOR]

Background: Retrospective analyses of randomized trials suggest that Black men with metastatic castration‐resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race. Methods: This race‐stratified, multicenter study estimated radiographic progression‐free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate‐specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome‐wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self‐identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients. Results: The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men. Conclusions: Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side‐effect rates than White men. This exploratory genome‐wide analysis of TTP identified a possible candidate marker of ancestry‐dependent treatment outcomes. This is the first prospective, race‐stratified study in advanced prostate cancer demonstrating important trends in outcomes previously only observed in retrospective reports. These results demonstrate the feasibility of this approach in a multicenter setting and establish important preliminary data with regard to differences in toxicity profiles and predictive biomarkers by race. [ABSTRACT FROM AUTHOR]

A major emphasis in precision medicine is to optimally treat subgroups of patients who may benefit from certain therapeutic agents. And as such, enormous resources and innovative clinical trials designs in oncology are devoted to identifying predictive biomarkers. Predictive biomarkers are ones that will identify patients that are more likely to respond to specific therapies and they are usually discovered through retrospective analysis from large randomized phase II or phase III trials. One important design to consider is the stratified biomarker design, where patients will have their specimens obtained at baseline and the biomarker status will be assessed prior to random assignment. Regardless of their biomarker status, patients will be randomized to either an experimental arm or the standard of care arm. The stratified biomarker design can be used to test for a treatment-biomarker interaction in predicting a time-to event outcome. Many biomarkers, however, are derived from tissues from patients, and their levels may be heterogeneous. As a result, biomarker levels may be measured with error and this would have an adverse impact on the power of a stratified biomarker clinical trial. We present a trial design and an analysis framework for the stratified biomarker design. We show that the naïve test is biased and provide bias-corrected estimators for computing the sample size and the 95% confidence interval when testing for a treatment-biomarker interaction in predicting a time to event outcome. We propose a sample size formula that adjusts for misclassification and apply it in the design of a phase III clinical trial in renal cancer. [ABSTRACT FROM AUTHOR]

Summary: Assuming the proportional hazards model and non‐informative censoring, the full likelihood approach is used to obtain two new residuals. The first residual is based on the ideas used in obtaining score‐type residuals similar to the partial likelihood approach. The second type of residual is based on the concept of deviance residuals. Extensive simulations are conducted to compare the performance of the residuals from the full likelihood‐based approach with those of the partial likelihood method. We demonstrate through simulation studies that the full likelihood‐based residuals are more efficient than their partial likelihood counterpart in identifying potential outliers when the censoring proportion is high. The graphical techniques are used to illustrate the applications of these residuals using some examples. [ABSTRACT FROM AUTHOR]

In a clinical trial comparing two treatment groups, one commonly-used endpoint is time to death. Another is time until the first nonfatal event (if there is one) or until death (if not). Both endpoints have drawbacks. The wrong choice may adversely affect the value of the study by impairing power if deaths are too few (with the first endpoint) or by lessening the role of mortality if not (with the second endpoint). We propose a compromise that provides a simple test based on the time to death if the patient has died or time since randomization augmented by an increment otherwise. The test applies the ordinary two-sample Wilcoxon statistic to these values. The formula for the increment (the same for experimental and control patients) must be specified before the trial starts. In the simplest (and perhaps most useful) case, the increment assumes only two values, according to whether or not the (surviving) patient had a nonfatal event. More generally, the increment depends on the time of the first nonfatal event, if any, and the time since randomization. The test has correct Type I error even though it does not handle censoring in a customary way. For conditions where investigators would face no easy (advance) choice between the two older tests, simulation results favor the new test. An example using a renal-cancer trial is presented. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

