A scoping review evaluating physical and cognitive functional outcomes in cancer survivors treated with chemotherapy: charting progress since the 2018 NCI think tank on cancer and aging phenotypes.

PURPOSE: The primary goal of this scoping review was to summarize the literature published after the 2018 National Cancer Institute think tank, "Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors," on physical and cognitive functional outcomes among cancer survivors treated with chemotherapy. We focused on the influence of chemotherapy on aging-related outcomes (i.e., physical functional outcomes, cognitive functional outcomes, and frailty), given the known associations between chemotherapy and biologic mechanisms that affect aging-related physiologic processes. METHODS: A search was conducted across electronic databases, including PubMed, Scopus, and Web of Science, for manuscripts published between August 2018 and July 2023. Eligible studies: 1) included physical function, cognitive function, and/or frailty as outcomes; 2) included cancer survivors (as either the whole sample or a subgroup); 3) reported on physical or cognitive functional outcomes and/or frailty related to chemotherapy treatment (as either the whole sample or a subgroup); and 4) were observational in study design. RESULTS: The search yielded 989 potentially relevant articles, of which 65 met the eligibility criteria. Of the 65 studies, 49 were longitudinal, and 16 were cross-sectional; 30 studies (46%) focused on breast cancer, 20 studies (31%) focused on the age group 60 + years, and 17 (26%) focused on childhood cancer survivors. With regards to outcomes, 82% of 23 studies reporting on physical function showed reduced physical function, 74% of 39 studies reporting on cognitive functional outcomes found reduced cognitive function, and 80% of 15 studies reporting on frailty found increasing frailty among cancer survivors treated with chemotherapy over time and/or compared to individuals not treated with chemotherapy. Fourteen studies (22%) evaluated biologic mechanisms and their relationship to aging-related outcomes. Inflammation was consistently associated with worsening physical and cognitive functional outcomes and epigenetic age increases. Further, DNA damage was consistently associated with worse aging-related outcomes. CONCLUSION: Chemotherapy is associated with reduced physical function, reduced cognitive function, and an increase in frailty in cancer survivors; these associations were demonstrated in longitudinal and cross-sectional studies. Inflammation and epigenetic age acceleration are associated with worse physical and cognitive function; prospective observational studies with multiple time points are needed to confirm these findings. IMPLICATIONS FOR CANCER SURVIVORS: This scoping review highlights the need for interventions to prevent declines in physical and cognitive function in cancer survivors who have received chemotherapy.

High-dose vitamin D to attenuate bone loss in patients with prostate cancer on androgen deprivation therapy: A phase 2 RCT.

BACKGROUND: Androgen deprivation therapy (ADT) inhibits prostate cancer growth. However, ADT causes loss of bone mineral density (BMD) and an increase in fracture risk; effective interventions for ADT-induced bone loss are limited. METHODS: A phase 2 randomized controlled trial investigated the feasibility, safety, and preliminary efficacy of high-dose weekly vitamin D (HDVD, 50,000 IU/week) versus placebo for 24 weeks in patients with prostate cancer receiving ADT, with all subjects receiving 600 IU/day vitamin D and 1000 mg/day calcium. Participants were ≥60 years (mean years, 67.7), had a serum 25-hydroxyvitamin D level <32 ng/mL, and initiated ADT within the previous 6 months. At baseline and after intervention, dual-energy x-ray absorptiometry was used to assess BMD, and levels of bone cell, bone formation, and resorption were measured. RESULTS: The HDVD group (N = 29) lost 1.5% BMD at the total hip vs. 4.1% for the low-dose group (N = 30; p = .03) and 1.7% BMD at the femoral neck vs. 4.4% in the low-dose group (p = .06). Stratified analyses showed that, for those with baseline 25-hydroxyvitamin D level <27 ng/mL, the HDVD group lost 2.3% BMD at the total hip vs 7.1% for the low-dose group (p < .01). Those in the HDVD arm showed significant changes in parathyroid hormone (p < .01), osteoprotegerin (p < 0.01), N-terminal telopeptide of type 1 collagen (p < 0.01) and C-terminal telopeptide of type 1 collagen (p < 0.01). No difference in adverse events or toxicity was noted between the groups. CONCLUSIONS: HDVD supplementation significantly reduced hip and femoral neck BMD loss, especially for patients with low baseline serum 25-hydroxyvitamin D levels, although demonstrating safety and feasibility in prostate cancer patients on ADT.

