Kristian Stensland

Adverse Event Reporting in Cancer Clinical Trial Publications

PURPOSE Reporting adverse events is a critical element of a clinical trial publication. In 2003, the Consolidated Standards of Reporting Trials (CONSORT) group generated recommendations regarding the appropriate reporting of adverse events. The degree to which these recommendations are followed in oncology publications has not been comprehensively evaluated. METHODS A review of citations from PubMed, Medline, and Embase published between Jan 1, 2009 and December 31, 2011, identified eligible randomized, controlled phase III trials in metastatic solid malignancies. Publications were assessed for 14 adverse event-reporting elements derived from the CONSORT harms extension statement; a completeness score (range, 0 to 14) was calculated by adding the number of elements reported. Linear regression analysis identified which publication characteristics associated with reporting completeness. RESULTS A total of 175 publications, with data for 96,125 patients, were included in the analysis. The median completeness score was eight (range, three to 12). Most publications (96%) reported only adverse events occurring above a threshold rate or severity, 37% did not specify the criteria used to select which adverse events were reported, and 88% grouped together adverse events of varying severity. Regression analysis revealed that trials without a stated funding source and with an earlier year of publication had significantly lower completeness scores. CONCLUSION Reporting of adverse events in oncology publications of randomized trials is suboptimal and characterized by substantial selectivity and heterogeneity. The development of oncology-specific standards for adverse event reporting should be established to ensure consistency and provide critical information required for medical decision-making.

Effectiveness of Adjuvant Chemotherapy for Locally Advanced Bladder Cancer

PURPOSE Given that randomized trials exploring adjuvant chemotherapy for bladder cancer have been underpowered and/or terminated prematurely, yielding inconsistent results and creating an evidence gap, we sought to compare the effectiveness of cystectomy versus cystectomy plus adjuvant chemotherapy in real-world patients. PATIENTS AND METHODS We conducted an observational study to compare the effectiveness of adjuvant chemotherapy versus observation postcystectomy in patients with pathologic T3-4 and/or pathologic node-positive bladder cancer using the National Cancer Data Base. We compared overall survival using propensity score (-adjusted, -stratified, -weighted, and -matched) analyses based on patient-, facility-, and tumor-level characteristics. A sensitivity analysis was performed to examine the impact of performance status. RESULTS A total of 5,653 patients met study inclusion criteria; 23% received adjuvant chemotherapy postcystectomy. Chemotherapy-treated patients were younger and more likely to have private insurance, live in areas with a higher median income and higher percentage of high school-educated residents, and have lymph node involvement and positive surgical margins (P < .05 for all comparisons). Stratified analyses adjusted for propensity score demonstrated an improvement in overall survival with adjuvant chemotherapy (hazard ratio, 0.70; 95% CI, 0.64 to 0.76), and similar results were achieved with propensity score matching and weighting. The association between adjuvant chemotherapy and improved survival was consistent in subset analyses and was robust to the effects of poor performance status. CONCLUSION In this observational study, adjuvant chemotherapy was associated with improved survival in patients with locally advanced bladder cancer. Although neoadjuvant chemotherapy remains the preferred approach based on level I evidence, these data lend further support for the use of adjuvant chemotherapy in patients with locally advanced bladder cancer postcystectomy who did not receive chemotherapy preoperatively.

Neoadjuvant Chemotherapy in Patients with Muscle-invasive Bladder Cancer: Which Patients Benefit?

Level I evidence supports neoadjuvant chemotherapy in the treatment of advanced bladder cancer. For the most benefit, it is suggested that neoadjuvant chemotherapy be restricted to patients with clinical T3 disease and/or clinical N+ disease.

Adult Cancer Clinical Trials That Fail to Complete: An Epidemic?

The number and diversity of cancer therapeutics in the pipeline has increased over the past decade due to an enhanced understanding of cancer biology and the identification of novel therapeutic targets. At the same time, the cost of bringing new drugs to market and the regulatory burdens associated with clinical drug development have progressively increased. The finite number of eligible patients and limited financial resources available to evaluate promising new therapeutics represent rate-limiting factors in the effort to translate preclinical discoveries into the next generation of standard therapeutic approaches. Optimal use of resources requires understanding and ultimately addressing inefficiencies in the cancer clinical trials system. Prior analyses have demonstrated that a large proportion of trials initiated by the National Cancer Institute (NCI) Cooperative Group system are never completed. While NCI Cooperative Group trials are important, they represent only a small proportion of all cancer clinical trials performed. Herein, we explore the problem of cancer clinical trials that fail to complete within the broader cancer clinical trials enterprise. Among 7776 phase II-III adult cancer clinical trials initiated between 2005-2011, we found a seven-year cumulative incidence of failure to complete of approximately 20% (95% confidence interval = 18% to 22%). Nearly 48000 patients were enrolled in trials that failed to complete. These trials likely contribute little to the scientific knowledge base, divert resources and patients from answering other critical questions, and represent a barrier to progress.

