Meta-analysis of sex and racial subgroup participation rates and differential treatment effects for trials in solid tumor malignancies leading to US Food and Drug Administration registration between 2010 and 2021.

BACKGROUND: The lack of sociodemographic diversity in clinical trials limits the generalizability of results. The authors examined participation rates and effect modification by sex and race in oncology trials. METHODS: The authors extracted outcome data stratified by sex and race for registration trials supporting US Food and Drug Administration (FDA) approval (2010-2021). Effect modification by race and sex was examined using quantitative and qualitative methods. A random-effects meta-analysis and pairwise comparison of progression-free survival (PFS) and overall survival (OS) outcomes was conducted by sex and race. RESULTS: Ninety-five trials with 123 end points and 54,365 patients provided information on sex. Trial patients were more often male (n = 35,482; 65% vs. 56% male patients in US Surveillance, Epidemiology, and End Results [SEER] data), although the proportion of male patients was similar after adjusting by tumor type (60% in FDA data vs. 58% in SEER data). There was no difference in pooled outcomes among male versus female patients (PFS: hazard ratio, 0.99; 95% confidence interval, 0.92-1.07; p = .89; OS: hazard ratio, 0.99; 95% confidence interval, 0.93-1.07; p = .90). In total, 111 trials including 74,217 patients provided information on race, and 68% of patients identified as White, compared with 72.3% in US SEER incidence data. Black patients were under-represented compared with US SEER incidence data, although ethnicity was poorly reported throughout the data set. In the authors' network meta-analysis by race, there were no statistically significant differences in PFS or OS outcomes. CONCLUSIONS: No significant differences in PFS or OS outcomes were identified when the analyses were stratified by sex or race. Certain racial minorities remain under-represented, and clearer reporting of race and ethnicity is needed. Representation of female patients in FDA trials is similar to that in SEER data after adjusting for tumor type.

Utilization of older deceased donors for pediatric liver transplant may negatively impact long-term survival.

BACKGROUND: Multiple adult studies have investigated the role of older donors (ODs) in expanding the donor pool. However, the impact of donor age on pediatric liver transplantation (LT) has not been fully elucidated. METHODS: UNOS database was used to identify pediatric (≤18 years) LTs performed in the United States during 2002-22. Donors ≥40 years at donation were classified as older donors (ODs). Propensity analysis was performed with 1:1 matching for potentially confounding variables. RESULTS: A total of 10,024 pediatric liver transplantation (PLT) patients met inclusion criteria; 669 received liver grafts from ODs. Candidates receiving OD liver grafts were more likely to be transplanted for acute liver failure, have higher Model End-Stage Liver Disease/Pediatric End-Stage Liver Disease (MELD/PELD) scores at LT, listed as Status 1/1A at LT, and be in the intensive care unit (ICU) at time of LT (all p < 0.001). Kaplan-Meier (KM) analyses showed that recipients of OD grafts had worse patient and graft survival (p < 0.001) compared to recipients of younger donor (YD) grafts. KM analyses performed on candidates matched for acuity at LT revealed inferior patient and graft survival in recipients of deceased donor grafts (p < 0.001), but not living donor grafts (p > 0.1) from ODs. Cox regression analysis demonstrated that living donor LT, diagnosis of biliary atresia and first liver transplant were favorable predictors of recipient outcomes, whereas ICU stay before LT and transplantation during 2002-12 were unfavorable. CONCLUSION: Livers from ODs were used for candidates with higher acuity. Pediatric recipients of livers from ODs had worse outcome compared to YDs; however, living donor LT from ODs had the least negative impact on recipient outcomes.

Differential treatment effect between younger and older adults for new cancer therapies in solid tumors supporting US Food and Drug Administration approval between 2010 and 2021.

