Faculty Bibliography

INTRODUCTION: Although most seriously ill Americans wish to avoid burdensome and aggressive care at the end of life, such care is often provided unless patients or family members specifically request otherwise. Advance directives (ADs) were created to provide opportunities to set limits on aggressive care near life's end. This study tests the hypothesis that redesigning ADs such that comfort-oriented care is provided as the default, rather than requiring patients to actively choose it, will promote better patient-centred outcomes. METHODS AND ANALYSIS: This multicentre trial randomises seriously ill adults to receive 1 of 3 different ADs: (1) a traditional AD that requires patients to actively choose their goals of care or preferences for specific interventions (eg, feeding tube insertion) or otherwise have their care guided by their surrogates and the prevailing societal default toward aggressive care; (2) an AD that defaults to life-extending care and receipt of life-sustaining interventions, enabling patients to opt out from such care; or (3) an AD that defaults to comfort care, enabling patients to opt into life-extending care. We seek to enrol 270 patients who return complete, legally valid ADs so as to generate sufficient power to detect differences in the primary outcome of hospital-free days (days alive and not in an acute care facility). Secondary outcomes include hospital and intensive care unit admissions, costs of care, hospice usage, decision conflict and satisfaction, quality of life, concordance of preferences with care received and bereavement outcomes for surrogates of patients who die. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Boards at all trial centres, and is guided by a data safety and monitoring board and an ethics advisory board. Study results will be disseminated using methods that describe the results in ways that key stakeholders can best understand and implement. TRIAL REGISTRATION NUMBER: NCT02017548; Pre-results.

Sorafenib has an antitumor activity in patients with radioactive iodine-refractory differentiated thyroid carcinoma (RAIR-DTC). Prior research has implicated signaling through the MAPK and AKT/PI3K pathways in the progression of DTC. To assess whether the activity of these pathways is predictive of response to sorafenib, we retrospectively studied molecular tumor markers from these two pathways from a phase 2 study of sorafenib in RAIR-DTC. Tumor samples from 40 of 53 DTC subjects obtained prior to initiation of sorafenib were immunostained with DAB-labeled antibodies to phospho-AKT (pAKT), phospho-ERK (pERK), and phospho-S6 (pS6). BRAFV600E genetic mutation analysis was performed on all samples. Expression levels and mutational status were compared to response and progression-free survival (PFS) for each patient. Low tumor expression of nuclear pAKT was associated with partial response to sorafenib (p < 0.01). Patients with nuclear pAKT expression that was below the median for our sample were more than three times as likely to have a partial response as patients with equal to or above median expression. There was no correlation between tumor expression of nuclear pERK or pS6 and response. Endothelial cell and pericyte expression of pERK, pAKT, and pS6 were not predictive of response. There was no correlation between BRAFV600E mutation status and partial response. No correlation was observed between either the expression of pAKT, pERK, or pS6, or the presence of the BRAFV600E mutation, and PFS. In conclusion, lower tumor expression of nuclear pAKT was associated with higher rate of response to sorafenib. This observation justifies evaluation of combination therapy with sorafenib and an inhibitor of the PI3K/AKT signaling pathway in RAIR-DTC.

PURPOSE: Reporting of adverse events (AEs) in clinical trials is critical to understanding treatment safety, but data on AE accuracy are limited. This study sought to determine the accuracy of AE reporting for pediatric acute myeloid leukemia clinical trials and to test whether an external electronic data source can improve reporting. METHODS: Reported AEs were evaluated on two trials, Children's Oncology Group AAML03P1 and AAML0531 arm B, with identical chemotherapy regimens but with different toxicity reporting requirements. Chart review for 12 AEs for patients enrolled in AAML0531 at 14 hospitals was the gold standard. The sensitivity and positive predictive values (PPV) of the AAML0531 AE report and AEs detected by review of Pediatric Health Information System (PHIS) billing and microbiology data were compared with chart data. RESULTS: Select AE rates from AAML03P1 and AAML0531 arm B differed significantly and correlated with the targeted toxicities of each trial. Chart abstraction was performed on 204 patients (758 courses) on AAML0531. AE report sensitivity was < 50% for eight AEs, but PPV was > 75% for six AEs. AE reports for viridans group streptococcal bacteremia, a targeted toxicity on AAML0531, had a sensitivity of 78.3% and PPV of 98.1%. PHIS billing data had higher sensitivity (> 50% for nine AEs), but lower PPV (< 75% for 10 AEs). Viridans group streptococcal detection using PHIS microbiology data had high sensitivity (92.3%) and PPV (97.3%). CONCLUSION: The current system of AE reporting for cooperative oncology group clinical trials in pediatric acute myeloid leukemia underestimates AE rates. The high sensitivity and PPV of PHIS microbiology data suggest that using external data sources may improve the accuracy of AE reporting.