Comparative Effectiveness of Treatment Strategies for Bladder Cancer With Clinical Evidence of Regional Lymph Node Involvement

PURPOSE Patients with bladder cancer with clinical lymph node involvement (cN+) are at high risk for distant metastases, but are potentially curable. Such patients are excluded from neoadjuvant chemotherapy trials and pooled with patients with distant metastases in first-line chemotherapy trials not suited to define the role of combined-modality therapy. To address this evidence void, we performed a comparative effectiveness analysis. METHODS We included cTanyN1-3M0 bladder cancer patients from the National Cancer Data Base (2003-2012) treated with chemotherapy and/or cystectomy. We used multistate survival analysis, allowing for delayed entry, to assess overall survival (OS) according to various treatment strategies. Effectiveness was estimated with multivariable adjustment for tumor-, patient-, and facility-level characteristics. RESULTS Among 1,739 patients (cN1, 48%; cN2, 45%; cN3, 7%), 1,104 underwent cystectomy and 635 were treated with chemotherapy alone. Of the cystectomy patients, 363 received preoperative and 328 received adjuvant chemotherapy. The crude 5-year OS for chemotherapy alone, cystectomy alone, preoperative chemotherapy followed by cystectomy, and cystectomy followed by adjuvant chemotherapy was 14% (95% CI, 11% to 17%), 19% (95% CI, 15% to 24%), 31% (95% CI, 25% to 38%), and 26% (95% CI, 21% to 34%), respectively. Compared with cystectomy alone, preoperative chemotherapy was associated with a significant improvement in OS (hazard ratio, 0.80; 95% CI, 0.66 to 0.97). Adjuvant chemotherapy was also associated with a significant improvement in survival compared with cystectomy alone. The survival of patients treated with chemotherapy alone was worse than those treated with cystectomy alone. CONCLUSION A subset of patients with cN+ bladder cancer achieves long-term survival. Combined-modality therapy, with chemotherapy and cystectomy, is associated with the best outcomes.

Decisional regret after robotic-assisted laparoscopic prostatectomy is higher in African American men

OBJECTIVES Longitudinal studies report racial disparities in prostate cancer (PCa) including greater incidence, more aggressive tumor biology, and increased cancer-specific mortality in African American (AA) men. Regret concerning primary treatment selection is underevaluated in patients with PCa. We investigated the relationships between clinicopathologic variables across racial and socioeconomic lines following robotic-assisted laparoscopic prostatectomy. MATERIALS AND METHODS We assessed treatment decisional regret using a validated questionnaire in a total of 484 white and 72 AA patients with PCa who were followed up for a median of 16.6 months post-robotic-assisted laparoscopic prostatectomy. Socioeconomic status (SES) information was aggregated from 2010 US census zip code data. Perioperative clinicopathologic characteristics and functional outcomes were compared between groups. Univariate and multivariate regression analyses were used to evaluate the influence of race, aggregate SES, and other clinical and demographic characteristics on decisional regret. RESULTS The majority (87.7%) of the population was not regretful of their decision to undergo treatment. However, a greater proportion of AA vs. white patients were regretful (20.6% vs. 11.2%, respectively; P = 0.03). AA and white men were similar on all functional, clinical, and pathologic features with the exception of younger age among AA men (56 vs. 60 y, respectively; P<0.001). Although there were significant differences in SES by race (P<0.001), regret did not differ by SES (β =-1.53; P = 0.15). Race, postoperative sexual dysfunction, pad usage, and length of hospital stay, however, were significantly associated with decisional regret. CONCLUSIONS AA men were more regretful than white men, after adjusting for clinicopathologic characteristics and postoperative functional outcomes.

Robotic-assisted laparoscopic prostatectomy in men with metabolic syndrome.