A whole food, plant-based randomized controlled trial in metastatic breast cancer: feasibility, nutrient, and patient-reported outcomes.

PURPOSE: Quality of life (QOL) is among the most important outcomes for women with metastatic breast cancer (MBC), and it predicts survival. QOL is negatively impacted by cognitive impairment, fatigue, and weight gain. We assessed whether a whole food, plant-based (WFPB) diet-promoting weight loss is feasible and might improve QOL. METHODS: Women with MBC on stable systemic treatments were randomized 2:1 to 1) WFPB dietary intervention (n = 21) or 2) usual care (n = 11) for 8 weeks. Participants attended weekly education visits and consumed an ad libitum WFPB diet (3 prepared meals/day provided). Patient-reported outcomes and 3-day food records were assessed at baseline and 8 weeks. The effects of WFPB diet on changes in outcomes were assessed by analysis of covariance model controlling for baseline. RESULTS: 20 intervention and 10 control participants completed the trial. Intervention participants were highly adherent to the WFPB diet (94.3 % total calories on-plan). Intervention group nutrient intakes changed significantly including dietary fat (35.8 % to 20.4 % percent calories from fat, p < 0.001) and fiber content (12.7 to 30.8 g fiber/1000 kcal, p < 0.001). Perceived cognitive function (FACT-Cog total + 16.1; 95 % confidence interval [CI] = 0.8-31.7; p = 0.040) and emotional well-being (FACT-B emotional well-being subscale + 2.3; CI = 0.5-4.1; p = 0.016) improved in the WFPB versus the control group. Fatigue, measured by the BFI, improved within the WFPB group for fatigue severity (M = 4.7 ± 2.5[SD] to 3.7 ± 2.3, p = 0.047) and fatigue at its worst (5.8 ± 2.8 to 4.4 ± 2.4, p = 0.011). CONCLUSIONS: Significant dietary changes in this population are feasible and may improve QOL by improving treatment-related symptoms. Additional study is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03045289. Registered 7 February 2017.

A whole-food, plant-based randomized controlled trial in metastatic breast cancer: weight, cardiometabolic, and hormonal outcomes.

PURPOSE: Breast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy. METHODS: Women with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole-food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks. RESULTS: Within the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01), and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15-3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline. CONCLUSION: WFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight, cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes. Trial registration First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017.

Exercise and inflammatory cytokine regulation among older adults with myeloid malignancies.

Tumor necrosis factor (TNF)α is a major regulator of inflammation. However, the epigenetic regulation of TNFα in the context of an exercise intervention among older adults with cancer is understudied. In this exploratory analysis, we used data from a single-arm mobile health (mHealth) exercise intervention among older adults with myeloid malignancies to 1) assess changes in TNFα promoter methylation, TNFα mRNA expression, serum TNFα and other related-cytokine levels after intervention; and 2) assess correlations between blood markers and exercise levels. Twenty patients were included. From baseline to post-intervention, there was no statistical changes in TNFα promoter methylation status at seven CpG sites, TNFα mRNA expression, and serum TNFα levels. Effect sizes, however, were moderate to large for several CpG sites (-120, -147, -162, and -164; Cohen's d = 0.44-0.75). Median serum TNFα sR1 levels increased (83.63, IQR 130.58, p = 0.06; Cohen's d = 0.18) but not the other cytokines. Increases in average daily steps were correlated with increases in TNFα promoter methylation at CpG sites -147 (r = 0.48; p = 0.06) and -164 (r = 0.51; p = 0.04). Resistance training minutes were negatively correlated with TNFα promoter methylation at CpG site -120 (r = -0.62; p = 0.02). All effect sizes were moderate to large. In conclusion, after a mHealth exercise intervention, we demonstrated changes with moderate to large effect sizes in several CpG sites in the TNFα promoter region. Exercise levels were correlated with increases in TNFα promoter methylation. Larger exercise trials are needed to better evaluate TNFα regulation to inform interventions to augment TNFα regulation in order to improve outcomes in older adults with cancer.

Epigenetic and inflammatory markers in older adults with cancer: A Young International Society of Geriatric Oncology narrative review.