BACKGROUND The current study was conducted to investigate the dependence between progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) and to explore whether PFS can be used as an intermediate endpoint of OS in this patient population. METHODS A total of 1381 patients from 2 prospective phase 3 trials (Cancer and Leukemia Group B [CALGB] 90206 and AVOREN) of interferon-alpha with or without bevacizumab were analyzed. Both trials recruited previously untreated patients with clear cell mRCC with an Eastern Cooperative Oncology Group performance status of 0 to 2; adequate bone marrow, hepatic, cardiac, and renal function; and controlled blood pressure. The CALGB study served as the training data set, and the AVOREN study served as the testing data set. The dependence between PFS and OS was investigated using the Kendall tau for bivariate time-to-event endpoints. RESULTS In the training data set, the median OS times among patients who experienced progressive disease at 3 months or 6 months were 6 months and 8 months, respectively, compared with 25 months and 30 months, respectively, ( P < .001) in patients who did not develop disease progress. The adjusted hazard ratios (HR) were 2.6 ( P < .0001) and 2.8 ( P < .0001), respectively, for patients who did and did not progress at 3 months or 6 months. The dependence between PFS and OS was 0.53. These associations were confirmed in the testing data set. CONCLUSIONS In patients with mRCC who were treated with interferon-alpha with or without bevacizumab, the PFS at 3 months and 6 months was found to be predictive of OS. A high dependence between PFS and OS was observed, suggesting that PFS may be used as a surrogate endpoint for OS. Although this is a novel observation for RCC, these findings require validation in patients with mRCC who are treated with other targeted agents. Cancer 2014;120:52-60. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Prognosis plays a pivotal role in patient management and trial design. A useful prognostic model should correctly identify important risk factors and estimate their effects. In this article, we discuss several challenges in selecting prognostic factors and estimating their effects using the Cox proportional hazards model. Although a flexible semiparametric form, the Cox's model is not entirely exempt from model misspecification. To minimize possible misspecification, instead of imposing traditional linear assumption, flexible modeling techniques have been proposed to accommodate the nonlinear effect. We first review several existing nonparametric estimation and selection procedures and then present a numerical study to compare the performance between parametric and nonparametric procedures. We demonstrate the impact of model misspecification on variable selection and model prediction using a simulation study and an example from a phase III trial in prostate cancer. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel.Methods: In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm.Results: Baseline characteristics between patients who did (N=277) and did not (N=728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P=.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P=.342), the proportion achieving a decline ≥ 50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P=.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P=.366).Conclusions: As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC. [ABSTRACT FROM AUTHOR]

BACKGROUND: Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. METHODS: In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and predni-sone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. RESULTS: Baseline characteristics between patients who did (N = 277) and did not (N = 728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respec-tively; stratified log-rank P = .635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P = .342), the propor-tion achieving a decline >50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P = .129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P = .366). CONCLUSIONS: As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC [ABSTRACT FROM AUTHOR]

BACKGROUND: The treatment for prostate cancer patients with biochemical failure after local therapy remains controversial. Peripheral androgen blockade using a combination of a 5-alpha reductase inhibitor and an antiandrogen may allow control of the prostate-specific antigen (PSA). Because testosterone levels are not suppressed, this approach may be associated with less morbidity than conventional gonadal androgen suppression. METHODS: All patients had undergone previous definitive local therapy and had evidence of a rising PSA >1ng/mL, with no evidence of recurrent disease. Patients received both finasteride, 5 mg orally per day, and flutamide, 250 mg orally 3× a day. Patients were followed for a PSA response and quality of life assessment. RESULTS: Ninety-nine of 101 accrued patients were eligible. A ≥80% PSA decline was seen in 96 (96%) patients. The median time to PSA progression was 85 months. With a median follow-up of 10 years, the median survival time had not been reached, and the 5-year overall survival rate was 87%. Toxicity was mild, with 18 patients stopping for toxicity; 15 had diarrhea, 4 had gynecomastia, and 3 had transaminase elevation. Baseline Functional Assessment of Cancer Therapy Prostate Module and Treatment Outcome Index scores decreased by 5 points each at 6 months after enrollment. CONCLUSIONS: The use of the finasteride/flutamide combination is feasible, and results in PSA declines of ≥80% in 96% of patients with serologic progression after definitive local therapy. There were no unexpected toxicities, and the change in quality of life was mild. Further evaluation of this or a similar regimen in a controlled clinical trial is warranted. Cancer 2012. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

