Gillian Gresham

Integrating multiple data sources (MUDS) for meta-analysis to improve patient-centered outcomes research: a protocol for a systematic review

BackgroundSystematic reviews should provide trustworthy guidance to decision-makers, but their credibility is challenged by the selective reporting of trial results and outcomes. Some trials are not published, and even among clinical trials that are published partially (e.g., as conference abstracts), many are never published in full. Although there are many potential sources of published and unpublished data for systematic reviews, there are no established methods for choosing among multiple reports or data sources about the same trial.MethodsWe will conduct systematic reviews of the effectiveness and safety of two interventions following the Institute of Medicine (IOM) guidelines: (1) gabapentin for neuropathic pain and (2) quetiapine for bipolar depression. For the review of gabapentin, we will include adult participants with neuropathic pain who do not require ventilator support. For the review of quetiapine, we will include adult participants with acute bipolar depression (excluding mixed or rapid cycling episodes). We will compare these drugs (used alone or in combination with other interventions) with placebo or with the same intervention alone; direct comparisons with other medications will be excluded. For each review, we will conduct highly sensitive electronic searches, and the results of the searches will be assessed by two independent reviewers. Outcomes, study characteristics, and risk of bias ratings will be extracted from multiple reports by two individuals working independently, stored in a publicly available database (Systematic Review Data Repository) and analyzed using commonly available statistical software. In each review, we will conduct a series of meta-analyses using data from different sources to determine how the results are affected by the inclusion of data from multiple published sources (e.g., journal articles and conference abstracts) as well as unpublished aggregate data (e.g., “clinical study reports”) and individual participant data (IPD). We will identify patient-centered outcomes in each report and identify differences in the reporting of these outcomes across sources.Systematic review registrationCRD42015014037, CRD42015014038

Understanding physical activity in cancer patients and survivors: new methodology, new challenges, and new opportunities

Since the early 1990s, accumulating evidence has suggested that regular, sustained participation in physical activity may help prevent the onset and development of certain types of cancer. Given the worldwide incidence and prevalence of cancer, there is increasing interest in physical activity as a nonpharmacological intervention and prevention method. Moreover, the effectiveness of new and improved cancer therapies has also increased interest in the potential health benefits of physical activity during and after treatment. The development of wearable device technology (e.g., accelerometers) to monitor physical activity has created unprecedented opportunities to better understand the potential health benefits of physical activity in cancer patients and survivors by allowing researchers to observe, quantify, and define physical activity in real-world settings. This granular, detailed level of measurement provides the opportunity for researchers and clinicians to obtain a greater understanding of the health benefits of daily physical activity beyond the well-established benefits of “moderate-to-vigorous” physical activity and to tailor recommendations to a feasible level of activity for older and/or sicker patients and survivors. This article provides an overview of accelerometers, the potential benefits—and challenges—of using these devices in the research and clinical settings, and recommendations for future applications.

Population-Based Patterns and Factors Associated With Underuse of Palliative Systemic Therapy in Elderly Patients With Metastatic Colon Cancer

Micro‐Abstract Elderly (≥ 70 years) and young (< 70 years) patients with metastatic colon cancer were identified and their treatments and outcomes compared. The rates of adverse events, frequency of treatment interruptions, and magnitude of survival benefit from systemic therapy were similar between carefully selected elderly and young patients. Background: We compared the patterns and factors associated with chemotherapy and bevacizumab use in elderly versus young patients with metastatic colon cancer (mCC) and determined the effect of systemic therapy on overall survival (OS) according to age. Materials and Methods: Patients diagnosed with mCC from 2009 to 2010 in British Columbia, Canada were reviewed and categorized as elderly patients (age ≥ 70 years) and young patients (age < 70 years). Cox regression models adjusted for age and confounders were used to determine the effect of systemic therapy on OS. Results: We identified 1013 patients with a median age of 67 years. Of the 1013 patients, 42% were elderly and 58% were young; 57% were men; and 66% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Fewer elderly patients were offered systemic therapy compared with young patients (48% vs. 77%; P < .001). Among those treated, elderly patients were less likely than young patients to receive combination chemotherapy (47% vs. 81%; P < .0001) and bevacizumab (19% vs. 47%; P < .0001). The most common reasons for no treatment were similar for the elderly and young patients: patient choice, poor ECOG PS, and significant comorbidities. Advanced age alone was also cited as a reason for elderly but not for young patients (7% vs. 0%). When treated, the risk of adverse events and treatment interruptions was comparable between age groups. The receipt of systemic therapy was associated with improved OS in both elderly (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.37‐0.56; P < .0001) and young (HR, 0.43; 95% CI, 0.35‐0.53; P < .0001) patients, regardless of age (interaction P > .05). Conclusion: In carefully selected elderly patients, the outcomes from systemic therapy were comparable to those for young patients. Thus, age alone should not be a barrier to treatment of mCC.

