Effect of physical exercise on the hippocampus and global grey matter volume in breast cancer patients: A randomized controlled trial (PAM study).

BACKGROUND: Physical exercise in cancer patients is a promising intervention to improve cognition and increase brain volume, including hippocampal volume. We investigated whether a 6-month exercise intervention primarily impacts total hippocampal volume and additionally hippocampal subfield volumes, cortical thickness and grey matter volume in previously physically inactive breast cancer patients. Furthermore, we evaluated associations with verbal memory. METHODS: Chemotherapy-exposed breast cancer patients (stage I-III, 2-4 years post diagnosis) with cognitive problems were included and randomized in an exercise intervention (n = 70, age = 52.5 ± 9.0 years) or control group (n = 72, age = 53.2 ± 8.6 years). The intervention consisted of 2x1 hours/week of supervised aerobic and strength training and 2x1 hours/week Nordic or power walking. At baseline and at 6-month follow-up, volumetric brain measures were derived from 3D T1-weighted 3T magnetic resonance imaging scans, including hippocampal (subfield) volume (FreeSurfer), cortical thickness (CAT12), and grey matter volume (voxel-based morphometry CAT12). Physical fitness was measured with a cardiopulmonary exercise test. Memory functioning was measured with the Hopkins Verbal Learning Test-Revised (HVLT-R total recall) and Wordlist Learning of an online cognitive test battery, the Amsterdam Cognition Scan (ACS Wordlist Learning). An explorative analysis was conducted in highly fatigued patients (score of ≥ 39 on the symptom scale 'fatigue' of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), as previous research in this dataset has shown that the intervention improved cognition only in these patients. RESULTS: Multiple regression analyses and voxel-based morphometry revealed no significant intervention effects on brain volume, although at baseline increased physical fitness was significantly related to larger brain volume (e.g., total hippocampal volume: R = 0.32, B = 21.7 mm3, 95 % CI = 3.0 - 40.4). Subgroup analyses showed an intervention effect in highly fatigued patients. Unexpectedly, these patients had significant reductions in hippocampal volume, compared to the control group (e.g., total hippocampal volume: B = -52.3 mm3, 95 % CI = -100.3 - -4.4)), which was related to improved memory functioning (HVLT-R total recall: B = -0.022, 95 % CI = -0.039 - -0.005; ACS Wordlist Learning: B = -0.039, 95 % CI = -0.062 - -0.015). CONCLUSIONS: No exercise intervention effects were found on hippocampal volume, hippocampal subfield volumes, cortical thickness or grey matter volume for the entire intervention group. Contrary to what we expected, in highly fatigued patients a reduction in hippocampal volume was found after the intervention, which was related to improved memory functioning. These results suggest that physical fitness may benefit cognition in specific groups and stress the importance of further research into the biological basis of this finding.

Effect of physical exercise on cognitive function after chemotherapy in patients with breast cancer: a randomized controlled trial (PAM study).

