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Immune checkpoint inhibitors (ICIs) have changed perspectives for patients with cancer, but come with severe immune-related adverse events (irAEs). To prevent fatality or chronicity, these irAEs are often promptly treated with high-dose immunosuppressants. Until recently, evidence on the effects of irAE management on ICI efficacy has been sparse. As a result, algorithms for irAE management are mostly expert-opinion based and barely consider possible detrimental effects of immunosuppressants on ICI efficacy. However, recent growing evidence suggests that vigorous immunosuppressive management of irAEs comes with unfavourable effects on ICI efficacy and survival. With expansion of the indications of ICIs, evidence-based treatment of irAEs without hampering tumour control becomes more and more important. In this review, we discuss novel evidence from pre-clinical and clinical studies on the effects of different irAE management regimens including corticosteroids, TNF inhibition and tocilizumab on cancer control and survival. We provide recommendations for pre-clinical research, cohort studies and clinical trials that can help clinicians in tailored irAE management, minimising patients’ burden while maintaining ICI efficacy.

ObjectiveIn healthy populations, leisure-time physical activity (LTPA) improves health outcomes, while, paradoxically, occupational physical activity (OPA) is associated with detrimental health effects. This study aimed to investigate the associations of LTPA and OPA with mortality, cardiovascular events and type 2 diabetes (T2D) in patients with cardiovascular disease (CVD).MethodsIn 7058 outpatients with CVD (age 61±10 years, 75% male) from the prospective Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease cohort, Cox models were used to quantify the associations between self-reported LTPA and OPA and all-cause mortality, cardiovascular events and T2D.ResultsOver 8.6 years (IQR: 4.6–12.5) of follow-up, 1088 vascular events, 1254 deaths and 447 incident T2D cases occurred. The top LTPA quarter had a lower risk of all-cause mortality (HR 0.63, 95% CI 0.54 to 0.74), recurrent cardiovascular events (HR 0.72, 95% CI 0.60 to 0.84) and incident T2D (HR 0.71, 95% CI 0.55 to 0.93), compared with the lowest quarter. The continuous LTPA associations were reverse J-shaped for all-cause mortality and vascular events and linear for T2D. OPA (heavy manual vs sedentary) showed a trend towards an increased risk of all-cause mortality (HR 1.08, 95% CI 0.86 to 1.35), cardiovascular events (HR 1.15, 95% CI 0.91 to 1.45) and T2D (HR 1.04, 95% CI 0.72 to 1.50). The detrimental effects of higher OPA were more pronounced in men, never-smokers, people with higher education and active employment.ConclusionsIn patients with CVD, LTPA was associated with lower risk of all-cause mortality, recurrent cardiovascular events and incident T2D. In contrast, OPA seemed to increase the risk of these outcomes. These findings support the existence of a physical activity paradox in patients with CVD.

Background Worldwide physical activity levels of adults are declining, which is associated with increased chronic disease risk. Wearables and smartphone applications offer new opportunities to change physical activity behaviour. This systematic review summarizes the evidence regarding the effect of wearables and smartphone applications on promoting physical activity. Methods PubMed, EMBASE and Cochrane databases were searched for RCTs, published since January 2008, on wearables and smartphone applications to promote physical activity. Studies were excluded when the study population consisted of children or adolescents, the intervention did not promote physical activity or comprised a minor part of the intervention, or the intervention was Internet-based and not accessible by smartphone. Risk of bias was assessed by the Cochrane collaboration tool. The primary outcome was changed in physical activity level. Meta-analyses were performed to assess the pooled effect on (moderate-to-vigorous) physical activity in minutes per day and daily step count. Results Eighteen RCTs were included. Use of wearables and smartphone applications led to a small to moderate increase in physical activity in minutes per day (SMD = 0.43, 95% CI = 0.03 to 0.82; I 2  = 85%) and a moderate increase in daily step count (SMD = 0.51, 95% CI = 0.12 to 0.91; I 2  = 90%). When removing studies with an unclear or high risk of bias, intervention effects improved and statistical heterogeneity was removed. Conclusions This meta-analysis showed a small to moderate effect of physical activity interventions comprising wearables and smartphone applications on physical activity. Hence, wearables and smartphone applications are likely to bring new opportunities in delivering tailored interventions to increase levels of physical activity.