The number of adults aged ≥ 65 years with cancer is rapidly increasing. Older adults with cancer are susceptible to treatment-related acute and chronic adverse events, resulting in loss of independence, reduction in physical function, and decreased quality of life. Nevertheless, evidence-based interventions to prevent or treat acute and chronic adverse events in older adults with cancer are limited. Several promising blood-based biomarkers related to inflammation and epigenetic modifications are available to identify older adults with cancer who are at increased risk of accelerated aging and physical, functional, and cognitive impairments caused by the cancer and its treatment. Inflammatory changes and epigenetic modifications can be reversible and targeted by lifestyle changes and interventions. Here we discuss ways in which changes in inflammatory and epigenetic pathways influence the aging process and how these pathways can be targeted by interventions aimed at reducing inflammation and aging-associated biological markers. As the number of older adults with cancer entering survivorship continues to increase, it is becoming progressively more important to understand ways in which the benefit from treatment can be enhanced while reducing the effects of accelerated aging.

A Whole Food, Plant-Based Randomized Controlled Trial in Metastatic Breast Cancer: Feasibility, Nutrient, and Patient-Reported Outcomes.

Purpose: Quality of life (QOL) is among the most important outcomes for women with metastatic breast cancer (MBC) and it predicts survival. QOL is negatively impacted by cognitive impairment, fatigue, and weight gain. We assessed whether a whole food, plant-based (WFPB) diet promoting weight loss is feasible and might improve QOL. Methods: Women with MBC on stable systemic treatments were randomized 2:1 to 1) WFPB dietary intervention (n = 21) or 2) usual care (n = 11) for 8 weeks. Participants attended weekly education visits and consumed an ad libitum WFPB diet (3 prepared meals/day provided). Patient-reported outcomes and 3-day food records were assessed at baseline and 8 weeks. The effects of WFPB diet on changes in outcomes were assessed by analysis of covariance model controlling for baseline. Results: 20 intervention and 10 control participants completed the trial. Intervention participants were highly adherent to the WFPB diet (94.3% total calories on-plan). Intervention group nutrient intakes changed significantly including dietary fat (35.8-20.4% percent calories from fat, p < 0.001) and fiber content (22.1 to 40.8 grams fiber/1000 kcal, p < 0.001). Perceived cognitive function (FACT-Cog total + 16.1; 95% confidence interval [CI] = 0.8-31.7; p = 0.040) and emotional well-being (FACT-B emotional well-being subscale + 2.3; CI = 0.5-4.1; p = 0.016) improved in the WFPB versus the control group. Fatigue, measured by the BFI, improved within the WFPB group for fatigue severity (M = 4.7 ± 2.5[SD] to 3.7 ± 2.3, p = 0.047) and fatigue at its worst (5.8 ± 2.8 to 4.4 ± 2.4, p = 0.011). Conclusions: Significant dietary changes in this population are feasible and may improve QOL by improving treatment-related symptoms. Additional study is warranted. Trial registration: ClinicalTrials.gov identifier: NCT03045289. Registered 7 February 2017.

Association of Radiation Dose to the Amygdala-Orbitofrontal Network with Emotion Recognition Task Performance in Patients with Low-Grade and Benign Brain Tumors.

BACKGROUND: Although data are limited, difficulty in social cognition occurs in up to 83% of patients with brain tumors. It is unknown whether cranial radiation therapy (RT) dose to the amygdala-orbitofrontal network can impact social cognition. METHODS: We prospectively enrolled 51 patients with low-grade and benign brain tumors planned for cranial RT. We assessed longitudinal changes on an emotion recognition task (ERT) that measures the ability to recognize emotional states by displaying faces expressing six basic emotions and their association with the RT dose to the amygdala-orbitofrontal network. ERT outcomes included the median time to choose a response (ERTOMDRT) or correct response (ERTOMDCRT) and total correct responses (ERTHH). RESULTS: The RT dose to the amygdala-orbitofrontal network was significantly associated with longer median response times on the ERT. Increases in median response times occurred at lower doses than decreases in total correct responses. The medial orbitofrontal cortex was the most important variable on regression trees predicting change in the ERTOMDCRT. DISCUSSION: This is, to our knowledge, the first study to show that off-target RT dose to the amygdala-orbitofrontal network is associated with performance on a social cognition task, a facet of cognition that has previously not been mechanistically studied after cranial RT.

Effects of mammary cancer and chemotherapy on neuroimmunological markers and memory function in a preclinical mouse model.