BACKGROUND: Up to 60% of breast cancer patients treated with chemotherapy is confronted with cognitive problems, which can have a significant impact on daily activities and quality of life (QoL). We investigated whether exercise training improves cognition in chemotherapy-exposed breast cancer patients 2-4 years after diagnosis. METHODS: Chemotherapy-exposed breast cancer patients, with both self-reported cognitive problems and lower than expected performance on neuropsychological tests, were randomized to an exercise or control group. The 6-month exercise intervention consisted of supervised aerobic and strength training (2 h/week), and Nordic/power walking (2 h/week). Our primary outcome was memory functioning (Hopkins Verbal Learning Test-Revised; HVLT-R). Secondary outcomes included online neuropsychological tests (Amsterdam Cognition Scan; ACS), self-reported cognition (MD Anderson Symptom Inventory for multiple myeloma; MDASI-MM), physical fitness (relative maximum oxygen uptake; VO2peak), fatigue (Multidimensional Fatigue Inventory), QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ C-30), depression (Patient Health Questionnaire-9, Hospital Anxiety and Depression Scale; HADS), and anxiety (HADS). HVLT-R total recall was analyzed with a Fisher exact test for clinically relevant improvement (≥ 5 words). Other outcomes were analyzed using multiple regression analyses adjusted for baseline and stratification factors. RESULTS: We randomized 181 patients to the exercise (n = 91) or control group (n = 90). Two-third of the patients attended ≥ 80% of the exercise sessions, and physical fitness significantly improved compared to control patients (B VO2peak 1.4 ml/min/kg, 95%CI:0.6;2.2). No difference in favor of the intervention group was seen on the primary outcome. Significant beneficial intervention effects were found for self-reported cognitive functioning [MDASI-MM severity (B-0.7, 95% CI - 1.2; - 0.1)], fatigue, QoL, and depression. A hypothesis-driven analysis in highly fatigued patients showed positive exercise effects on tested cognitive functioning [ACS Reaction Time (B-26.8, 95% CI - 52.9; - 0.6) and ACS Wordlist Learning (B4.4, 95% CI 0.5; 8.3)]. CONCLUSIONS: A 6-month exercise intervention improved self-reported cognitive functioning, physical fitness, fatigue, QoL, and depression in chemotherapy-exposed breast cancer patients with cognitive problems. Tested cognitive functioning was not affected. However, subgroup analysis indicated a positive effect of exercise on tested cognitive functioning in highly fatigued patients. Trial Registration Netherlands Trial Registry: Trial NL5924 (NTR6104). Registered 24 October 2016, https://www.trialregister.nl/trial/5924 .

Effect of physical exercise on cognitive function and brain measures after chemotherapy in patients with breast cancer (PAM study): protocol of a randomised controlled trial.

INTRODUCTION: After treatment with chemotherapy, many patients with breast cancer experience cognitive problems. While limited interventions are available to improve cognitive functioning, physical exercise showed positive effects in healthy older adults and people with mild cognitive impairment. The Physical Activity and Memory study aims to investigate the effect of physical exercise on cognitive functioning and brain measures in chemotherapy-exposed patients with breast cancer with cognitive problems. METHODS AND ANALYTICS: One hundred and eighty patients with breast cancer with cognitive problems 2-4 years after diagnosis are randomised (1:1) into an exercise intervention or a control group. The 6-month exercise intervention consists of twice a week 1-hour aerobic and strength exercises supervised by a physiotherapist and twice a week 1-hour Nordic or power walking. The control group is asked to maintain their habitual activity pattern during 6 months. The primary outcome (verbal learning) is measured at baseline and 6 months. Further measurements include online neuropsychological tests, self-reported cognitive complaints, a 3-tesla brain MRI, patient-reported outcomes (quality of life, fatigue, depression, anxiety, work performance), blood sampling and physical fitness. The MRI scans and blood sampling will be used to gain insight into underlying mechanisms. At 18 months online neuropsychological tests, self-reported cognitive complaints and patient-reported outcomes will be repeated. ETHICS AND DISSEMINATION: Study results may impact usual care if physical exercise improves cognitive functioning for breast cancer survivors. TRIAL REGISTRATION NUMBER: NTR6104.

Physical activity levels of women with breast cancer during and after treatment, a comparison with the Dutch female population.

Background: Physical activity has been shown to reduce side-effects of breast cancer and its treatment. As physical activity levels of patients with breast cancer are largely unknown, we investigated these levels and compared them to women from the general population. Methods: In this prospective cohort study, physical activity levels of women with breast cancer participating in the UMBRELLA cohort were assessed at radiotherapy intake and thereafter every 6 months up to 3 years with the SQUASH questionnaire, which was also used in a random sample of the Dutch population. We compared physical activity levels (no activity, low, moderate or high levels of sports, leisure time or total activity) between patients and the Dutch female population using multinomial logistic regression. Standardized Prevalence Ratios (SPR) were calculated to compare adherence to Dutch physical activity guidelines. Results: Women with breast cancer (nbaseline = 1655, n6 months = 1414, n12 months = 1186, n18 months = 957, n24 months = 744, n30 months = 555, and n36 months = 377) were less likely to spend time in physical activity compared to the general population (n = 11,710) until 3 years post-diagnosis, especially after 6 months (ORhigh-vs.-no activity = 0.34, 95% CI: 0.28-0.41). From 12 months onwards, patients were more likely to perform sports compared to the general population, especially patients who underwent systemic therapy. Guideline adherence was significantly lower in patients at baseline and 6 months (SPRbaseline = 89, 95% CI: 82-97; SPR6 months = 88, 95% CI: 81-96), and comparable to the general population at 12-36 months, especially in older women. Conclusions: Physical activity levels in women with breast cancer during and after treatment were lower compared to the Dutch female population. Three years post-treatment, they were still less physically active, although they spend more time in sport activities. As about half of the patients did not perform any sports, physical activity needs to be stimulated during and after treatment.