The analysis of case-control studies with matched controls per case is well documented in the medical literature. Of primary interest is the estimation of the relative risk of disease. Matched case-control studies fall into two scenarios: the probability of exposure is constant within each of the case and control groups, or the probability of exposure varies within each group. Numerous estimation procedures have been developed for both scenarios. Often these procedures are developed under the rare disease assumption, where the relative risk of disease is approximated by the odds ratio. In this paper, without making the rare disease assumption, we develop consistent estimators of the relative risk of disease for both scenarios. Exact derivations of the relative risk of disease are provided. Estimators, confidence intervals, and test statistics for the relative risk of disease are developed. We then make the following observations based on extensive simulations. First, our estimators are as close or closer to the relative risk of disease than other estimators. Second, our estimators produce mean square errors for the relative risk of disease that are as good as or better than these other estimators. Third, our confidence intervals provide accurate coverage probabilities. Therefore, these new estimators, confidence intervals, and test statistics can be used to either estimate or test the relative risk of disease in matched case-control studies. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

BACKGROUND: Combined transperineal prostate brachytherapy and external beam radiation therapy (EBRT) is widely used for treatment of prostate cancer. Long-term efficacy and toxicity results of a multicenter phase 2 trial assessing combination of EBRT and transperineal prostate brachytherapy boost with androgen deprivation therapy (ADT) for intermediate-risk prostate cancer are presented. METHODS: Intermediate-risk patients per Memorial Sloan-Kettering Cancer Center/National Comprehensive Cancer Network criteria received 6 months of ADT, and 45 grays (Gy) EBRT to the prostate and seminal vesicles, followed by transperineal prostate brachytherapy with I125 (100 Gy) or Pd103 (90 Gy). Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2 and Radiation Therapy Oncology Group late radiation morbidity scoring systems. Disease-free survival (DFS) was defined as time from enrollment to progression (biochemical, local, distant, or prostate cancer death). In addition to the protocol definition of biochemical failure (3 consecutive prostate-specific antigen rises >1.0 ng/mL after 18 months from treatment start), the 1997 American Society for Therapeutic Radiology and Oncology (ASTRO) consensus and Phoenix definitions were also assessed in defining DFS. The Kaplan-Meier method was used to estimate DFS and overall survival. RESULTS: Sixty-one of 63 enrolled patients were eligible. Median follow-up was 73 months. Late grade 2 and 3 toxicity, excluding sexual dysfunction, occurred in 20% and 3% of patients. Six-year DFS applying the protocol definition, 1997 ASTRO consensus, and Phoenix definitions was 87.1%, 75.1%, and 84.9%. Six deaths occurred; only 1 was attributed to prostate cancer. Six-year overall survival was 96.1%. CONCLUSIONS: In a cooperative setting, combination of EBRT and transperineal prostate brachytherapy boost plus ADT resulted in excellent DFS with acceptable late toxicity for patients with intermediate-risk prostate cancer. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: The use of docetaxel prolongs survival for patients with castrate-resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with bevacizumab may further enhance the antitumor effect of docetaxel and estramustine in patients with CRPC. METHODS: This cooperative group trial enrolled men with CRPC. Patients received oral estramustine 280 mg 3 times daily on Days 1 through 5 of every cycle plus 70 mg/m² docetaxel and 15 mg/kg bevacizumab on Day 2 every 3 weeks. Prostate-specific antigen (PSA) values were monitored every cycle, and imaging studies were obtained every 3 cycles. The primary endpoint was progression-free survival (PFS), and the secondary objectives were safety, PSA decline, measurable disease response, and overall survival. RESULTS: Seventy-nine patients were enrolled; and 77 patients received a median of 8 cycles and were evaluable. A 50% PSA decline was observed in 58 patients (75%). Twenty-three of 39 patients with measurable disease had a partial response (59%). The median PFS was 8 months, and the overall median survival was 24 months. Neutropenia without fever (69%), fatigue (25%), and thrombosis/emboli (9%) were the most common severe toxicities. Twenty-four of 77 patients were removed from protocol treatment because of disease progression, 35 of 77 patients were removed because of a physician or patient decision, and 15 patients were removed secondary to toxicity. CONCLUSIONS: The combination of docetaxel, estramustine, and bevacizumab was tolerable but complicated by toxicity. Although the endpoint of PFS did not meet the desired level, encouraging antitumor activity and overall survival were observed. Further phase 3 evaluation of the role of bevacizumab in CRPC is ongoing. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluates the safety and feasibility of radiotherapy after paclitaxel, estramustine phosphate and carboplatin (TEC) plus androgen therapy in previously treated prostate cancer patients. It mentions that patients with localized high-risk prostate cancer were treated with four cycles of paclitaxel in a period of 16 weeks. It affirms that the authors concluded that neoadjuvant chemohormonal therapy with TEC followed by high-dose radiation therapy is safe.