BACKGROUND: Over one half of cancer diagnoses occur in patients aged 65 and older. The authors quantified how treatment effects differ between older and younger patients in oncology registration trials. METHODS: The authors performed a retrospective cohort study of registration trials supporting US Food and Drug Administration approval of cancer drugs (from January 2010 to December 2021). The primary outcome was differential treatment effect by age (younger than 65 years vs. 65 years or older) for progression-free survival and overall survival. Random effects meta-analysis and a pairwise comparison of outcomes by age group also were performed. RESULTS: Among 263 trials that met the inclusion criteria, 120 trials with 153 end points and 83,152 patients presented age-specific outcome data. Among the included randomized patients, 38% were aged 65 years and older compared with an incidence proportion of 55% in data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Studies evaluating prostate cancer had the highest representation of patients aged 65 years or older (73%), whereas breast cancer studies had the lowest (20%). There were no changes in the proportion of patients aged 65 years or older over time (p = .86). Only 7% of end points showed a statistically significant interaction between outcome and age group. In a pooled analysis, there was an association between treatment effect and age for progression-free survival that approached but did not meet significance (hazard ratio, 0.95; p = .06), and there was no difference for overall survival (hazard ratio, 0.97; p = .79). CONCLUSIONS: Older adults remain under-represented in oncology registration trials. Significant differences in outcomes by age group were uncommon in individual trials and pooled analyses. However, clinical trial participants differ from real-world patients older than 65 years, and increased enrollment and ongoing research into differential treatment effects by age are needed.

Rationale and design of IMPACT-women: a randomised controlled trial of the effect of time-restricted eating, healthy eating and reduced sedentary behaviour on metabolic health during chemotherapy for early-stage breast cancer.

Metabolic dysfunction and excess accumulation of adipose tissue are detrimental side effects from breast cancer treatment. Diet and physical activity are important treatments for metabolic abnormalities, yet patient compliance can be challenging during chemotherapy treatment. Time-restricted eating (TRE) is a feasible dietary pattern where eating is restricted to 8 h/d with water-only fasting for the remaining 16 h. The purpose of this study is to evaluate the effect of a multimodal intervention consisting of TRE, healthy eating, and reduced sedentary time during chemotherapy treatment for early-stage (I-III) breast cancer on accumulation of visceral fat (primary outcome), other fat deposition locations, metabolic syndrome and cardiovascular disease risk (secondary outcomes) compared with usual care. The study will be a two-site, two-arm, parallel-group superiority randomised control trial enrolling 130 women scheduled for chemotherapy for early-stage breast cancer. The intervention will be delivered by telephone, including 30-60-minute calls with a registered dietitian who will provide instructions on TRE, education and counselling on healthy eating, and goal setting for reducing sedentary time. The comparison group will receive usual cancer and supportive care including a single group-based nutrition class and healthy eating and physical activity guidelines. MRI, blood draws and assessment of blood pressure will be performed at baseline, after chemotherapy (primary end point), and 2-year follow-up. If our intervention is successful in attenuating the effect of chemotherapy on visceral fat accumulation and cardiometabolic dysfunction, it has the potential to reduce risk of cardiometabolic disease and related mortality among breast cancer survivors.

Perceived guideline clarity impacts guideline-concordant care for breast cancer screening in women age 40-49.

BACKGROUND: Canadian and US Task Forces recommend against routine mammography screening for women age 40-49 at average breast cancer risk as harms outweigh benefits. Both suggest individualized decisions based on the relative value women place on potential screening benefits and harms. Population-based data reveal variation in primary care professionals (PCPs) mammography rates in this age group after adjusting for sociodemographic factors, highlighting the need to explore PCP screening perspectives and how this informs clinical behaviours. Results from this study will inform interventions that can improve guideline concordant breast screening for this age group. METHODS: Qualitative semi-structured interviews were performed with PCPs in Ontario, Canada. Interviews were structured using the theoretical domains framework (TDF) to explore determinants of breast cancer screening best-practice behaviours: (1) risk assessment; (2) discussion regarding benefits and harms; and (3) referral for screening. ANALYSIS: Interviews were transcribed and analyzed iteratively until saturation. Transcripts were coded deductively by behaviour and TDF domain. Data that did not fit within a TDF code were coded inductively. The research team met repeatedly to identify potential themes that influenced or were important consequences of the screening behaviours. The themes were tested against further data, disconfirming cases, and different PCP demographics. RESULTS: Eighteen physicians were interviewed. The theme of perceived guideline clarity (a lack of clarity on guideline-concordant practices) influenced all behaviours and moderated the extent to which the risk assessment and discussion occurred. Many were unaware of how risk-assessment factored into the guidelines and/or did not perceive that a shared-care discussion was guideline-concordant. Deferral to patient preference (screening referral without a complete discussion of benefits and harms) occurred when the PCPs had low knowledge regarding harms and/or if they experienced regret (TDF domain: emotion) resulting from prior clinical experiences. Older providers described patient's influence impacting their decisions and physicians trained outside Canada, practicing in higher-resourced areas, and female physicians described being influenced by beliefs about consequences of benefits of screening. CONCLUSION: Perceived guideline clarity is an important driver of physician behaviour. Improving guideline concordant care should start by clarifying the guideline itself. Thereafter, targeted strategies include building skills in identifying and overcoming emotional factors and communication skills important for evidence-based screening discussions.