Treatment modalities for breast cancer, including cyclophosphamide chemotherapy, have been associated with the development of cognitive decline (CRCD), which is characterized by impairments in memory, concentration, attention, and executive functions. We and others have identified a link between inflammation and decreased cognitive performance in patients with breast cancer receiving chemotherapy. In order to better understand the inflammation-associated molecular changes within the brain related to tumor alone or in combination with chemotherapy, we orthotopically implanted mouse mammary tumors (E0771) into female C57BL/6 mice and administered clinically relevant doses of cyclophosphamide and doxorubicin intravenously at weekly intervals for four weeks. We measured serum cytokines and markers of neuroinflammation at 48 h and up to one month post-treatment and tested memory using a reward-based delayed spatial alternation paradigm. We found that breast tumors and chemotherapy altered systemic inflammation and neuroinflammation. We further found that the presence of tumor and chemotherapy led to a decline in memory over time at the longest delay, when memory was the most taxed, compared to shorter delay times. These findings in a clinically relevant mouse model shed light on possible biomarkers for CRCD and add to the growing evidence that anti-inflammatory strategies have the potential to mitigate cancer- or treatment-related side effects.

A Whole-Food, Plant-Based Randomized Controlled Trial in Metastatic Breast Cancer: Weight, Cardiometabolic, and Hormonal Outcome.

Purpose: Breast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy. Methods: Women with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks. Results: Within the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01) and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15 - 3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline. Conclusion: WFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight and cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes. Trial registration: First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017.

Relationships among Inflammatory Biomarkers and Objectively Assessed Physical Activity and Sleep during and after Chemotherapy for Gynecologic Malignancies.

Little is known regarding associations between inflammatory biomarkers and objectively measured physical activity and sleep during and after chemotherapy for gynecologic cancer; thus, we conducted a longitudinal study to address this gap. Women with gynecologic cancer (patients) and non-cancer controls (controls) completed assessments before chemotherapy cycles 1, 3, and 6 (controls assessed contemporaneously), as well as at 6- and 12-month follow-ups. Physical activity and sleep were measured using wrist-worn actigraphs and sleep diaries, and blood was drawn to quantify circulating levels of inflammatory markers. Linear and quadratic random-effects mixed models and random-effects fluctuation mixed models were used to examine physical activity and sleep over time, as well as the associations with inflammatory biomarkers. On average, patients (n = 97) and controls (n = 104) were 62 and 58 years old, respectively. Compared to controls, patients were less active, more sedentary, had more time awake after sleep onset, and had lower sleep efficiency (p-values < 0.05). Across groups, higher levels of TNF-α were associated with more sedentary time and less efficient sleep (p-values ≤ 0.05). Higher levels of IL-1ß, TNF-α, and IL-6 were associated with lower levels of light physical activity (p-values < 0.05). Associations between inflammatory biomarkers, physical activity, and sleep did not differ between patients and controls. Given these results, we speculate that inflammation may contribute to less physical activity and more sleep problems that persist even 12 months after completing chemotherapy.

Stroke death in patients receiving radiation for head and neck cancer in the modern era.

Objectives: Head and neck cancer is a common malignancy frequently treated with chemotherapy and radiotherapy. Studies have shown an increased risk of stroke with the receipt of radiotherapy, but data on stroke-related mortality are limited, particularly in the modern era. Evaluating stroke mortality related to radiotherapy is vital given the curative nature of head and neck cancer treatment and the need to understand the risk of severe stroke in this population. Methods: We analyzed the risk of stroke death among 122,362 patients (83,651 patients who received radiation and 38,711 patients who did not) with squamous cell carcinoma of the head and neck (HNSCC) diagnosed between 1973 and 2015 in the SEER database. Patients in radiation vs. no radiation groups were matched using propensity scores. Our primary hypothesis was that radiotherapy would increase the hazard of death from stroke. We also examined other factors impacting the hazard of stroke death, including whether radiotherapy was performed during the modern era when IMRT and modern stroke care were available as well as increased HPV-mediated cancers of the head and neck. We hypothesized that the hazard of stroke death would be less in the modern era. Results: There was an increased hazard of stroke-related death in the group receiving radiation therapy (HR 1.203, p = 0.006); however, this was a very small absolute increase, and the cumulative incidence function of stroke death was significantly reduced in the modern era (p < 0.001), cohorts with chemotherapy (p=0.003), males (p=0.002), younger cohorts (p<0.001) and subsites other than nasopharynx (p=0.025). Conclusions: While radiotherapy for head and neck cancer increases the hazard of stroke death, this is reduced in the modern era and remains a very small absolute risk.