OBJECTIVE To conduct a phase II trial to determine the efficacy of cisplatin, a fixed dose-rate infusion of gemcitabine and gefitinib (an orally active epidermal growth factor receptor tyrosine kinase inhibitor) in patients with advanced urothelial carcinoma. PATIENTS AND METHODS Eligible patients had previously untreated measurable disease, an Eastern Cooperative Oncology Group performance status of 0–2 and creatinine clearance of >50 mL/min. The treatment regimen consisted of cisplatin 70 mg/m2 on day 1, gemcitabine 1000 mg/m2 on day 1 and 8, administered at a fixed dose rate of 10 mg/m2/min, given every 3 weeks concurrent with gefitinib 500 mg/day orally for a maximum of six cycles. Maintenance gefitinib 500 mg/day was continued for responding or stable disease. RESULTS In all, 27 patients were accrued before the study was halted because the dose-limiting toxicity (DLT) exceeded pre-established stopping rules. The DLT events were two grade 5 (one infection, one cardiovascular accident) and three with grade 4 non-haematological toxicity. In 25 evaluable patients there were nine objective responses, for an overall response rate of 36% (95% confidence interval, CI, 18–57%). The median (95% CI) survival time was 11.1 (5.2–35.3) months. CONCLUSION The combination of cisplatin, fixed dose-rate gemcitabine and gefitinib is active in advanced TCC, although the relative contribution of gefitinib cannot be determined. However, this regimen was associated with excessive toxicity. [ABSTRACT FROM AUTHOR]

The article focuses on a study that aims to evaluate the correlation between an elevated body mass index (BMI) and clinical outcomes in patients with metastatic, castration-recurrent prostate cancer (CRPC). It cites the association between obesity and the risk of certain malignancies such as colon cancer and renal cell carcinoma. It concludes that patients with metastatic CRPC, obesity appears to have a protective effect against overall mortality and prostate cancer-specific mortality.