Reasons for (non)participation in supplemental population-based MRI breast screening for women with extremely dense breasts.

AIM: To determine the willingness of women with extremely dense breasts to undergo breast cancer screening with magnetic resonance imaging (MRI) in a research setting, and to examine reasons for women to participate or not. MATERIALS AND METHODS: Between 2011 and 2015, 8,061 women (50-75 years) were invited for supplemental MRI as part of the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial (ClinicalTrials.gov Identifier: NCT01315015), after a negative screening mammography in the national population-based mammography screening programme. Demographics of participants and non-participants were compared. All invitees were asked to report reasons for (non)participation. Ethical approval was obtained. Participants provided written informed consent. RESULTS: Of the 8,061 invitees, 66% answered that they were interested, and 59% eventually participated. Participants were on average 54-years old (interquartile range: 51-59 years), comparable to women with extremely dense breasts in the population-based screening programme (55 years). Women with higher socio-economic status (SES) were more often interested in participation than women with lower SES (68% versus 59%, p<0.001). The most frequently stated reasons for non-participation were "MRI-related inconveniences and/or self-reported contraindications to MRI" (27%) and "anxiety regarding the result of supplemental screening" (21%). "Expected personal health benefit" (68%) and "contribution to science" (43%) were the most frequent reasons for participation. CONCLUSION: Of women invited for MRI because of extremely dense breasts, 59% participated. Common reasons for non-participation were "MRI-related inconveniences" and "anxiety regarding the result of supplemental screening". In case of future implementation, availability of precise evidence on benefits and harms might reduce this anxiety.

The proportion of postmenopausal breast cancer cases in the Netherlands attributable to lifestyle-related risk factors.

We aimed to estimate the proportion of Dutch postmenopausal breast cancer cases in 2010 that is attributable to lifestyle-related risk factors. We calculated population attributable fractions (PAFs) of potentially modifiable risk factors for postmenopausal breast cancer in Dutch women aged >50 in 2010. First, age-specific PAFs were calculated for each risk factor, based on their relative risks for postmenopausal breast cancer (from meta-analyses) and age-specific prevalence in the population (from national surveys) around the year 2000, assuming a latency period of 10 years. To obtain the overall PAF, age-specific PAFs were summed in a weighted manner, using the age-specific breast cancer incidence rates (2010) as weights. 95 % confidence intervals for PAF estimates were derived by Monte Carlo simulations. Of Dutch women >40 years, in 2000, 51 % were overweight/obese, 55 % physically inactive (<5 days/week 30 min activity), 75 % regularly consumed alcohol, 42 % ever smoked cigarettes and 79 % had a low-fibre intake (<3.4 g/1000 kJ/day). These factors combined had a PAF of 25.7 % (95 % CI 24.2-27.2), corresponding to 2,665 Dutch postmenopausal breast cancer cases in 2010. PAFs were 8.8 % (95 % CI 6.3-11.3) for overweight/obesity, 6.6 % (95 % CI 5.2-8.0) for alcohol consumption, 5.5 % (95 % CI 4.0-7.0) for physical inactivity, 4.6 % (95 % CI 3.3-6.0) for smoking and 3.2 % (95 % CI 1.6-4.8) for low-fibre intake. Our findings imply that modifiable risk factors are jointly responsible for approximately one out of four Dutch postmenopausal breast cancer cases. This suggests that incidence rates can be lowered substantially by living a more healthy lifestyle.

Physical activity, sex steroid, and growth factor concentrations in pre- and post-menopausal women: a cross-sectional study within the EPIC cohort.