Timing chemotherapy on the basis of the body's intrinsic circadian clock—ie, chronomodulated chemotherapy—might improve efficacy and reduce treatment toxicity. This systematic review summarises the available clinical evidence on the effects of chronomodulated chemotherapy from randomised, controlled trials in adult patients with cancer, published between the date of database inception and June 1, 2021. This study complies with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered on the International Prospective Register of Systematic Reviews (CRD42020177878). The protocol was published on Oct 21, 2020, before study initiation. The primary outcome measures comprised toxicity incidence, overall survival, progression-free survival, and objective response rate. Of 1455 identified abstracts, 18 studies including 2547 patients were selected. Studies were heterogeneous in study design, treatment, and population. 14 (77%) of 18 studies reported differences among groups in toxicity. 11 (61%) studies reported that chronomodulated chemotherapy resulted in a significant decrease in toxicity while maintaining anti-cancer activity. Two (11%) studies showed that chronomodulated chemotherapy reduced some toxic effects but increased others, and one (6%) study reported worse toxicity outcomes than standard chemotherapy. Three (17%) studies reported improved efficacy (survival measures, objective response rate, or time to treatment failure) of chronomodulated chemotherapy, and no studies reported a decrease in efficacy. In conclusion, most studies provide evidence of the reduction of toxicity resulting from chronomodulated chemotherapy, while efficacy is maintained. More and larger, carefully designed, randomised, controlled trials are needed to provide recommendations for clinical practice.

A Trial within Cohorts (TwiCs) study design is a trial design that uses the infrastructure of an observational cohort study to initiate a randomized trial. Upon cohort enrollment, the participants provide consent for being randomized in future studies without being informed. Once a new treatment is available, eligible cohort participants are randomly assigned to the treatment or standard of care. Patients randomized to the treatment arm are offered the new treatment, which they can choose to refuse. Patients who refuse will receive standard of care instead. Patients randomized to the standard of care arm receive no information about the trial and continue receiving standard of care as part of the cohort study. Standard cohort measures are used for outcome comparisons. The TwiCs study design aims to overcome some issues encountered in standard Randomized Controlled Trials (RCTs). An example of an issue in standard RCTs is the slow patient accrual. A TwiCs study aims to improve this by selecting patients using a cohort and only offering the intervention to patients in the intervention arm. In oncology, the TwiCs study design has gained increasing interest during the last decade. Despite its potential advantages over RCTs, the TwiCs study design has several methodological challenges that need careful consideration when planning a TwiCs study. In this article, we focus on these challenges and reflect on them using experiences from TwiCs studies initiated in oncology. Important methodological challenges that are discussed are the timing of randomization, the issue of non-compliance (refusal) after randomization in the intervention arm, and the definition of the intention-to-treat effect in a TwiCs study and how this effect is related to its counterpart in standard RCTs.

Background Whether cancer risk associated with a higher body mass index (BMI), a surrogate measure of adiposity, differs among adults with and without cardiovascular diseases (CVD) and/or type 2 diabetes (T2D) is unclear. The primary aim of this study was to evaluate separate and joint associations of BMI and CVD/T2D with the risk of cancer. Methods This is an individual participant data meta-analysis of two prospective cohort studies, the UK Biobank (UKB) and the European Prospective Investigation into Cancer and nutrition (EPIC), with a total of 577,343 adults, free of cancer, T2D, and CVD at recruitment. We used Cox proportional hazard regressions to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and incidence of obesity-related cancer and in turn overall cancer with a multiplicative interaction between BMI and the two cardiometabolic diseases (CMD). HRs and 95% CIs for separate and joint associations for categories of overweight/obesity and CMD status were estimated, and additive interaction was quantified through relative excess risk due to interaction (RERI). Results In the meta-analysis of both cohorts, BMI (per ~ 5 kg/m 2 ) was positively associated with the risk of obesity-related cancer among participants without a CMD (HR: 1.11, 95%CI: 1.07,1.16), among participants with T2D (HR: 1.11, 95% CI: 1.05,1.18), among participants with CVD (HR: 1.17, 95% CI: 1.11,1.24), and suggestively positive among those with both T2D and CVD (HR: 1.09, 95% CI: 0.94,1.25). An additive interaction between obesity (BMI ≥ 30 kg/m 2 ) and CVD with the risk of overall cancer translated into a meta-analytical RERI of 0.28 (95% CI: 0.09–0.47). Conclusions Irrespective of CMD status, higher BMI increased the risk of obesity-related cancer among European adults. The additive interaction between obesity and CVD suggests that obesity prevention would translate into a greater cancer risk reduction among population groups with CVD than among the general population.