Fatigability and endurance performance in cancer survivors: Analyses from the Baltimore Longitudinal Study of Aging

Fatigue is prevalent and distressing among cancer survivors, but its subjective nature makes it difficult to identify. Fatigability, defined as task‐specific fatigue, and endurance performance may be useful supplemental measures of functional status in cancer survivors.

Characteristics and trends of clinical trials funded by the National Institutes of Health between 2005 and 2015

Background The National Institutes of Health is one of the largest biomedical research agencies in the world. Clinical trials are an important component of National Institutes of Health research efforts. Given the recent updates in National Institutes of Health trial reporting requirements, more information regarding the current state of National Institutes of Health–funded clinical trials is warranted. The objective of this analysis was to describe characteristics and trends of clinical trials funded by the National Institutes of Health over time and by Institutes and Centers of the National Institutes of Health. Methods Interventional studies funded by the National Institutes of Health and registered in ClinicalTrials.gov between 2005 and 2015 were included in the analysis. Trials were identified from the 27 March 2016 Clinical Trials Transformation Initiative Aggregate Analysis of ClinicalTrials.gov database. A descriptive analysis of trials by year and National Institutes of Health Institute/Center was performed. Results There were 12,987 National Institutes of Health–funded clinical trials registered between 2005 and 2015. There were 1,580, 1,116, and 930 trials registered in 2005, 2010, and 2015, respectively. The majority were early-development trials (phases 0, 1, or 2; 53%), randomized (61%), and single-center (63%). Trial demographics have remained unchanged over time. Median trial sample size was 64 (interquartile range 29–192) with 10% of trials enrolling ≥500 participants. Most trials were completed within 5 years of enrollment start (69%). Trial characteristics varied considerably across National Institutes of Health Institutes and Centers. Results were reported under the assumptions that most National Institutes of Health–funded trials are registered in ClinicalTrials.gov and that trials are being registered completely and accurately. Conclusion In conclusion, there has been a decline in the number of trials being funded over time, explained in part by a relatively constant budget, increases in trial costs, or other factors that cannot be quantified. National Institutes of Health–funded trials are relatively small and tend to be single-centered. There are substantial differences in the number and types of trials done by Institutes and Centers within the National Institutes of Health.

Wearable activity monitors to assess performance status and predict clinical outcomes in advanced cancer patients

An objective evaluation of patient performance status (PS) is difficult because patients spend the majority of their time outside of the clinic, self-report to providers, and undergo dynamic changes throughout their treatment experience. Real-time, objective activity data may allow for a more accurate assessment of PS and physical function, while reducing the subjectivity and bias associated with current assessments. Consenting patients with advanced cancer wore a wearble activity monitor for three consecutive visits in a prospective, single-cohort clinical trial. Provider-assessed PS (ECOG/Karnofsky) and NIH PROMIS® patient-reported outcomes (PROs) were assessed at each visit. Associations between wearable activity monitor metrics (steps, distance, stairs) and PS, clinical outcomes (adverse events, hospitalizations, survival), and PROs were assessed using correlation statistics and in multivariable logistic regression models. Thirty-seven patients were evaluated (54% male, median 62 years). Patients averaged 3700 steps, 1.7 miles, and 3 flights of stairs per day. Highest correlations were observed between average daily steps and ECOG-PS and KPS (r = 0.63 and r = 0.69, respectively p < 0.01). Each 1000 steps/day increase was associated with reduced odds for adverse events (OR: 0.34, 95% CI 0.13, 0.94), hospitalizations (OR: 0.21 95% CI 0.56, 0.79), and hazard for death (HR: 0.48 95% CI 0.28–0.83). Significant correlations were also observed between activity metrics and PROs. Our trial demonstrates the feasibility of using wearable activity monitors to assess PS in advanced cancer patients and suggests their potential use to predict clinical and patient-reported outcomes. These findings should be validated in larger, randomized trials.Wearable tech: Activity monitor tracks wellbeing of advanced cancer patientsWearable activity monitors provide an objective and continuous measure of general wellbeing and physical function among patients with advanced cancer. Gillian Gresham from Cedars-Sinai Medical Center in Los Angeles, California, USA, and colleagues enlisted 37 patients with metastatic or inoperable cancer to wear wristbands that wireless measure heart rate and activity patterns over the span of 2 weeks. At weekly clinic visits, the patients also filled in health questionnaires and their healthcare providers made independent evaluations. The researchers found a reasonably high correlation between the clinician-assessed performance status and the average daily step total calculated by the wristband. More steps also translated into lower odds of serious complications, hospitalizations or death. The study shows the feasibility of using wearable technology to track the ability of patients with advanced cancer to perform certain activities of daily living.