Ahnn and Anderson derived sample size formulae for unstratified and stratified designs assuming equal allocation of subjects to three or more treatment groups. We generalize the sample size formulae to allow for unequal allocation. In addition, we define the overall probability of death to be equal to one minus the censored proportion for the stratified design. This definition also leads to a slightly different definition of the non-centrality parameter than that of Ahnn and Anderson for the stratified case. Assuming proportional hazards, sample sizes are determined for a prespecified power, significance level, hazard ratios, allocation of subjects to several treatment groups, and known censored proportion. In the proportional hazards setting, three cases are considered: (1) exponential failures-exponential censoring, (2) exponential failures-uniform censoring, and (3) Weibull failures (assuming same shape parameter for all groups)-uniform censoring. In all three cases of the unstratified case, it is assumed that the censoring distribution is the same for all of the treatment groups. For the stratified log-rank test, it is assumed the same censoring distribution across the treatment groups and the strata. Further, formulae have been developed to provide approximate powers for the test, based upon the first two or first four-moments of the asymptotic distribution. We observe the following two major findings based on the simulations. First, the simulated power of the log-rank test does not depend on the censoring mechanism. Second, for a significance level of 0.05 and power of 0.80, the required sample size n is independent of the censoring pattern. Moreover, there is very close agreement between the exact (asymptotic) and simulated powers when a sequence of alternatives is close to the null hypothesis. Two-moment and four-moment power series approximations also yield powers in close agreement with the exact (asymptotic) power. With unequal allocations, our simulations show that the empirical powers are consistently above the target value of prespecified power of 0.80 when 50 per cent of the patients are allocated to the treatment group with the smallest hazard. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACTObjectives: To explore whether serum prostate specific antigen (PSA) decline can be used as a prognostic factor for survival among patients with androgen-independent prostate cancer (AIPC) who are treated with a secondary hormonal therapy, megestrol acetate. Materials and Methods: One hundred forty-nine patients were randomized with equal probability to either low-dose (160 mg/day) or high-dose (640 mg/day) megestrol acetate. Patients were stratified on performance status (0–1, or 2) and on disease measurability (measurable, or evaluable disease). Results: Patients with high pretreatment PSA (≥95 ng/ml) had worse survival times than patients with low PSA (<95), with a hazard ratio of 1.6 (p = 0.003). The median survival times for patients with a ≥50% reduction in PSA at 8 weeks and those patients without a 50% reduction were 15 and 11 months, respectively (p = 0.763). A landmark analysis at 8 weeks showed that a PSA decline was significantly associated with survival. The survival time for patients whose PSA dropped below the pretreatment levels (median = 15 months) were significantly longer than for patients who did not have a decline in PSA (median = 9 months, p = 0.031). Similar significant results were observed between PSA reduction and survival when landmark analyses were performed at 12 and 16 weeks. PSA changes during the first 45 days after the initiation of therapy were significantly related to survival. The median survival time for patients whose PSA doubled during the first 45 days after treatment and for patients whose PSA did not double during the first 45 days were 10 and 14 months, respectively (p = 0.020). Conclusions: PSA decline is significantly associated with longer survival times in prostate patients treated with secondary hormonal manipulation. Longer survival time is observed among the following AIPC patients: 1) those whose pretreatment PSA were <95 ng/ml: 2) those whose PSA decline was >0% from baseline; and... [ABSTRACT FROM AUTHOR]

Few studies have examined the impact of abnormal mammograms on subsequent mammography screening and psychosocial outcomes specifically as a function of the length of time that has passed since the abnormal test result. This cross-sectional report compared breast cancer screening practices and psychosocial outcomes among three groups of women. These groups were women who (1) never had an abnormal mammogram, (2) had an abnormal mammogram 2 or more years prior to the study's baseline interview, and (3) had an abnormal mammogram within 2 years prior to the study's baseline interview. Women who had an abnormal mammogram at least 2 years prior to the baseline interview expressed greater 10-year and lifetime risks of getting breast cancer than women who never had an abnormal mammogram. Women who had abnormal mammograms, independent of when they occurred, were substantially more worried about getting breast cancer than were women who never had abnormal mammograms. Women who had an abnormal mammogram within 2 years prior to the baseline interview were more likely to be on schedule for mammography, compared with women who never had an abnormal mammogram. Copyright © 2000 John Wiley & Sons, Ltd. These results suggest that (1) few differences exist in perceived breast cancer risk and worry as a function of when an abnormal mammogram occurred, and (2) subsequent screening behavior is most affected by whether an abnormal mammogram occurred within 2 years from the interview. Not surprisingly, more recent experiences of abnormal mammograms had a greater influence on behavior. [ABSTRACT FROM AUTHOR]

Identifying exceptional responders or nonresponders is an area of increased research interest in precision medicine as these patients may have different biological or molecular features and therefore may respond differently to therapies. Our motivation stems from a real example from a clinical trial where we are interested in characterizing exceptional prostate cancer responders. We investigate the outlier detection and robust regression problem in the sparse proportional hazards model for censored survival outcomes. The main idea is to model the irregularity of each observation by assigning an individual weight to the hazard function. By applying a LASSO‐type penalty on both the model parameters and the log transformation of the weight vector, our proposed method is able to perform variable selection and outlier detection simultaneously. The optimization problem can be transformed to a typical penalized maximum partial likelihood problem and thus it is easy to implement. We further extend the proposed method to deal with the potential outlier masking problem caused by censored outcomes. The performance of the proposed estimator is demonstrated with extensive simulation studies and real data analyses in low‐dimensional and high‐dimensional settings. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Progression-free survival: does a correlation with survival justify its role as a surrogate clinical endpoint?" by A. Becker and colleagues in a 2014 issue.