Characterization of Biomarkers of Hemostasis and Bleeding-Related Outcomes in Children With Cirrhosis.

OBJECTIVES: We aimed to evaluate differences in laboratory tests, bleeding, transfusions, and thrombosis between (1) children without and with cirrhosis and (2) children and adults with cirrhosis, and to correlate thromboelastography (TEG) parameters with biomarkers of hemostasis, bleeding, and transfusions in children and adults with cirrhosis. METHODS: This single-center, retrospective study included 20 children without cirrhosis, 40 children with cirrhosis, and 40 adults with cirrhosis who underwent a liver transplant (LT). We collected demographic data, preoperative laboratory values, and intraoperative TEG parameters. Biomarkers of hemostasis just prior to the start of LT surgery were analyzed including international normalized ratio (INR), platelet, fibrinogen level, R time, K time, alpha angle (α), and maximum amplitude (MA). We also collected outcome data including blood loss, transfusion requirements, and thrombosis. RESULTS: A significantly higher proportion of children with cirrhosis had abnormal PT ( P = 0.001), platelet ( P = 0.001), K time ( P = 0.02), and MA ( P = 0.05) compared to children without cirrhosis. The incidences of thrombosis, bleeding events, blood loss or PRBC transfusion were not significantly different between these 2 groups. A significantly higher proportion of adults with cirrhosis had abnormal R time ( P = 0.01) and alpha angle ( P = 0.01) than children with cirrhosis. CONCLUSIONS: Children with cirrhosis had defects in fibrinogen and platelets compared to children without cirrhosis at time of LT; however, these abnormalities did not translate into higher rates of bleeding in the former. Adults with cirrhosis had more defects in clotting factors compared to children with cirrhosis.

Characteristics, risk factors, and outcomes of neutropenia after liver or kidney transplantation in children.

BACKGROUND: While prior adult studies have shown that approximately 20%-38% of subjects undergoing solid-organ transplant develop neutropenia, similar analyses in pediatric subjects are scarce. METHODS: We conducted a retrospective chart review of liver transplant (LT) and kidney transplant (KT) recipients at our center during the period 2008-2018. All of the KT and none of the LT subjects during this time period had induction with either anti-thymocyte globulin (ATG) or basiliximab at time of transplant. Neutropenia was defined as absolute neutrophil count (ANC) value ≤1000/mm3 . RESULTS: One hundred subjects with LT and 82 subjects with KT were included. The incidence of neutropenia within the first year of transplant in KT was higher compared to LT (54.8% vs 39%, p = .01). The median number of hospitalizations (p = .001) and infectious complications (p = .04) was significantly higher only in the KT subjects who developed neutropenia (compared to those who did not). Multivariate analysis identified factors associated with severity of liver disease at transplant, namely h/o upper gastrointestinal bleeding (p = .02), weight deficit (p = .01), and pre-LT ANC (p = .01), along with high or moderate risk cytomegalovirus status (p = .05) as predictors of neutropenia in LT subjects. Female gender (p = .03) predicted neutropenia, while BK virus infection was protective for neutropenia (p = .04) in KT subjects. CONCLUSIONS: The incidence of and morbidity associated with neutropenia within 1 year post-transplant is higher in KT subjects compared to LT subjects. The likely reason for this is the use of induction therapy (ATG, basiliximab) at the time of transplant in KT subjects.