Relationships among Inflammatory Biomarkers and Self-Reported Treatment-Related Symptoms in Patients Treated with Chemotherapy for Gynecologic Cancer: A Controlled Comparison.

Previous research suggests that inflammation triggers cancer-treatment-related symptoms (i.e., fatigue, depression, and disruptions in sleep and physical activity), but evidence is mixed. This study examined relationships between inflammatory biomarkers and symptoms in patients with gynecologic cancer compared to age-matched women with no cancer history (i.e., controls). Patients (n = 121) completed assessments before chemotherapy cycles 1, 3, and 6, and 6 and 12 months later. Controls (n = 105) completed assessments at similar timepoints. Changes in inflammation and symptomatology were evaluated using random-effects mixed models, and cross-sectional differences between patients and controls in inflammatory biomarkers and symptoms were evaluated using least squares means. Associations among inflammatory biomarkers and symptoms were evaluated using random-effects fluctuation mixed models. The results indicated that compared to controls, patients typically have higher inflammatory biomarkers (i.e., TNF-alpha, TNFR1, TNFR2, CRP, IL-1ra) and worse fatigue, depression, and sleep (ps < 0.05). Patients reported lower levels of baseline physical activity (p = 0.02) that became more similar to controls over time. Significant associations were observed between CRP, depression, and physical activity (ps < 0.05), but not between inflammation and other symptoms. The results suggest that inflammation may not play a significant role in fatigue or sleep disturbance among gynecologic cancer patients but may contribute to depression and physical inactivity.

Exercise and epigenetic ages in older adults with myeloid malignancies.

BACKGROUND: Older adults with myeloid malignancies are susceptible to treatment-related toxicities. Accelerated DNAm age, or the difference between DNA methylation (DNAm) age and chronological age, may be used as a biomarker of biological age to predict individuals at risk. In addition, cancer treatment can also lead to accelerated DNAm age. Exercise is a promising intervention to reduce or prevent functional, psychological, and cognitive impairments in older patients with myeloid malignancies, yet there is little evidence of the effects of exercise on DNAm age. We explored (1) the associations of accelerated DNAm age with physical, psychological, and cognitive functions at baseline; (2) changes in DNAm age from baseline to post-intervention; and (3) the associations of changes in accelerated DNAm age with changes in functions from baseline to post-intervention. METHODS: We enrolled older patients with myeloid malignancies to a single-arm pilot study testing a mobile health (mHealth) exercise intervention that combines an exercise program (EXCAP©®) with a mobile application over 2 cycles of chemotherapy (8-12 weeks). Patients completed measures of physical, psychological, and cognitive functions and provided blood samples for analyses of DNAm age at baseline and post-intervention. Paired t-tests or Wilcoxon signed rank tests assessed changes in DNAm ages, and Spearman's correlation assessed the relationships between accelerated ages and functions. RESULTS: We included 20 patients (mean age: 72 years, range 62-80). Accelerated GrimAge, accelerated PhenoAge, and DunedinPACE were stable from baseline to post-intervention. At baseline, DunedinPACE was correlated with worse grip strength (r = -0.41, p = 0.08). From baseline to post-intervention, decreases in accelerated GrimAge (r = -0.50, p = 0.02), accelerated PhenoAge (r = - 0.39, p = 0.09), and DunedinPace (r = - 0.43, p = 0.06) were correlated with increases in distance walked on 6-min walk test. Decreases in accelerated GrimAge (r = - 0.49, p = 0.03), accelerated PhenoAge (r = - 0.40, p = 0.08), and DunedinPace (r = - 0.41, p = 0.07) were correlated with increases in in grip strength. CONCLUSIONS: Among older adults with myeloid malignancies receiving chemotherapy, GrimAge and PhenoAge on average are stable after a mHealth exercise intervention. Decreases in accelerated GrimAge, accelerated PhenoAge, and DunedinPACE over 8-12 weeks of exercise were correlated with increased physical performance. Future trials assessing the effects of exercise on treatment-related toxicities should evaluate DNAm age. Trial registration Clinicaltrials.gov identifier: NCT04981821.

Effect of Yoga and Mediational Influence of Fatigue on Walking, Physical Activity, and Quality of Life Among Cancer Survivors.