PURPOSE: Increased physical activity (PA) is associated with a reduced risk of several cancers. PA may reduce cancer risk by changing endogenous hormones levels, but relatively little research has focused on this topic. The purpose of this study was to elucidate the relation between PA and endogenous hormone concentrations. METHODS: A cross-sectional analysis of 798 pre- and 1,360 post-menopausal women included as controls in case-control studies on endogenous hormones (steroids, progesterone, sex-hormone-binding globulin (SHBG), and growth factors) levels, and cancer risk nested within European Prospective Investigation into Cancer and Nutrition cohort was performed. Multivariate regression analyses were performed to compare geometric mean levels of hormones and SHBG by categories of PA. RESULTS: In pre-menopausal women, active women had 19 % significantly lower concentrations of androstenedione, 14 % lower testosterone, and 20 % lower free testosterone than inactive women, while no differences were observed for estrogens, progesterone, SHBG, and growth factors. In post-menopausal women, active women had 18 % significantly lower estradiol and 20 % lower free estradiol concentrations than inactive women, while no differences were observed for the other hormones and SHBG. More vigorous forms of physical activity were associated with higher insulin-like growth factor-I concentrations. Adjustment for body mass index did not alter the associations. Overall, the percentage of variance in hormone concentrations explained by PA levels was <2 %. CONCLUSIONS: Our results support the hypothesis of an influence, although small in magnitude, of PA on sex hormone levels in blood, independent of body size.

Importance of tumor volume in supraglottic and glottic laryngeal carcinoma.

PURPOSE: The aim of our study was to assess the prognostic value of tumor volume compared to and in addition to T-stage on local control (LC), disease-free survival (DFS), and overall survival (OS) in glottic and supraglottic laryngeal carcinoma patients. PATIENTS AND METHODS: In 150 patients, we determined tumor volume on diagnostic CT scans. We applied crude and multivariable Cox regression analysis to relate volume (continuous), T-stage and the combination to 5-year DFS, OS, and LC. Before, we examined the linearity assumption of the association between volume and outcome with restricted cubic spline functions. Prognostic performance of the models was examined by determination of the model's discrimination. Discriminative ability was determined with the C statistic referring to the ability to discriminate between patients who do and do not develop an event during follow-up. RESULTS: A strong association between tumor volume and DFS and OS was found. The restricted cubic spline plot did not indicate a non-linear relationship between tumor volume and DFS and local control. Tumor volume demonstrated a better discriminative ability to predict DFS and OS compared to T-stage (0.68 and 0.57 vs. 0.59 and 0.54, respectively). For local control, T-stage showed a higher discriminative ability than tumor volume (0.63 vs. 0.61). The combined model increased discriminative power (0.69). CONCLUSION: Volume seems to be more important than T-stage in prediction of DFS or OS in laryngeal squamous cell carcinoma patients. Perhaps prediction of DFS, OS, and LC could be improved by including tumor volume into the staging process.

Excised and irradiated volumes in relation to the tumor size in breast-conserving therapy.

In early-stage breast cancer and DCIS patients, breast-conserving therapy is today's standard of care. The purpose of this study was to evaluate the relation between the microscopic tumor diameter (mTD), the excised specimen (ES) volume, and the irradiated postoperative complex (POC) volume, in patients treated with breast-conserving therapy. In 186 patients with pTis-2N0 breast cancer, the mTDs, ES, and POC volumes (as delineated on the radiotherapy-planning CT scan), were retrospectively determined. Linear regression analysis was performed to study the association between the mTD, and the ES and POC volumes. The explained variance (r (2)) was calculated to establish the proportion of variation in the outcome variable that could be explained by the determinant (P ≤ 0.05). Moreover, the influence of tumor characteristics, age, surgical procedures, and breast size was studied. Median mTD was 1.2 cm (range 0.1-3.6 cm), median ES volume was 60 cm(3) (range 6-230 cm(3)) and median POC volume was 15 cm(3) (range 0.5-374 cm(3)). The POC was not clearly visible on the majority of the CT scans, based on a median assigned cavity visualization score of 3 (range 1-5). The explained variance for the mTD on the ES volume was low (r(2) = 0.08, P < 0.001). A slightly stronger association was observed in palpable tumors (r(2) = 0.23, P < 0.001) and invasive lobular carcinomas (r(2) = 0.39, P = 0.01). Furthermore, weak associations were observed between POC volume and mTD (r(2) = 0.04, P = 0.01), and POC and ES volume (r(2) = 0.23, P < 0.001). A weak association was observed between breast volume and ES volume (r(2) = 0.27, P < 0.001). In conclusion, both the excised and the irradiated POC volumes did not show a clinically relevant association with the mTD in women with early-stage breast cancer treated with breast-conserving therapy. Future studies should focus on improvement of surgical localization, development of image-guided, minimally invasive operation techniques, and more accurate image-guided target volume delineation in radiotherapy.