Outcomes Analyses of Pediatric Acute Liver Failure Subjects Listed for Liver Transplantation.

BACKGROUND: We characterized recent outcomes in US pediatric acute liver failure (PALF) subjects listed for liver transplantation (LT) using the Scientific Registry of Transplant Recipients (SRTR) database. METHODS: Pediatric subjects listed for LT from 2002 to 2015 were assigned to the "PALF" group based on status 1/1A listing, INR >2, no hepatic artery thrombosis, and no primary graft nonfunction (N = 397). Subjects were assigned to the "non-PALF" group if listed with any status other than 1/1A (N = 4509). RESULTS: The PALF group had more infants <3 months of age and males at listing for LT compared to the non-PALF group. Two-thirds of PALF subjects had an indeterminate etiology. LT waitlist survival was significantly worse in the PALF group compared to the non-PALF group. Likelihood of removal from the LT waitlist for being "too sick" was higher, while that of removal for "spontaneous recovery" was lower in PALF subjects. Post-LT short-term (30 days) and long-term (60 months) outcomes were also significantly worse in PALF versus non-PALF subjects. PALF subjects who underwent living-donor-liver-transplant (LDLT) had similar LT waitlist times and post-LT survival compared to those undergoing deceased-donor-liver-transplant (DDLT). Over the study period, we observed a decreased number of liver transplants, and increase in LT waitlist- and short-term post-LT-survival in PALF subjects. CONCLUSION: LT waitlist and post-LT outcomes are worse in PALF subjects compared to non-PALF subjects. PALF subjects who undergo LDLT have similar waitlist times and post-LT outcomes compared to those undergoing DDLT.

Patient and provider determinants of breast cancer screening among Ontario women aged 40-49: a population-based retrospective cohort study.

PURPOSE: Canadian breast cancer screening guidelines state that mammography screening for women 40-49 should be individualized based on risk assessment and preferences. This retrospective cohort study describes the frequency of screening in women aged 40-49 and identifies patient and provider-level associations with screening. METHODS: Administrative databases were linked. The overall cohort included Ontario women aged 40-49 between April 1, 2009 and March 31, 2019. Subgroups were created: the "screen" group included women who received a mammogram defined as screening (using a set of exclusion criteria) and the "routine screen" group included women with three or more screening mammograms. A multivariable multilevel logistic regression model accounting for patient and provider characteristics was fit to determine characteristics associated with routine screening. The intracluster correlation co-efficient was used to quantify the degree of variation across providers. RESULTS: Of approximately 2 million eligible women, there were 532,596 (25.5%) in the screen group and 90,651 (4.3%) the routine screen group. There was an average of 0.30 and 0.52 screening mammograms per woman year, in the screen and routine screen groups, respectively. Routine screening was associated with periodic health exams (OR 1.21, 95% CI 1.20-1.22), receiving pap smears (OR 1.38, 95% CI 1.37-1.39), and fee-for-service models of care (OR 1.32, 95% CI 1.27-1.36). Over 20% of the variation in screening was due to systematic between-provider differences. CONCLUSIONS: Approximately 4.3% of women aged 40-49 in Ontario received routine breast cancer screening with substantial variation across providers. Routine screening is associated with periodic health examinations, receipt of pap smears, and fee-for-service models of care.

Coronary artery disease in patients with cancer: challenges and opportunities for improvement.

PURPOSE OF REVIEW: Coronary artery disease (CAD) is a common comorbidity in patients with cancer. We review shared risk factors between the two diseases and cancer treatments that increase the risk of CAD. We also discuss outcomes and management considerations of patients with cancer who develop CAD. RECENT FINDINGS: Several traditional and novel risk factors promote the development of both CAD and cancer. Several cancer treatments further increase the risk of CAD. The presence of cancer is associated with a higher burden of comorbidities and thrombocytopenia, which predisposes patients to higher bleeding risks. Patients with cancer who develop acute coronary syndromes are less likely to receive timely revascularization or appropriate medical therapy, despite evidence showing that receipt of these interventions is associated with substantial benefit. Accordingly, a cancer diagnosis is associated with worse outcomes in patients with CAD. The risk-benefit balance of revascularization is becoming more favorable due to the improving prognosis of many cancers and safer revascularization strategies, including shorter requirements for dual antiplatelet therapy after revascularization. SUMMARY: Several factors increase the complexity of managing CAD in patients with cancer. A multidisciplinary approach is recommended to guide treatment decisions in this high-risk and growing patient group.