BACKGROUND: Cancer-related fatigue (CRF) negatively affects survivors' walking, engagement in physical activity (PA), and quality of life (QoL). Yoga is an effective therapy for treating CRF; however, evidence from large clinical trials regarding how reducing CRF through yoga influences CRF's interference with survivors' walking, engagement in PA, and QoL is not available. We examined the effects of yoga and the mediational influence of CRF on CRF's interference with walking, PA, and QoL among cancer survivors in a multicenter phase III randomized controlled trial. PATIENTS AND METHODS: Cancer survivors (n=410) with insomnia 2 to 24 months posttreatment were randomized to a 4-week yoga intervention-Yoga for Cancer Survivors (YOCAS)-or standard care. A symptom inventory was used to assess how much CRF interfered with survivors' walking, PA, and QoL. The Multidimensional Fatigue Symptom Inventory-Short Form was used to assess CRF. Two-tailed t tests and analyses of covariance were used to examine within-group and between-group differences. Path analysis was used to evaluate mediational relationships between CRF and changes in CRF's interference with walking, PA, and QoL among survivors. RESULTS: Compared with standard care controls, YOCAS participants reported significant improvements in CRF's interference with walking, PA, and QoL at postintervention (all effect size = -0.33; all P≤.05). Improvements in CRF resulting from yoga accounted for significant proportions of the improvements in walking (44%), PA (53%), and QoL (45%; all P≤.05). CONCLUSIONS: A significant proportion (44%-53%) of the YOCAS effect on CRF's interference with walking, PA, and QoL was due to improvements in CRF among cancer survivors. Yoga should be introduced and included as a treatment option for survivors experiencing fatigue. By reducing fatigue, survivors further improve their walking, engagement in PA, and QoL.

The Effects of a Mediterranean Diet Intervention on Cancer-Related Fatigue for Patients Undergoing Chemotherapy: A Pilot Randomized Controlled Trial.

Cancer-related fatigue is a common, burdensome symptom of cancer and a side-effect of chemotherapy. While a Mediterranean Diet (MedDiet) promotes energy metabolism and overall health, its effects on cancer-related fatigue remain unknown. In a randomized controlled trial, we evaluated a rigorous MedDiet intervention for feasibility and safety as well as preliminary effects on cancer-related fatigue and metabolism compared to usual care. Participants had stage I−III cancer and at least six weeks of chemotherapy scheduled. After baseline assessments, randomization occurred 2:1, MedDiet:usual care. Measures were collected at baseline, week 4, and week 8 including MedDiet adherence (score 0−14), dietary intake, and blood-based metabolic measures. Mitochondrial respiration from freshly isolated T cells was measured at baseline and four weeks. Participants (n = 33) were 51.0 ± 14.6 years old, 94% were female, and 91% were being treated for breast cancer. The study was feasible, with 100% completing the study and >70% increasing their MedDiet adherence at four and eight weeks compared to baseline. Overall, the MedDiet intervention vs. usual care had a small-moderate effect on change in fatigue at weeks 4 and 8 (ES = 0.31, 0.25, respectively). For those with a baseline MedDiet score <5 (n = 21), the MedDiet intervention had a moderate-large effect of 0.67 and 0.48 at weeks 4 and 8, respectively. The MedDiet did not affect blood-based lipids, though it had a beneficial effect on fructosamine (ES = −0.55). Fatigue was associated with mitochondrial dysfunction including lower basal respiration, maximal respiration, and spare capacity (p < 0.05 for FACIT-F fatigue subscale and BFI, usual fatigue). In conclusion, the MedDiet was feasible and attenuated cancer-related fatigue among patients undergoing chemotherapy, especially those with lower MedDiet scores at baseline.

The association between cancer-related fatigue and diabetes from pre-chemotherapy to 6 months post-chemotherapy.