PURPOSE: Incidence of head and neck cancer (HNC) due to human papillomavirus (HPV) infection has been increasing. Treatment regimens have evolved. These changes might result in alterations of assumed treatment-related weight changes for HNC patients. We aimed to compare the trajectory of pre- to post-treatment weight changes of oropharyngeal squamous cell carcinoma (OPSCC) versus oral cavity squamous cell carcinoma (OCSCC) patients and to compare weight changes between patients with primary surgery +/- adjuvant therapy to patients with primary radiation and/or chemotherapy. METHODS: This retrospective cohort study examined adult OPSCC and OCSCC patients with initial definitive treatment at the University of Pennsylvania from January 1, 2009 to December 31, 2010. Patient demographics, medical history, treatments, and pre- and post-treatment body weight data were collected from electronic medical records. Mixed-effects modeling was performed. RESULTS: Among 354 patients who met the inclusion criteria, 290 (82 %) survivors were available for inclusion by 24-month follow-up. More than 70 % OPSCC and OCSCC patients were overweight or obese at all pre- and post-treatment time points. The average weight among OPSCC patients was 6.63 kg higher than OCSCC patients at all time points (mean = 6.63, 95 % confidence interval (CI), 2.46-10.79, p = 0.002). After adjusting for potential confounders, patients with primary surgery had significantly more weight gain from pre-treatment to 12-18 month post-treatment follow-up as compared to patients with primary radiation and/or chemotherapy (adjusted mean = 4.01, 95 % CI, 0.16-7.87, p = 0.041). CONCLUSION: Overweight and obesity may be a new challenge in OPSCC and OCSCC patient care. Further study is needed to evaluate whether exercise and nutritional interventions can improve their survivorship.

BACKGROUND: Medication nonadherence is an important obstacle to cardiovascular disease management. OBJECTIVE: To improve adherence through real-time feedback based on theories of how social forces influence behavior. DESIGN: Two randomized controlled pilot trials called PROMOTE and SUPPORT. Participants stored statin medication in wireless-enabled pill bottles that transmitted adherence data to researchers. PARTICIPANTS: Adults with diabetes and a history of low statin adherence based on pharmacy refills (i.e., Medication Possession Ratio [MPR] <80% in the pre-randomization screening period). INTERVENTION: In PROMOTE, each participant was randomized to 1) weekly messages in which that participant's statin adherence was compared to that of other participants (comparison), 2) weekly summaries of that participant's statin adherence (summary), or 3) control. In SUPPORT, each participant identified another person (the Medication Adherence Partner [MAP]) to receive reports about that participant's adherence, and was randomized to 1) daily reports to MAP, 2) weekly reports to MAP, 3) reports to MAP only if dose was missed, or 4) control. MAIN OUTCOMES MEASURE: Adherence measured by pill bottle. KEY RESULTS: Among 45,000 health plan members contacted by mail, <1% joined the trial. Participants had low baseline MPRs (median = 60%, IQR 41-72%) but high pill-bottle adherence (90% in PROMOTE, 92% in SUPPORT) during the trial. In PROMOTE (n = 201) and SUPPORT (n = 200), no intervention demonstrated significantly better adherence vs. CONTROL: In a subgroup of PROMOTE participants with the lowest pre-study MPR, pill-bottle-measured adherence in the comparison arm (89%) was higher than the control (86%) and summary (76%) arms, but differences were non-significant (p = 0.10). CONCLUSIONS: Interventions based on social forces did not improve medication adherence vs. control over a 3-month period. Given the low percentage of invited individuals who enrolled, the studies may have attracted participants who required little encouragement to improve adherence other than study participation.