Diagnostic accuracy can be improved considerably by combining multiple biomarkers. Although the likelihood ratio provides optimal solution to combination of biomarkers, the method is sensitive to distributional assumptions which are often difficult to justify. Alternatively simple linear combinations can be considered whose empirical solution may encounter intensive computation when the number of biomarkers is relatively large. Moreover, the optimal linear combinations derived under multivariate normality may suffer substantial loss of efficiency if the distributions are apart from normality. In this paper, we propose a new approach that linearly combines the minimum and maximum values of the biomarkers. Such combination only involves searching for a single combination coefficient that maximizes the area under the receiver operating characteristic (ROC) curves and is thus computation-effective. Simulation results show that the min-max combination may yield larger partial or full area under the ROC curves and is more robust against distributional assumptions. The methods are illustrated using the growth-related hormones data from the Growth and Maturation in Children with Autism or Autistic Spectrum Disorder Study (Autism/ASD Study). Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Summary: The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for "intercurrent" events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions ("does the drug delay recurrence if no patient had received subsequent therapy?" vs "does the drug delay recurrence with or without subsequent therapy?" vs "does the drug delay recurrence or start of subsequent therapy?"). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross‐industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation. [ABSTRACT FROM AUTHOR]

BACKGROUND Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE); however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on the factors that increase the risk of ATE/VTE in patients with prostate cancer. The authors investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients who were treated on Cancer and Leukemia Group B (CALGB) trial 90401. METHODS Patients with metastatic, castration-resistant prostate cancer were randomized to receive docetaxel and prednisone with or without bevacizumab once every 21 days. Cycle-to-event Cox regression models were used to investigate the association of bevacizumab with the incidence of grade 3 or greater (≥3) ATE and VTE. Age, prior ATE/VTE, baseline antiplatelet/anticoagulant use, and VTE risk score (based on leukocyte count, hemoglobin, platelet count, body mass index, and tumor location) were evaluated in univariate and multivariable analyses. RESULTS Of 1008 randomized patients, the odds of experiencing grade ≥3 ATE were significantly greater in those who received bevacizumab compared with those who received placebo (odds ratio, 2.79; P = .02), whereas an opposite trend was noted for grade ≥3 VTE (odds ratio, 0.60; P = .08). In the multivariable analysis, bevacizumab treatment (hazard ratio [HR], 3.00; P = .01) and age (HR, 1.06; P = .02) were significantly associated with the risk of ATE; whereas age (HR, 1.05; P = .01) and VTE risk score (HR, 1.83; P = .03) were significantly associated with the risk of VTE. CONCLUSIONS Bevacizumab was significantly associated with a greater risk of ATE in patients with metastatic, castration-resistant prostate cancer, but it was not significantly associated with the risk of VTE. Understanding clinical factors that increase the risk for experiencing ATE/VTE is essential to mitigate the risks and reduce the burden of these prevalent complications in cancer care. Cancer 2015;121:1025-1031. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Clinical trials utilizing predictive biomarkers have become a research focus in personalized medicine. We investigate the effects of biomarker misclassification on the design and analysis of stratified biomarker clinical trials. For a variety of inference problems including marker-treatment interaction in particular, we show that marker misclassification may have profound adverse effects on the coverage of confidence intervals, power of the tests, and required sample sizes. For each inferential problem, we propose methods to adjust for the classification errors. [ABSTRACT FROM AUTHOR]

Background: The treatment for prostate cancer patients with biochemical failure after local therapy remains controversial. Peripheral androgen blockade using a combination of a 5-alpha reductase inhibitor and an antiandrogen may allow control of the prostate-specific antigen (PSA). Because testosterone levels are not suppressed, this approach may be associated with less morbidity than conventional gonadal androgen suppression.Methods: All patients had undergone previous definitive local therapy and had evidence of a rising PSA >1ng/mL, with no evidence of recurrent disease. Patients received both finasteride, 5 mg orally per day, and flutamide, 250 mg orally 3× a day. Patients were followed for a PSA response and quality of life assessment.Results: Ninety-nine of 101 accrued patients were eligible. A ≥80% PSA decline was seen in 96 (96%) patients. The median time to PSA progression was 85 months. With a median follow-up of 10 years, the median survival time had not been reached, and the 5-year overall survival rate was 87%. Toxicity was mild, with 18 patients stopping for toxicity; 15 had diarrhea, 4 had gynecomastia, and 3 had transaminase elevation. Baseline Functional Assessment of Cancer Therapy Prostate Module and Treatment Outcome Index scores decreased by 5 points each at 6 months after enrollment.Conclusions: The use of the finasteride/flutamide combination is feasible, and results in PSA declines of ≥80% in 96% of patients with serologic progression after definitive local therapy. There were no unexpected toxicities, and the change in quality of life was mild. Further evaluation of this or a similar regimen in a controlled clinical trial is warranted. [ABSTRACT FROM AUTHOR]