OBJECTIVES Metabolic syndrome (MetS), the constellation of obesity and related risk factors for cardiovascular disease, is an expanding epidemiologic concern in the United States and the developed world. However, the relationship between MetS and prostate cancer remains to be definitively assessed. We evaluated the association between obesity and MetS with prostate cancer pathology and surgical and functional outcomes. MATERIALS AND METHODS A total of 2,639 patients underwent robotic-assisted laparoscopic prostatectomy (RALP) for localized prostate cancer between March 2003 and July 2012. Of them, 186 patients met the criteria for MetS as defined by the presence of obesity (body mass index [BMI] ≥ 30 kg/m(2)) in conjunction with 2 or more of the following: hypertension (HTN), dyslipidemia (D), and diabetes (DM). Additionally, reference cohorts of (1) 663 nonobese men without HTN, D, or DM; (2) 184 obese patients without HTN, D, or DM; and (3) 211 obese men with solitary risk factors were identified for comparison. Demographic, histopathologic, and perioperative clinical parameters were compared. RESULTS In comparison with patients without MetS, patients with MetS had larger prostates (Odds Ratio (OR) = 1.609, 95% Confidence Interval (CI) = 1.04-2.49, P = 0.03), increased blood loss (OR = 1.592, 95% CI = 1.15-2.21, P = 0.01), and surgical complexity (OR = 4.940, 95% CI = 2.29-10.69, P<0.001). There was no statistical difference observed between these groups in regard to complication rates, pathologic grade, stage, and postoperative continence or erectile function. With the exception of larger prostates found among men with MetS, men with obesity alone and obesity with 1 additional risk factor appeared similar to those with MetS. CONCLUSIONS Patients with MetS had similar perioperative, histopathologic, and functional outcomes compared with reference cohorts undergoing RALP. RALP is safe, feasible, and efficacious in men with MetS.

The Relationship between Centralization of Care and Geographic Barriers to Cystectomy for Bladder Cancer.

Background: Centralization of cystectomy treatment for bladder cancer, while associated with improved outcomes, may impose geographic barriers to care. However, whether this effect may be counterbalanced by an increased number of high volume centers has not previously been explored. Objective: To characterize changes in geographic disparities to high volume cystectomy centers over time. Methods: Data on all inpatient admissions for cystectomy in New York State (NYS) from 1997–2011 was obtained from the Department of Health. Using these data, we classified hospitals according to cystectomy volume and measured patient distance traveled to a cystectomy center. Population weights, from the US Census, were used to describe changes in minimum travel distance to high- or very high-volume (HV/VHV) facilities across the NYS population. Results: Bladder cancer patients underwent cystectomies at 195 hospitals during the study period. In 1997–2001, eleven HV/VHV facilities accounted for 37.5% of all cystectomies, while sixteen HV/VHV hospitals accounted for 71.5% of all procedures during 2007–2011. Median distance traveled by cystectomy patients to all hospitals increased from 9.6 to 14.4 miles in 1997–2001 to 2007–2011, respectively. In the same time span, the median travel distance for the NYS population to a HV/VHV center decreased by 1.9 and 9.4 miles at the median and 75th percentile, respectively. Conclusions: Our findings demonstrate a complicated relationship between centralization and geographic access. While centralization has led to a decrease in overall access to cystectomy facilities, the process simultaneously improved access to high volume centers.

Geographic accessibility to clinical trials for advanced cancer in the United States.

Geographic Accessibility to Clinical Trials for Advanced Cancer in the United States Clinical trials yield critical evidence to guide the care of patients with cancer. According to commonly used practice guidelines, “...the best management of any cancer patient is in a clinical trial.”1 Nonetheless, only about 2% to 7% of US adult patients with cancer participate in clinical trials.2 Poor accrual to clinical trials has far-reaching implications in the way it affects the pace of progress, cost of drug development, and generalizability of study findings. Prior studies exploring trial enrollment have identified several barriers.3 However, geographic barriers to participation in clinical trials remain underexplored. A survey of patients with cancer revealed that most were not willing to travel for trial participation.4 We sought to estimate the geographic accessibility of clinical trials for advanced cancer in the United States.

Circumcision on the web: a comparison of quality, content, and bias online.

OBJECTIVE In 2012, the American Academy of Pediatrics (AAP) newborn circumcision policy statement expressed that although benefits outweigh risks, final decisions lie with parents. Although health information on the Internet is plentiful, the quality and availability of information on circumcision, including dissemination of AAP and AUA policy statements, is unknown. We analyzed English and Spanish circumcision websites to evaluate their overall quality, detail, accuracy, and bias. METHODS In April 2013, three search engines were queried for English and Spanish circumcision websites, which were analyzed utilizing the DISCERN Plus scale for content quality as well as additional study-specific criteria. RESULTS We analyzed 214 websites (141 English, 73 Spanish). Most websites in both languages had very good content quality and were neutral regarding circumcision. Regardless of language, only 21% of sites mentioned the updated AAP guidelines. Surprisingly, the AUA circumcision policy statement did not appear in the top results. Spanish sites were more likely to give good descriptions of circumcision procedures than English sites (p < 0.04), less likely to cite sources (p < 0.01), and more likely to describe benefits (p = 0.02).. CONCLUSIONS Newborn circumcision information on the Internet is of very good quality, but different English and Spanish characteristics possibly reflect cultural bias, which may explain the disparate rates of circumcision between different groups in the USA. The AAPs circumcision policy statement was referenced by a minority (20%) of websites, and AUAs policy statement was not even part of the top results. The AUA should have a more active role in providing accurate and comprehensive online information to parents regarding circumcision.