The impact of using different symptom-based exacerbation algorithms in patients with COPD.

Not all exacerbations are captured by reliance on healthcare contacts. Symptom-based exacerbation definitions have shown to provide more adequate measures of exacerbation rates, severity and duration. However, no consensus has been reached on what is the most useful method and algorithm to identify these events. This article provides an overview of the existing symptom-based definitions and tests the hypothesis that differences in exacerbation characteristics depend on the algorithms used. We systematically reviewed symptom-based methods and algorithms used in the literature, and quantified the impact of the four most referenced algorithms on exacerbation-related outcome using an existing chronic obstructive pulmonary disease (COPD) cohort (n = 137). We identified 51 studies meeting our criteria using 14 widely varying symptom algorithms to define onset, severity and recovery. The most (71%) frequently referenced algorithm (modified Anthonisen) identified an incidence rate of 1.7 episodes·patient-yr⁻¹ (95% CI 1.4-2.1), while for requiring only one major or two major symptoms this was 1.9 episodes·patient-yr⁻¹ (95% CI 1.6-2.3) and 1.5 episodes·patient-yr⁻¹ (95% CI 0.6-1.0), respectively. Studies were generally lacking methods to enhance validity and accuracy of symptom recording. This review revealed large inconsistencies in definitions, methods and accuracy to define symptom-based COPD exacerbations. We demonstrated that minor changes in symptom criteria substantially affect incidence rates, clustering type and classification of exacerbations.

Self-management education for patients with chronic obstructive pulmonary disease.

BACKGROUND: There is great interest in chronic obstructive pulmonary disease (COPD) and the associated large burden of disease. COPD is characterised by frequent day by day fluctuations, and repetitive clinical exacerbations are typical. Self-management is a term applied to educational programmes aimed at teaching skills needed to carry out medical regimens specific to the disease, guide health behaviour change, and provide emotional support for patients to control their disease and live functional lives. In COPD, the value of self-management education is not yet clear. The first Cochrane review about self-management was published in 2003. It was intended to shed light on the effectiveness of self-management programmes in COPD and the relative efficacy of their constitutive elements. No conclusions about the effectiveness of self-management could be drawn because of the large variation in outcome measures used in the limited number of included studies. This article describes the first update of this review. OBJECTIVES: The objective of this review was to assess the settings, methods and efficacy of COPD self-management education programmes on health outcomes and use of health care services. SEARCH STRATEGY: We searched the Cochrane Airways Group trial register, MEDLINE (January 1985 to January 2006), reference lists, and abstracts of medical conferences. SELECTION CRITERIA: Controlled trials (randomised and non-randomised) of self-management education in patients with COPD. Studies focusing mainly on pulmonary rehabilitation and studies without usual care as a control group were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study quality and extracted data. Investigators were contacted for additional information. MAIN RESULTS: The reviewers included 15 group comparisons drawn from 14 trials. They assessed a broad-spectrum of interventions and health outcomes with different follow-up times. Meta-analyses could often not appropriately be performed because of heterogeneity among studies. The studies showed a significant reduction in the probability of at least one hospital admission among patients receiving self-management education compared to those receiving usual care (OR 0.64; 95% CI (0.47 to 0.89)). This translates into a one year NNT ranging from 10 (6 to 35) for patients with a 51% risk of exacerbation, to an NNT of 24 (16 to 80) for patients with a 13% risk of exacerbation. On the disease specific SGRQ, differences reached statistical significance at the 5% level on the total score (WMD -2.58; 95% CI (-5.14 to -0.02)) and impact domain (WMD -2.83; 95% CI (-5.65 to -0.02)), but these difference did not reach the clinically relevant improvement of 4 points. A small but significant reduction was detected in dyspnoea measured with the BORG-scale (WMD -0.53; 95% CI (-0.96 to -0.10)). No significant effects were found either in number of exacerbations, emergency department visits, lung function, exercise capacity, and days lost from work. Inconclusive results were observed in doctor and nurse visits, on symptoms other than dyspnoea, the use of courses of oral corticosteroids and antibiotics, and the use of rescue medication. AUTHORS' CONCLUSIONS: It is likely that self-management education is associated with a reduction in hospital admissions with no indications for detrimental effects in other outcome parameters. This would in itself already be enough reason for recommending self-management education in COPD. However, because of heterogeneity in interventions, study populations, follow-up time, and outcome measures, data are still insufficient to formulate clear recommendations regarding the form and contents of self-management education programmes in COPD. There is an evident need for more large RCTs with a long-term follow-up, before more conclusions can be drawn.