For an exercise intervention to be successful, it is important that cancer survivors adhere to the prescribed program. To be able to improve adherence and to preserve achieved beneficial effects, insights into the relevant and modifiable determinants is important. Therefore, we aimed to systematically review determinants of exercise adherence and maintenance in cancer survivors using a socio-ecological approach. Studies were identified in PubMed, Embase, PsycINFO and SPORTDiscus up to July 2013. We included full-text articles that: 1) were conducted among adult cancer survivors; 2) quantitatively assessed factors associated with intervention adherence and maintenance, and 3) were published in English. The methodological quality of the selected studies was examined. A best evidence synthesis was applied. Eighteen studies were included. Median methodological quality was 53% and ranged from 21-78% of maximum score. Twelve studies focused on determinants of exercise adherence and evaluated 71 potential determinants: 29 demographic and clinical, 27 psychological, ten physical, four social factors, and one environmental factor. Six studies focused on determinants of exercise maintenance after completion of an intervention, and investigated 63 factors: 22 demographic and clinical, 28 psychosocial, nine physical, three social and one environmental factor. We found moderate evidence for a positive association between exercise history and exercise adherence. Inconsistent findings were found for age, gender and education as well as for psychological factors such as stage of change, perceived behavioral control, self-efficacy, extraversion, attitude, intention, fatigue, and quality of life, and physical factors including cardiovascular fitness, body mass index, and baseline physical activity. Exercise history is positively associated with exercise adherence. Future trials should further study the influence of social and environmental determinants on exercise adherence and maintenance in addition to demographic, psychological and physical determinants.

Important considerations for exercise trials in cancer patients are contamination and differential drop-out among the control group members that might jeopardize the internal validity. This systematic review provides an overview of different control groups design characteristics of exercise-oncology trials and explores the association with contamination and drop-out rates. Randomized controlled exercise-oncology trials from two Cochrane reviews were included. Additionally, a computer-aided search using Medline (Pubmed), Embase and CINAHL was conducted after completion date of the Cochrane reviews. Eligible studies were classified according to three control group design characteristics: the exercise instruction given to controls before start of the study (exercise allowed or not); and the intervention the control group was offered during (any (e.g., education sessions or telephone contacts) or none) or after (any (e.g., cross-over or exercise instruction) or none) the intervention period. Contamination (yes or no) and excess drop-out rates (i.e., drop-out rate of the control group minus the drop-out rate exercise group) were described according to the three design characteristics of the control group and according to the combinations of these three characteristics; so we additionally made subgroups based on combinations of type and timing of instructions received. 40 exercise-oncology trials were included based on pre-specified eligibility criteria. The lowest contamination (7.1% of studies) and low drop-out rates (excess drop-out rate -4.7±9.2) were found in control groups offered an intervention after the intervention period. When control groups were offered an intervention both during and after the intervention period, contamination (0%) and excess drop-out rates (-10.0±12.8%) were even lower. Control groups receiving an intervention during and after the study intervention period have lower contamination and drop-out rates. The present findings can be considered when designing future exercise-oncology trials.