BACKGROUND: Observational studies indicate that higher volumes of physical activity are associated with improved disease outcomes among colon cancer survivors. The aim of this report is to describe the purpose, study design, methods, and recruitment results of the courage trial, a National Cancer Institute (NCI) sponsored, phase II, randomized, dose-response exercise trial among colon cancer survivors. METHODS/RESULTS: The primary objective of the courage trial is to quantify the feasibility, safety, and physiologic effects of low-dose (150 min.week(-1)) and high-dose (300 min.week(-1)) moderate-intensity aerobic exercise compared to usual-care control group over six months. The exercise groups are provided with in-home treadmills and heart rate monitors. Between January and July 2015, 1433 letters were mailed using a population-based state cancer registry; 126 colon cancer survivors inquired about participation, and 39 were randomized onto the study protocol. Age was associated with inquiry about study participation (P<0.001) and randomization onto the study protocol (P<0.001). No other demographic, clinical, or geographic characteristics were associated with study inquiry or randomization. The final trial participant was randomized in August 2015. Six month endpoint data collection was completed in February 2016. DISCUSSION: The recruitment of colon cancer survivors into an exercise trial is feasible. The findings from this trial will inform key design aspects for future phase 2 and phase 3 randomized controlled trials to examine the efficacy of exercise to improve clinical outcomes among colon cancer survivors.

Employers commonly use adjustments to health insurance premiums as incentives to encourage healthy behavior, but the effectiveness of those adjustments is controversial. We gave 197 obese participants in a workplace wellness program a weight loss goal equivalent to 5 percent of their baseline weight. They were randomly assigned to a control arm, with no financial incentive for achieving the goal, or to one of three intervention arms offering an incentive valued at $550. Two intervention arms used health insurance premium adjustments, beginning the following year (delayed) or in the first pay period after achieving the goal (immediate). A third arm used a daily lottery incentive separate from premiums. At twelve months there were no statistically significant differences in mean weight change either between the control group (whose members had a mean gain of 0.1 pound) and any of the incentive groups (delayed premium adjustment, -1.2 pound; immediate premium adjustment, -1.4 pound; daily lottery incentive, -1.0 pound) or among the intervention groups. The apparent failure of the incentives to promote weight loss suggests that employers that encourage weight reduction through workplace wellness programs should test alternatives to the conventional premium adjustment approach by using alternative incentive designs, larger incentives, or both.

Copula-based approaches can be useful in multivariate modeling settings where multivariate dependency is of primary interest, such as estimating the reliability of self-reported sexual behavior assessed independently for male and female partners (dyad) in a couple-based HIV risk reduction study. Specifically, we investigate the reliability of couple reports using copulas, adjusting for key individual baseline covariates. We propose applying a copula modeling approach to measure the reliability of self-reported, shared sexual behaviors from couples where measures are assessed independently from male and female partners. In particular, we estimate measures of dependence, such as the odds ratios and binary correlations, using mixtures of max-infinitely divisible copulas with a bivariate logit model. This approach is flexible in measuring the effect of covariates on dependence parameters and for estimating marginal probabilities for multiple outcomes simultaneously. In this paper, we focus on estimating these two dependencies and explore the influences of additional covariate information on the copula parameter. We provide simulation results comparing copula-based estimates to moment estimates of the generalized estimating equation (GEE) for the correlation coefficients with respect to bias and 95% coverage probability. We illustrate that copulas have better performance in terms of bias, while their performance is similar with respect to efficiency. The estimator of the marginal probability using copula methods is robust to the choice of copula family. The choice of copula may affect the estimator of dependency when the dependency of the outcomes is very low. We apply these methods to data from the Multisite HIV/STD Prevention Trial for African American Couples (AAC) Study.

Introduction. High BMI is a risk factor for upper body breast cancer-related lymphedema (BCRL) onset. Black cancer survivors are more likely to have high BMI than White cancer survivors. While observational analyses suggest up to 2.2 times increased risk of BCRL onset for Black breast cancer survivors, no studies have explored race or other social factors that may affect BCRL severity, operationalized by interlimb volume difference (ILD). Materials and Methods. ILD was measured by perometry for 296 overweight (25 > BMI < 50) Black (n = 102) or White (n = 194) breast cancer survivors (>6 months from treatment) in the WISER Survivor trial. Multivariable linear regression examined associations between social and physical factors and ILD. Results. Neither Black race (-0.26, p = 0.89) nor BMI (0.22, p = 0.10) was associated with ILD. Attending college (-4.89, p = 0.03) was the strongest factor associated with ILD, followed by having more lymph nodes removed (4.75, p = 0.01), >25% BCRL care adherence (4.10, p = 0.01), and years since treatment (0.55, p < 0.001). Discussion. Neither race nor BMI was associated with ILD among overweight cancer survivors. Education, a proxy for resource level, was the strongest factor associated with greater ILD. Tailoring physical activity and weight loss interventions designed to address BCRL severity by resource rather than race should be considered.