PURPOSE: To quantify the relationship between diabetes and fatigue from pre-chemotherapy to 6 months post-chemotherapy for women with breast cancer compared to women without a history of cancer (controls). METHODS: This was a secondary analysis from a nationwide prospective longitudinal study of female patients with breast cancer undergoing chemotherapy and controls. Diabetes diagnosis (yes/no) was obtained at baseline, and cancer-related fatigue was measured using the Multidimensional Fatigue Symptom Inventory (MFSI) pre-, post-, and 6 months post-chemotherapy in patients; controls were assessed at equivalent time points. Repeated measures mixed effects models estimated the association between fatigue and diabetes controlling for cancer (yes/no), body mass index, exercise and smoking habits, baseline anxiety and depressive symptoms, menopausal status, marital status, race, and education. RESULTS: Among 439 patients and 235 controls (52.8 ± 10.5 years old), diabetes was twice as prevalent among patients as controls (11.6% vs. 6.8%). At baseline, diabetes was associated with worse fatigue (4.1 ± 1.7 points, p = 0.017). Also, diabetes was associated with clinically meaningful worse fatigue throughout the study period among all participants (5.2 ± 1.9 points, p = 0.008) and patients alone (4.5 ± 2.0, p = 0.023). For the MFSI subdomains among patients, diabetes was associated with worse general (p = 0.005) and mental fatigue (p = 0.026). CONCLUSIONS: Diabetes was twice as prevalent in women with breast cancer compared to controls, and diabetes was associated with more severe cancer-related fatigue in patients before and after chemotherapy and at 6 months post-chemotherapy. Interventions that address diabetes management may also help address cancer-related fatigue during chemotherapy treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01382082, first posted June 27, 2011.

Exploratory Analysis of Associations Between Whole Blood Mitochondrial Gene Expression and Cancer-Related Fatigue Among Breast Cancer Survivors.

BACKGROUND: Cancer-related fatigue is a prevalent, debilitating, and persistent condition. Mitochondrial dysfunction is a putative contributor to cancer-related fatigue, but relationships between mitochondrial function and cancer-related fatigue are not well understood. OBJECTIVES: We investigated the relationships between mitochondrial DNA (mtDNA) gene expression and cancer-related fatigue, as well as the effects of fish and soybean oil supplementation on these relationships. METHODS: A secondary analysis was performed on data from a randomized controlled trial of breast cancer survivors 4-36 months posttreatment with moderate-severe cancer-related fatigue. Participants were randomized to take 6 g fish oil, 6 g soybean oil, or 3 g each daily for 6 weeks. At pre- and postintervention, participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire and provided whole blood for assessment of mtDNA gene expression. The expression of 12 protein-encoding genes was reduced to a single dimension using principal component analysis for use in regression analysis. Relationships between mtDNA expression and cancer-related fatigue were assessed using linear regression. RESULTS: Among 68 participants, cancer-related fatigue improved and expression of all mtDNA genes decreased over 6 weeks with no effect of treatment group on either outcome. Participants with lower baseline mtDNA gene expression had greater improvements in cancer-related fatigue. No significant associations were observed between mtDNA gene expression and cancer-related fatigue at baseline or changes in mtDNA gene expression and changes in cancer-related fatigue. DISCUSSION: Data from this exploratory study add to the growing literature that mitochondrial dysfunction may contribute to the etiology and pathophysiology of cancer-related fatigue.

A single-arm pilot study of a mobile health exercise intervention (GO-EXCAP) in older patients with myeloid neoplasms.

Many older patients with myeloid neoplasms experience treatment-related toxicities. We previously demonstrated that a home-based, progressive aerobic walking and resistance exercise program (EXCAP) improved physical and psychological outcomes in patients with cancer. However, older patients have more difficulty adhering to exercise than younger patients. Reasons may include low motivation, difficulty with transportation, and limited access to exercise professionals. To improve exercise adherence, we integrated a mobile app with EXCAP (GO-EXCAP) and assessed its feasibility and usability in a single-arm pilot study among older patients with myeloid neoplasms undergoing outpatient chemotherapy. GO-EXCAP intervention lasts for 2 cycles of treatment, and the primary feasibility metric was data reporting on the app. Usability was evaluated via the system usability scale (SUS). Patients were interviewed at mid and postintervention to elicit their feedback, and deductive thematic analysis was applied to the transcripts. Twenty-five patients (mean age, 72 years) were recruited. Recruitment and retention rates were 64% and 88%, respectively. Eighty-two percent (18/22) of patients entered some exercise data on the app at least half of the study days, excluding hospitalization (a priori, we considered 70% as feasible). Averaged daily steps were 2848 and 3184 at baseline and after intervention, respectively. Patients also performed resistance exercises 26.2 minutes per day, 2.9 days per week at low intensity (rate of perceived exertion 3.8/10). Usability was above average (SUS, 70.3). In qualitative analyses, 3 themes were identified, including positive experience with the intervention, social interactions, and flexibility. The GO-EXCAP intervention is feasible and usable for older patients with myeloid neoplasms undergoing outpatient chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT04035499.