Self-management education for chronic obstructive pulmonary disease.

BACKGROUND: In asthma, self-management programmes have been proven to be effective. In COPD, their value is not clear. OBJECTIVES: To assess the efficacy of COPD self-management/ education programmes on health outcomes and use of health services SEARCH STRATEGY: We searched the Cochrane Airways Group trial registers, MEDLINE (January 1985 to October 2001), reference lists, and abstracts of medical conferences. We also contacted research groups in the field for ongoing trials and unpublished material. SELECTION CRITERIA: Controlled trials (randomised and non-randomised) of self-management education in patients with COPD. Studies focusing mainly on physical pulmonary rehabilitation were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Investigators were contacted for additional information. MAIN RESULTS: The reviewers included 12 articles describing 8 randomised-controlled trials and 1 controlled clinical trial. Self-management education was compared with usual care in 8 studies. The studies in this review assessed a broad-spectrum of outcome measures with different follow-up times. Synthesis of the results using meta-analysis was always not possible. The studies showed no effect of self-management education on hospital admissions, emergency room visits, days lost from work and lung function. Inconclusive results were observed on health-related quality of life (HRQoL): studies using the disease specific SGRQ showed a better quality of life in the patients in the intervention group, but only in the activity component where there was heterogeneity between the results of the two included studies. A potential reason for the absence of convincing effects on HRQoL is the limited use of COPD-specific instruments. Inconclusive results were observed on COPD-symptoms and use of other health care resources such as doctor and nurse visits. Self-management education reduced the need for rescue medication, and led to an increased use of courses of oral steroids and antibiotics for respiratory symptoms. REVIEWER'S CONCLUSIONS: The data available for this review are insufficient for forming recommendations. Further research on the effectiveness of self-management programmes should be focussed on behavioural change evaluated in well designed randomised controlled trials with standardised outcomes designed for use in COPD patients, and with long follow-up time so that definite conclusions can be made.

Early age at menopause and breast cancer: are leaner women more protected? A prospective analysis of the Dutch DOM cohort.

To investigate the relationship between age at menopause, body mass index, and breast cancer risk, we used data from a prospective cohort study (DOM cohort) in the Netherlands. Participants in this breast cancer-screening project included 10,591 women living in Utrecht, aged 49-66 years at enrolment. During a median follow-up period of 19 years, women attended screening rounds at which anthropometric measurements were taken and questions were asked about menopausal status, age at menopause, medication use and other risk factors for breast cancer. Cox regression analysis was used to investigate the relationship between age at menopause and subsequent breast cancer risk. Breast cancer incidence decreased with an earlier age at menopause. Women with a menopausal age of 44 years or younger had a 34% lower risk of breast cancer, than women with a menopausal age over 54 years (hazard ratio is 0.66 (95% confidence interval 0.43-0.91)). The annual hazard of breast cancer incidence decreased by 2.6% per year reduction in age at menopause. The protective effect of an early age at menopause was stronger for women with a low body mass index (< or = 27 kg/m2; reduction of 44%) than for women with a high body mass index (>27 kg/m2; reduction of 24%), although this difference was not statistically significant (P for interaction = 0.58). This difference was most pronounced in women who had ever smoked. Adjustment for known breast cancer risk factors did not alter the crude risk estimates significantly. In conclusion, this study provides evidence of the protective effect of lower age at menopause on subsequent breast cancer risk. This protective effect may be even stronger in leaner women.