Background: Combined transperineal prostate brachytherapy and external beam radiation therapy (EBRT) is widely used for treatment of prostate cancer. Long-term efficacy and toxicity results of a multicenter phase 2 trial assessing combination of EBRT and transperineal prostate brachytherapy boost with androgen deprivation therapy (ADT) for intermediate-risk prostate cancer are presented.Methods: Intermediate-risk patients per Memorial Sloan-Kettering Cancer Center/National Comprehensive Cancer Network criteria received 6 months of ADT, and 45 grays (Gy) EBRT to the prostate and seminal vesicles, followed by transperineal prostate brachytherapy with I125 (100 Gy) or Pd103 (90 Gy). Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2 and Radiation Therapy Oncology Group late radiation morbidity scoring systems. Disease-free survival (DFS) was defined as time from enrollment to progression (biochemical, local, distant, or prostate cancer death). In addition to the protocol definition of biochemical failure (3 consecutive prostate-specific antigen rises>1.0 ng/mL after 18 months from treatment start), the 1997 American Society for Therapeutic Radiology and Oncology (ASTRO) consensus and Phoenix definitions were also assessed in defining DFS. The Kaplan-Meier method was used to estimate DFS and overall survival.Results: Sixty-one of 63 enrolled patients were eligible. Median follow-up was 73 months. Late grade 2 and 3 toxicity, excluding sexual dysfunction, occurred in 20% and 3% of patients. Six-year DFS applying the protocol definition, 1997 ASTRO consensus, and Phoenix definitions was 87.1%, 75.1%, and 84.9%. Six deaths occurred; only 1 was attributed to prostate cancer. Six-year overall survival was 96.1%.Conclusions: In a cooperative setting, combination of EBRT and transperineal prostate brachytherapy boost plus ADT resulted in excellent DFS with acceptable late toxicity for patients with intermediate-risk prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The use of docetaxel prolongs survival for patients with castrate-resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with bevacizumab may further enhance the antitumor effect of docetaxel and estramustine in patients with CRPC.Methods: This cooperative group trial enrolled men with CRPC. Patients received oral estramustine 280 mg 3 times daily on Days 1 through 5 of every cycle plus 70 mg/m² docetaxel and 15 mg/kg bevacizumab on Day 2 every 3 weeks. Prostate-specific antigen (PSA) values were monitored every cycle, and imaging studies were obtained every 3 cycles. The primary endpoint was progression-free survival (PFS), and the secondary objectives were safety, PSA decline, measurable disease response, and overall survival.Results: Seventy-nine patients were enrolled; and 77 patients received a median of 8 cycles and were evaluable. A 50% PSA decline was observed in 58 patients (75%). Twenty-three of 39 patients with measurable disease had a partial response (59%). The median PFS was 8 months, and the overall median survival was 24 months. Neutropenia without fever (69%), fatigue (25%), and thrombosis/emboli (9%) were the most common severe toxicities. Twenty-four of 77 patients were removed from protocol treatment because of disease progression, 35 of 77 patients were removed because of a physician or patient decision, and 15 patients were removed secondary to toxicity.Conclusions: The combination of docetaxel, estramustine, and bevacizumab was tolerable but complicated by toxicity. Although the endpoint of PFS did not meet the desired level, encouraging antitumor activity and overall survival were observed. Further phase 3 evaluation of the role of bevacizumab in CRPC is ongoing. [ABSTRACT FROM AUTHOR]