Quantifying Withdrawal of Consent, Loss to Follow-Up, Early Drug Discontinuation, and Censoring in Oncology Trials.

BACKGROUND: Censoring due to early drug discontinuation (EDD) or withdrawal of consent or loss to follow-up (WCLFU) can result in postrandomization bias. In oncology, censoring rules vary with no defined standards. In this study, we sought to describe the planned handling and transparency of censoring data in oncology trials supporting FDA approval and to compare EDD and WCLFU in experimental and control arms. METHODS: We searched FDA archives to identify solid tumor drug approvals and their associated trials between 2015 and 2019, and extracted the planned handling and reporting of censored data. We compared the proportion of WCLFU and EDD between the experimental and control arms by using generalized estimating equations, and performed logistic regression to identify trial characteristics associated with WCLFU occurring more frequently in the control group. RESULTS: Censoring rules were defined adequately in 48 (59%) of 81 included studies. Only 14 (17%) reported proportions of censored participants clearly. The proportion of WCLFU was higher in the control group than in the experimental group (mean, 3.9% vs 2.5%; ß-coefficient, -2.2; 95% CI, -3.1 to -1.3; P<.001). EDD was numerically higher in the experimental arm in 61% of studies, but there was no statistically significant difference in the proportion of EDD between the experimental and control groups (mean, 21.6% vs 19.9%, respectively; ß-coefficient, 0.27; 95% CI, -0.32 to 0.87; P=.37). The proportion of EDD due to adverse effects (AEs) was higher in the experimental group (mean, 13.2% vs 8.5%; ß-coefficient, 1.5; 95% CI, 0.57-2.45; P=.002). WCLFU was higher in the control group in studies with an active control group (odds ratio [OR], 10.1; P<.001) and in open label studies (OR, 3.00; P=.08). CONCLUSIONS: There are significant differences in WCLFU and EDD for AEs between the experimental and control arms in oncology trials. This may introduce postrandomization bias. Trials should improve the reporting and handling of censored data so that clinicians and patients are fully informed regarding the expected benefits of a treatment.

Random forest analysis identifies change in serum creatinine and listing status as the most predictive variables of an outcome for young children on liver transplant waitlist.

Young children listed for liver transplant have high waitlist mortality (WL), which is not fully predicted by the PELD score. SRTR database was queried for children < 2 years listed for initial LT during 2002-17 (n = 4973). Subjects were divided into three outcome groups: bad (death or removal for too sick to transplant), good (spontaneous improvement), and transplant. Demographic, clinical, listing history, and laboratory variables at the time of listing (baseline variables), and changes in variables between listing and prior to outcome (trajectory variables) were analyzed using random forest (RF) analysis. 81.5% candidates underwent LT, and 12.3% had bad outcome. RF model including both baseline and trajectory variables improved prediction compared to model using baseline variables alone. RF analyses identified change in serum creatinine and listing status as the most predictive variables. 80% of subjects listed with a PELD score at time of listing and outcome underwent LT, while ~70% of subjects in both bad and good outcome groups were listed with either Status 1 (A or B) prior to an outcome, regardless of initial listing status. Increase in creatinine on LT waitlist was predictive of bad outcome. Longer time spent on WL was predictive of good outcome. Subjects with biliary atresia, liver tumors, and metabolic disease had LT rate >85%, while >20% of subjects with acute liver failure had a bad outcome. Change in creatinine, listing status, need for RRT, time spent on LT waitlist, and diagnoses were the most predictive variables.

Moving Cancer Care Ontario's Exercise for People with Cancer guidelines into oncology practice: using the Theoretical Domains Framework to validate a questionnaire.