Background Physical inactivity and being overweight are modifiable lifestyle risk factors that consistently have been associated with a higher risk of postmenopausal breast cancer in observational studies. One biologic hypothesis underlying this relationship may be via endogenous sex hormone levels. It is unclear if changes in dietary intake, physical activity, or both, are most effective in changing these hormone levels. Objective This systematic review and meta-analysis examines the effect of reduced caloric dietary intake and/or increased exercise levels on breast cancer-related endogenous sex hormones. Methods We conducted a systematic literature search in MEDLINE, Embase, and Cochrane’s Central Register of Controlled Trials (CENTRAL) up to March 2017. Main outcome measures were breast cancer-related endogenous sex hormones. Randomized controlled trials (RCTs) reporting effects of reduced caloric intake and/or exercise interventions on endogenous sex hormones in healthy, physically inactive postmenopausal women were included. Studies including women using hormone therapy were excluded. The methodological quality of each study was assessed by the Cochrane’s risk of bias tool. Results From the 2599 articles retrieved, seven articles from six RCTs were included in this meta-analysis. These trials investigated 1588 healthy postmenopausal women with a mean age ranging from 58 to 61 years. A combined intervention of reduced caloric intake and exercise, with durations ranging from 16 to 52 weeks, compared with a control group (without an intervention to achieve weight loss) resulted in the largest beneficial effects on estrone treatment effect ratio (TER) = 0.90 (95% confidence interval (CI) = 0.83–0.97), total estradiol TER = 0.82 (0.75–0.90), free estradiol TER = 0.73 (0.66–0.81), free testosterone TER = 0.86 (0.79–0.93), and sex hormone biding globulin (SHBG) TER = 1.23 (1.15–1.31). A reduced caloric intake without an exercise intervention resulted in significant effects compared with control on total estradiol TER = 0.86 (0.77–0.95), free estradiol TER = 0.77 (0.69–0.84), free testosterone TER = 0.91 (0.84–0.98), and SHBG TER = 1.20 (1.06–1.36). Exercise without dietary change, versus control, resulted in borderline significant effects on androstenedione TER = 0.97 (0.94–1.00), total estradiol TER = 0. 97 (0.94–1.00), and free testosterone TER = 0. 0.97 (0.95–1.00). Conclusions and relevance This meta-analysis of six RCTs demonstrated that there are beneficial effects of exercise, reduced caloric dietary intake or, preferably, a combination of exercise and diet on breast cancer-related endogenous sex hormones in physically inactive postmenopausal women.

Maintaining high adherence rates (session attendance and compliance) in exercise programs during breast cancer treatment can be challenging. We aimed to identify adherence rates and predictors to an exercise program during adjuvant breast cancer treatment. Ninety-two patients with localized breast cancer undergoing chemotherapy were randomly assigned to an 18-week supervised moderate-to-high intensity aerobic and resistance exercise program, including two 1-hour sessions/week. Additionally, participants were asked to be physically active for at least 30 minutes/day on at least three other days. We report median percentages for attendance, compliance with the prescribed duration and intensity of aerobic and muscle strength exercises, and the exercise advice given. Predictors included in univariate and multivariable linear regression models were demographical, tumor- and treatment-related factors, constructs of the theory of planned behavior, psychological and physical factors. Patients attended 83% (interquartile range: 69-91%) of the supervised sessions. Compliance with the duration of aerobic exercise, high-intensity aerobic exercise (cycling at the ventilatory threshold), muscle strength exercises and the exercise advice were 88%(64-97%), 50%(22-82%), 84%(65-94%) and 61%(33%-79%), respectively. Education, radiotherapy, BMI and physical fatigue were important predictors of adherence to supervised exercise. Beliefs about planned behaviors were important predictors, especially for compliance with the exercise advice. Attendance to and compliance with an 18-week aerobic and strength exercise program were high. The lowest compliance was found for high-intensity supervised aerobic exercise. The identified predictors should be considered when designing or adapting exercise programs for patients with localized breast cancer to increase adherence. Current Controlled Trials ISRCTN43801571 Dutch Trial Register NTR2138.