Correction to: Integrating multiple data sources (MUDS) for meta-analysis to improve patient-centered outcomes research: a protocol

The correct title of the article [1] should be “Integrating multiple data sources (MUDS) for meta-analysis to improve patient-centered outcomes research: a protocol”.

Generalizability of clinical trials of advanced melanoma in the real-world, population-based setting

Results from novel therapeutics trials are not always generalizable to real-world patients. We aimed to determine the pattern in which trial findings are applied in a population-based setting of melanoma patients and consequent treatment outcomes. Patients with unresectable disease during 2011–2014 and referred to cancer centers in a large Canadian province were retrospectively reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified patients into trial-eligible and ineligible and those treated and untreated with these agents. We identified 290 patients with known BRAF status for the Vem analysis and 212 patients previously treated with first-line agents for the Ipi analysis. For the Vem cohort, a total of 49 patients were considered trial-eligible, of whom 36 (73%) received treatment. For the Ipi cohort, there were 119 trial-eligible cases of whom 43 (36%) received therapy. Factors other than eligibility criteria most frequently associated with non-treatment in these cohorts included concerns regarding treatment harm and patient preferences. In multivariable analysis, overall survival was improved in Vem cohort patients considered trial-eligible and treated compared to those who were ineligible. Within the Ipi cohort, survival was improved in trial-eligible patients regardless of whether they received Ipi compared to ineligible patients. Real-world uptake of new melanoma treatments was suboptimal, and non-use in trial-eligible patients was frequent. Future clinical trials that are more pragmatically designed to include participants who better reflect the real-world population may facilitate increased uptake of novel therapeutics into routine clinical practice.

Neoadjuvant PET and MRI-based intensity modulated radiotherapy leads to less toxicity and improved pathologic response rates in locally advanced rectal cancer

Background Neoadjuvant chemoradiation (NeoCRT) is standard of care for the treatment of locally advanced rectal cancer (LARC). Contemporary radiation techniques and pre-treatment imaging may impact toxicities and pathologic response (PR). Herein we compare intensity modulated radiotherapy (IMRT) and advanced pre-treatment imaging in the neoadjuvant treatment of LARC and resulting impact on toxicities and pathologic outcomes relative to 3 dimensional conformal radiotherapy (3DCRT). Methods LARC patients treated at 4 large academic centers in the US from 2007-2016 were reviewed. Patients received 5-FU-based NeoCRT concurrently with IMRT or 3DCRT. PR was recorded as none, partial, or complete. Common terminology for adverse events version 4 was used to grade toxicities. Toxicity rates were compared using Chi-square analysis. Multivariable models were fit adjusting for age, gender, pre-tx CT to identify independent predictors of PR and toxicity. Results A total of 128 patients were analyzed: 60.1% male and 39.8% female, median age 57.7 years (range, 31-85 years). Clinical characteristics were similar across RT groups. The outcome of partial and complete PR was similar for IMRT and 3DCRT (48.1%, 23.1% vs. 31.7%, 23.3%), respectively. After adjusting for gender, age, and pre-RT chemotherapy type, IMRT and pretreatment PET and/or MRI imaging was significantly associated with increased odds for complete and partial response (OR =2.95, 95% CI: 1.21-7.25, P=0.018; OR =14.70, 95% CI: 3.69-58.78, P<0.0001). Additionally, IMRT was associated with reduced rates of dehydration, dermatitis, rectal pain, rectal bleeding, and diverting ostomy (P<0.05). Overall rates of grade 2 and higher toxicities were significantly reduced in IMRT vs. 3DCRT after adjusting for confounders (OR =0.27, 95% CI: 0.08-0.87). Conclusions NeoCRT IMRT with pretreatment PET and/or MRI for LARC leads to reduced acute toxicities and improved PR compared to 3DCRT. Given the challenges associated with prospective validation of these data, IMRT with pretreatment PET and/or MRI should be considered standard treatment for LARC.

Contrasting characteristics of daily physical activity in older adults by cancer history

Using objectively collected physical activity (PA) data from the Baltimore Longitudinal Study of Aging, the authors tested whether patterns of daily activity and sedentary time differed by cancer survivorship in older adults.