Evidence supporting the benefits of exercise surrounding cancer treatment has led to internationally published guidelines, with minimal uptake by oncology care providers (OCPs). There is a need to understand how to implement research evidence into practice. Our team developed a questionnaire to assess OCPs' knowledge of exercise guidelines and barriers/facilitators to exercise counseling and program referral. We validated the questionnaire using the Theoretical Domains Framework, a knowledge translation (KT) framework used to implement evidence-based guidelines into practice. In this commentary, we describe this process and the rationale for integrating a KT framework into intervention development and implementation in oncology practice. The revised questionnaire, entitled Clinicians Perspectives on Exercise in Patients with Cancer (CliPEC), is shared to facilitate the implementation process and allow for comparison across oncology practices.

Oncology care provider perspectives on exercise promotion in people with cancer: an examination of knowledge, practices, barriers, and facilitators.

BACKGROUND: Despite the reported benefits of physical activity in alleviating the impact of cancer and its treatments, oncology care providers (OCPs) are not routinely discussing exercise with their patients, suggesting a knowledge to action gap. We sought to determine OCP's knowledge, beliefs, barriers, and facilitators to exercise discussion. METHODS: A survey was administered to OCPs at the cancer center in Hamilton, Ontario. Questions comprised of demographics, knowledge and beliefs regarding exercise guidelines, and barriers and facilitators to exercise discussion. Analysis of survey responses was descriptive. Pearson's chi-squared test was used to examine select associations. RESULTS: There were 120 respondents (61% response rate) representing a diversity of professions. Approximately, 80% of OCPs were not aware of any exercise guidelines in cancer and self-reported poor knowledge on when, how, and which patients to refer to exercise programs. OCPs who reported meeting Canada's Physical Activity guidelines were significantly more likely to identify correct guidelines (p = 0.023) and to report good knowledge on how to provide exercise counseling (p = 0.014). Across OCP groups, barriers to exercise discussion included poor knowledge, lack of time, and safety concerns. Most felt that educational sessions and having an exercise specialist on the clinical team would be beneficial. CONCLUSIONS: OCPs have low knowledge regarding exercise counseling, but believe that discussing exercise is a multidisciplinary task and expressed a desire for further training. Interventions will require a multi-pronged approach including education for OCPs and guidance on assessment for exercise safety.

Pediatric solid organ transplant recipients: transition to home and chronic illness care.

Pediatric SOT recipients are medically fragile and present with complex care issues requiring high-level management at home. Parents of hospitalized children have reported inadequate preparation for discharge, resulting in problems transitioning from hospital to home and independently self-managing their child's complex care needs. The aim of this study was to investigate factors associated with the transition from hospital to home and chronic illness care for parents of heart, kidney, liver, lung, or multivisceral recipients. Fifty-one parents from five pediatric transplant centers completed questionnaires on the day of hospital discharge and telephone interviews at three wk, three months, and six months following discharge from the hospital. Care coordination (p = 0.02) and quality of discharge teaching (p < 0.01) was significantly associated with parent readiness for discharge. Readiness for hospital discharge was subsequently significantly associated with post-discharge coping difficulty (p = 0.02) at three wk, adherence with medication administration (p = 0.03) at three months, and post-discharge coping difficulty (p = 0.04) and family management (p = 0.02) at six months post-discharge. The results underscore the important aspect of education and care coordination in preparing patients and families to successfully self-manage after hospital discharge. Assessing parental readiness for hospital discharge is another critical component for identifying risk of difficulties in managing post-discharge care.

The impact of bone mineral density testing, fracture assessment, and osteoporosis education in men treated by androgen deprivation for prostate cancer: a pilot study.

PURPOSE: Men receiving androgen deprivation therapy for prostate cancer have low knowledge of osteoporosis (OP) and engage in few healthy bone behaviors (HBBs). A multicomponent intervention was piloted in this population. Changes in OP knowledge, self-efficacy, health beliefs, and engagement in HBBs were evaluated. METHODS: A pre-post pilot study was performed in a convenience sample of men recruited from the Princess Margaret Cancer Centre. Men were sent personalized letters explaining their dual x-ray absorptiometry (DXA) results and fracture risk assessment with an OP-related education booklet. Participants completed questionnaires assessing OP knowledge, self-efficacy, health beliefs, and current engagement in HBBs at baseline (T1) and 3 months post-intervention (T2). Paired t tests and McNemar's test were used to assess changes in outcomes. RESULTS: A total of 148 men completed the study. There was an increase in OP knowledge (9.7 ± 4.3 to 11.4 ± 3.3, p < 0.0001) and feelings of susceptibility (16.5 ± 4.3 to 17.4 ± 4.7, p = 0.015), but a decrease in total self-efficacy (86.3 ± 22.9 to 81.0 ± 27.6, p = 0.007) from baseline to post-intervention. Men made appropriate changes in their overall daily calcium intake (p ≤ 0.001), and there was uptake of vitamin D supplementation from 44 % (n = 65) to 68 % (n = 99) (p < 0.0001). Men with bone loss (osteopenia or OP) had a greater change in susceptibility (1.9 ± 4.3 vs. -0.22 ± 4.2, p = 0.005) compared to men with normal bone density. CONCLUSIONS: Our results provide preliminary evidence that a multicomponent intervention such as the one described can lead to increased knowledge and feelings of susceptibility regarding OP and can enhance uptake of some HBBs.

Magnitude of effect and sample size justification in trials supporting anti-cancer drug approval by the US Food and Drug Administration.

Approval of drugs is based on randomized trials observing statistically significant superiority of an experimental agent over a standard. Statistical significance results from a combination of effect size and sampling, with larger effect size more likely to translate to population effectiveness. We assess sample size justification in trials supporting cancer drug approvals. We identified US FDA anti-cancer drug approvals for solid tumors from 2015 to 2019. We extracted data on study characteristics, statistical plan, accrual, and outcomes. Observed power (Pobs) was calculated based on completed study characteristics and observed hazard ratio (HRobs). Studies were considered over-sampled if Pobs > expected with HRobs similar or worse than expected or if Pobs was similar to expected with HRobs worse than expected. We explored associations with over-sampling using logistic regression. Of 75 drug approvals (reporting 94 endpoints), 21% (20/94) were over-sampled. Over-sampling was associated with immunotherapy (OR: 5.5; p = 0.04) and associated quantitatively but not statistically with targeted therapy (OR: 3.0), open-label trials (OR: 2.5), and melanoma (OR: 4.6) and lung cancer (OR: 2.17) relative to breast cancer. Most cancer drug approvals are supported by trials with justified sample sizes. Approximately 1 in 5 endpoints are over-sampled; benefit observed may not translate to clinically meaningful real-world outcomes.

Comparative overall survival of CDK4/6 inhibitors in combination with endocrine therapy in advanced breast cancer.

Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall survival (OS). A robust comparative evaluation of OS, safety, and tolerability of the three drugs is warranted. A systematic literature search identified phase 3 randomized clinical trials reporting OS of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy in ER-positive/HER2-negative advanced breast cancer. Trial-level data on OS and common and serious adverse events (AE) were extracted for each drug. In the absence of direct comparisons, a network meta-analysis was performed to evaluate pairwise comparative efficacy, safety, and tolerability of each of the CDK4/6i. Seven studies comprising of 4415 patients met the inclusion criteria. Median follow-up was 73.3 months (range: 48.7-97.2 months). There were no statistically significant differences in OS between any of the CDK4/6i. Compared to palbociclib, ribociclib and abemaciclib both showed significantly higher GI toxicity (grade 1-2 vomiting OR 1.87 [95% CI 1.37-2.56] and OR 2.27 [95% CI 1.59-3.23] respectively). Compared to palbociclib, abemaciclib was associated with more grade 3-4 diarrhea OR 118.06 [95% CI 7.28-1915.32]. In contrast, palbociclib was associated with significantly more neutropenia than ribociclib and abemaciclib but significantly lower risk of grade 3-4 infections. Abemaciclib had significantly less grade 3-4 transaminitis and grade 3-4 neutropenia than ribociclib. Treatment discontinuation and death due to AE were significantly higher with abemaciclib than palbociclib and ribociclib. There is no statistically significant difference in OS between CDK4/6i despite differing statistical significance levels of individual trials. Real-world data analyses may help to identify if there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes.