Does circadian rhythm influence gastrointestinal toxicity?

PURPOSE OF REVIEW: The current review outlines the existing research on the impact of circadian rhythm on gastrointestinal toxicity associated with cancer treatment and explores clinical evidence for utilizing circadian-based approaches in addressing gastrointestinal symptoms such as nausea, vomiting, diarrhea, mucositis, and hepatotoxicity. RECENT FINDINGS: Recent evidence highlights circadian control of gastrointestinal physiology of appetite, digestion, nutrient absorption, and cellular proliferation in the digestive system. In addition, animal models support the mechanistic rationale of using chronotherapy (a type of anticancer therapy delivered at specific times with the goal of producing less toxicity and greater treatment response) to minimize gastrointestinal-impact of systemic cancer treatments. In addition, earlier research demonstrates that many chemotherapeutic agents are responsive to circadian timing in animals. On the contrary, clinical trials focused on minimizing gastrointestinal toxicity using chronotherapy have been limited in recent years and have not yielded the efficacy initially hoped for. Instead, researchers focused on understanding circadian rhythm's influence on the gastrointestinal system at a mechanistic level as well as measuring circadian rhythm at an individual level. SUMMARY: Although using circadian timing is a promising target for reducing gastrointestinal toxicity, recent evidence suggests that more research is needed to understand circadian rhythm before circadian-based interventions can be developed that will result in lessening of gastrointestinal toxicity.

Effects of childhood trauma exposure and cortisol levels on cognitive functioning among breast cancer survivors.

Cognitive functioning difficultiesin breast cancer patients receiving chemotherapy are common, but not all women experience these impairments. Exposure to childhood trauma may impair cognitive functioning following chemotherapy, and these impairments may be mediated by dysregulation of hypothalamic-pituitary-adrenal (HPA) axis function and cortisol slope. This study evaluated the association between childhood trauma exposure, cortisol, and cognition in a sample of breast cancer survivors. 56 women completed measures of trauma exposure (the Traumatic Events Survey), salivary cortisol, and self-reported cognitive functioning (the Functional Assessment of Cancer Therapy - Cognitive). We examined correlations between childhood trauma exposure and cognitive functioning, then used linear regression to control for factors associated with cognition (age, education, time since chemotherapy, depression, anxiety, and insomnia), and the MacArthur approach to test whether cortisol levels mediated the relationship between trauma and cognitive functioning. 57.1% of the sample had experienced at least one traumatic event in childhood, with 19.6% of the sample witnessing a serious injury, 17.9% experiencing physical abuse, and 14.3% experiencing sexual abuse. Childhood trauma exposure and cognitive functioning were moderately associated (r=-0.29). This association remained even when controlling for other factors associated with cognition; the final model explained 47% of the variance in cognitive functioning. The association between childhood trauma and cognitive functioning was mediated by steeper cortisol slope (partial r=0.35, p=0.02). Childhood trauma exposure is associated with self-reported cognitive functioning among breast cancer survivors and is mediated by cortisol dysregulation. Trauma should be considered, among other factors, in programs aiming to address cognition in this population.

Subjective sleep and overall survival in chemotherapy-naïve patients with metastatic colorectal cancer.

BACKROUND: Sleep disorders are prevalent in patients with advanced cancer. Their impact on clinical outcomes is not well understood. METHODS: A post-hoc analysis was conducted in 361 chemo-naïve patients with metastatic colorectal cancer completing twice the EORTC QLQ-C30 questionnaire within a randomized international phase III trial. The study assessed the effect on overall survival (OS) of subjective sleep complaint, used as a normal or a time-dependent covariate (TDC), using a multivariate Cox proportional hazard model. Prognostic analysis was conducted on the whole study population and separately in each treatment arm (conventional FOLFOX2, or chronomodulated chronoFLO4). RESULTS: Sleep problems were reported by 202 patients (56%) at baseline and by 188 (52%) on treatment. Sleep problems at baseline were independently associated with a higher risk of earlier death (HR: 1.36; p = 0.011), progression (HR: 1.43; p = 0.002) and poor treatment response (RR: 0.58; p = 0.016). TDC analysis confirmed the independent prognostic effect of sleep problems on OS (HR: 1.37; p = 0.008), while on treatment this effect was only observed using univariate analysis. The negative prognostic value of sleep problems on OS at baseline, on treatment, and as a TDC was greatest on chronoFLO4 compared to FOLFOX2. CONCLUSIONS: Subjective sleep problems are associated with poor clinical outcomes in metastatic colorectal cancer patients and affect chronotherapy effectiveness. There is a need for a well-tuned circadian timing system in order to increase chronotherapy activity. Prospective studies are needed for determining the impact of therapeutic approaches on sleep disorders upon quality of life and survival of cancer patients.

The circadian timing system in clinical oncology.

The circadian timing system (CTS) controls several critical molecular pathways for cancer processes and treatment effects over the 24 hours, including drug metabolism, cell cycle, apoptosis, and DNA damage repair mechanisms. This results in the circadian time dependency of whole-body and cellular pharmacokinetics and pharmacodynamics of anticancer agents. However, CTS robustness and phase varies among cancer patients, based on circadian monitoring of rest- activity, body temperature, sleep, and/or hormonal secretion rhythms. Circadian disruption has been further found in up to 50% of patients with metastatic cancer. Such disruption was associated with poor outcomes, including fatigue, anorexia, sleep disorders, and short progression-free and overall survival. Novel, minimally invasive devices have enabled continuous CTS assessment in non-hospitalized cancer patients. They revealed up to 12-hour differences in individual circadian phase. Taken together, the data support the personalization of chronotherapy. This treatment method aims at the adjustment of cancer treatment delivery according to circadian rhythms, using programmable-in-time pumps or novel release formulations, in order to increase both efficacy and tolerability. A fixed oxaliplatin, 5-fluorouracil and leucovorin chronotherapy protocol prolonged median overall survival in men with metastatic colorectal cancer by 3.3 months as compared to conventional delivery, according to a meta-analysis (P=0.009). Further analyses revealed the need for the prevention of circadian disruption or the restoration of robust circadian function in patients on chronotherapy, in order to further optimize treatment effects. The strengthening of external synchronizers could meet such a goal, through programmed exercise, meal timing, light exposure, improved social support, sleep scheduling, and the properly timed administration of drugs that target circadian clocks. Chrono-rehabilitation warrants clinical testing for improving quality of life and survival in cancer patients.

Acupuncture in the treatment of cancer-related psychological symptoms.

Acupuncture is being adopted by cancer patients for a wide range of cancer-related symptoms including highly prevalent psychological symptoms like depression, anxiety, insomnia, and impairment in quality of life. Pharmacological treatment of prevalent symptoms like anxiety, depression, and sleep disturbance can contribute to the high chemical burden already carried by cancer patients, creating additional side effects. As a result, patients and providers alike are interested in evidence-based nonpharmacologic alternatives like acupuncture for these symptoms. This article reviews the current literature (January 2000 through April 2013) for acupuncture in cancer-related psychological symptoms with attention to both efficacy and acupuncture-specific methodology. All published studies that met our review criteria demonstrate a positive signal for acupuncture for the treatment of depression, anxiety, sleep disturbance, and for improving quality of life with most results showing statistical significance. However, there are only a handful of acupuncture studies that were specifically designed to evaluate depression, sleep disturbance, and quality of life as primary outcomes, and no studies were found that looked at anxiety as a primary outcome in this population. Published studies in cancer patients and survivors show that acupuncture treatment is not only safe but also more acceptable with fewer side effects than standard of care pharmacological treatments like antidepressants. Finally, there is wide variability in both the implementation and reporting of acupuncture methods in the literature, with only 2 of 12 studies reporting full details of acupuncture methods as outlined in the revised Standards for Reporting Interventions in Clinical Trials of Acupuncture guidelines, published in 2010 and providing an essential framework for the reporting of acupuncture methodology. This lack of methodological detail affects outcomes, generalizability, and validity of research involving acupuncture. Reasons for ongoing challenges in the development of high-quality acupuncture trials are discussed. In conclusion, results are encouraging for the development of randomized trials to directly evaluate the therapeutic impact of acupuncture in cancer-related psychological symptoms, including depression, anxiety, sleep disturbance, and quality of life, but attention to acupuncture methodological specific challenges in the development of high-quality research is necessary.

Multicenter, randomized controlled trial of yoga for sleep quality among cancer survivors.

PURPOSE: Thirty percent to 90% of cancer survivors report impaired sleep quality post-treatment, which can be severe enough to increase morbidity and mortality. Lifestyle interventions, such as exercise, are recommended in conjunction with drugs and cognitive behavioral therapy for the treatment of impaired sleep. Preliminary evidence indicates that yoga-a mind-body practice and form of exercise-may improve sleep among cancer survivors. The primary aim of this randomized, controlled clinical trial was to determine the efficacy of a standardized yoga intervention compared with standard care for improving global sleep quality (primary outcome) among post-treatment cancer survivors. PATIENTS AND METHODS: In all, 410 survivors suffering from moderate or greater sleep disruption between 2 and 24 months after surgery, chemotherapy, and/or radiation therapy were randomly assigned to standard care or standard care plus the 4-week yoga intervention. The yoga intervention used the Yoga for Cancer Survivors (YOCAS) program consisting of pranayama (breathing exercises), 16 Gentle Hatha and Restorative yoga asanas (postures), and meditation. Participants attended two 75-minute sessions per week. Sleep quality was assessed by using the Pittsburgh Sleep Quality Index and actigraphy pre- and postintervention. RESULTS: In all, 410 survivors were accrued (96% female; mean age, 54 years; 75% had breast cancer). Yoga participants demonstrated greater improvements in global sleep quality and, secondarily, subjective sleep quality, daytime dysfunction, wake after sleep onset, sleep efficiency, and medication use at postintervention (all P ≤ .05) compared with standard care participants. CONCLUSION: Yoga, specifically the YOCAS program, is a useful treatment for improving sleep quality and reducing sleep medication use among cancer survivors.

Health-related quality of life and biomarkers in breast cancer survivors participating in tai chi chuan.

INTRODUCTION: Breast cancer survivors experience diminished health-related quality of life (HRQOL). We report on the influence of tai chi chuan exercise (TCC) on HRQOL and explore associations between changes in HRQOL and biomarkers. METHODS: Breast cancer survivors (N = 21) were randomly assigned to TCC or standard support therapy (SST) for 12 weeks (three times/week; 60 min/session). Interleukin-6, interleukin-8 (IL-8), insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein (IBFBP)-1, IGFBP-3, glucose, insulin, and cortisol were measured pre- and postintervention. Overall HRQOL and subdomains were assessed at preintervention (T1), midintervention (T2) and postintervention (T3) and biomarkers at T1 and T3. RESULTS: The TCC group improved in total HRQOL (T1-T2:CS = 8.54, P = 0.045), physical functioning (T1-T2:CS = 1.89, P = 0.030), physical role limitations (T1-T2 CS = 1.55, P = 0.023), social functioning (T1-T3:CS = 1.50, P = 0.020), and general mental health (T1-T2:CS = 2.67, P = 0.014; T1-T3:CS = 2.44, P = 0.019). The SST improved in social functioning (T1-T2:CS = 0.64, P = 0.043) and vitality (T1-T2:CS = 0.90, P = 0.01). There were relationships between changes in IGF-1 and overall HRQOL (r = -0.56; P < 0.05), physical role limitation (r = -0.68; P < 0.05), and social functioning (r = -0.56; P < 0.05). IGFBP-1 changes were associated with physical role limitations changes (r = 0.60; P < 0.05). IGFBP-3 changes were associated with physical functioning changes (r = 0.46; P ≤ 0.05). Cortisol changes were associated with changes in physical role limitations (r = 0.74; P < 0.05) and health perceptions (r = 0.46; P < 0.05). Glucose changes were associated with emotional role limitation changes (r = -0.70; P < 0.001). IL-8 changes were associated with emotional role limitation changes (r = 0.59; P < 0.05). DISCUSSION/CONCLUSIONS: TCC may improve HRQOL by regulating inflammatory responses and other biomarkers associated with side effects from cancer and its treatments. IMPLICATIONS FOR CANCER SURVIVORS: TCC may be an intervention capable of improving HRQOL in breast cancer survivors.

Effects of Tai Chi Chuan on insulin and cytokine levels in a randomized controlled pilot study on breast cancer survivors.

BACKGROUND: Tai Chi Chuan (TCC) is an integrative medicine mind-body practice with a physical activity component that has positive effects on aerobic capacity, muscular strength, and quality of life among cancer survivors, similar to the effects elicited by other modes of moderate-intensity exercise. Inflammatory cytokines and insulin and insulin-related signaling molecules may contribute to weight gain and affect cancer recurrence rates and survival; exercise can curb cancer- and treatment-related weight gain, increase survival, and reduce levels of insulin and inflammatory cytokines. Despite knowing the beneficial effects of conventional exercise interventions on these mediators, little is known about the physiologic effects of TCC on these pathways in breast cancer survivors. METHODS: We assessed the effects of a 12-week, moderately intense, TCC intervention (n = 9) compared with a non-physical activity control (n = 10) consisting of psychosocial support therapy (PST), on levels of insulin, insulin-like growth factor (IGF)-1, insulin growth factor-like binding protein (IGFBP)-1, IGFBP-3, and cytokines interleukin (IL)-6, IL-2, and interferon (IFN)-γ in breast cancer survivors. RESULTS: Levels of insulin are significantly different in TCC and PST groups; levels remained stable in the TCC group but increased in the PST control group (P = .099). Bivariate analysis revealed novel and significant correlations (all r > 0.45, all P ≤ .05) of both decreased fat mass and increased fat-free mass with increased IL-6 and decreased IL-2 levels. CONCLUSIONS: This pilot study shows that TCC may be associated with maintenance of insulin levels and changes in cytokine levels that may be important for maintenance of lean body mass in breast cancer survivors.

Polarity Therapy for cancer-related fatigue in patients with breast cancer receiving radiation therapy: a randomized controlled pilot study.

BACKGROUND: Cancer-related fatigue (CRF) is the most frequently reported side effect of cancer and its treatment. In previous research, Polarity Therapy (PT), an energy therapy, was shown to reduce CRF in patients receiving radiation. This study reports on a small randomized clinical trial designed to collect preliminary data on the efficacy of PT compared with an active control (massage) and passive control (standard care) for CRF among cancer patients receiving radiation therapy. METHODS: Forty-five women undergoing radiation therapy for breast cancer were randomized to 1 of 3 weekly treatment conditions. Patients received standard clinical care, 3 modified massages, or 3 PT treatments. CRF and health-related quality of life (HRQL) were assessed during baseline and the 3 intervention weeks. RESULTS: TResults show CRF ratings were reduced after PT. The effect sizes for PT versus modified massage and versus standard care were small when using the primary measure of CRF (Brief Fatigue Inventory) and large when using the secondary measure of CRF (Daily CRF Diaries).The effect size was medium when assessing the benefit of PT on maintaining HRQL compared with standard care with very little difference between the PT and modified massage conditions. Patients' feedback showed that both the modified massage and PT treatments were deemed useful by radiation patients. CONCLUSION: The present pilot randomized clinical trial supports previous experimental research showing that PT, a noninvasive and gentle energy therapy, may be effective in controlling CRF. Further confirmatory studies as well as investigations of the possible mechanisms of PT are warranted.

Effects of a structured weight-bearing exercise program on bone metabolism among breast cancer survivors: a feasibility trial.

PURPOSE: Treatments for breast cancer, specifically hormonal therapy, accelerate bone loss (BL) among breast cancer survivors, leading to osteoporosis and an increase in fracture risk. Tai Chi Chuan (TCC) is a moderate form of weight-bearing exercise, equivalent to walking, and it has been shown to improve aerobic capacity and strength among breast cancer survivors and might also be effective in slowing bone loss in breast cancer survivors. This pilot study compared the influence of TCC with that of standard support therapy (ST; exercise control) on BL biomarkers among breast cancer survivors. PATIENTS AND METHODS: Randomly assigned breast cancer survivors (N = 16; median age, 53 years; < 30 months after treatment) completed 12 weeks (3 times per week, 60 minutes per session) of TCC or ST. Serum levels of N-telopeptides of type I collagen (NTx), a marker of bone resorption, and bone-specific alkaline phosphatase (BSAP), a marker of bone formation, were determined according to enzyme-linked immunosorbent assay at baseline and after the intervention. RESULTS: Using analysis of covariance, survivors in the TCC group experienced a greater increase in levels of bone formation (BSAP [microg/L]: before, 8.3; after, 10.2; change, 1.9 microg/L and 22.4%), compared with survivors in ST (BSAP [microg/L]: before, 7.6; after, 8.1; change, 0.5 microg/L [6.3%]). Survivors in the TCC group also experienced a significant decrease in bone resorption (NTx [nanomoles bone collagen equivalent; nmBCE]: before, 17.6; after, 11.1; change, -6.5 nmBCE; -36.9%), whereas women in the ST group did not (NTx [nmBCE]: before, 20.8; after, 18.8; change, -2.0 nmBCE; -9.6%). CONCLUSION: This pilot study suggests that weight-bearing exercise exerts positive effects on BL, through increased bone formation and decreased bone resorption. Further examinations of the influence of TCC on bone health are warranted.

The Cancer and Deity Questionnaire: a new religion and cancer measure.

We evaluated a new measure, the Cancer and Deity Questionnaire (CDQ), which assesses perceived relations with God after a cancer diagnosis. Based on object relations theory, the 12-item CDQ assesses benevolent and abandoning God representations. Sixty-one older participants with recent cancer diagnoses completed the questionnaire at baseline, and 52 of these participants completed the same questionnaire at follow-up. Internal consistency was excellent for the Benevolence scale (alpha = .97) and good for the Abandonment scale (alpha = .80). Moderate correlations with the Spiritual Well-Being Scale support divergent validity. Correlations between CDQ scales and the Styles of Religious Coping scales support convergent validity. The CDQ is brief, easily scored, practical for psycho-oncology research, and adaptable for use with other illnesses.

Effects of supportive-expressive group therapy on pain in women with metastatic breast cancer.

OBJECTIVE: To examine whether a group intervention including hypnosis can reduce cancer pain and trait hypnotizability would moderate these effects. DESIGN: This randomized clinical trial examined the effects of group therapy with hypnosis (supportive-expressive group therapy) plus education compared to an education-only control condition on pain over 12 months among 124 women with metastatic breast cancer. MAIN OUTCOME MEASURES: Pain and suffering, frequency of pain, and degree of constant pain were assessed at baseline and 4-month intervals. Those in the treatment group also reported on their experiences using the hypnosis exercises. RESULTS: Intention-to-treat analyses indicated that the intervention resulted in significantly less increase in the intensity of pain and suffering over time, compared to the education-only group, but had no significant effects on the frequency of pain episodes or amount of constant pain, and there was no interaction of the intervention with hypnotizability. Within the intervention group, highly hypnotizable participants, compared to those less hypnotizable, reported greater benefits from hypnosis, employed self-hypnosis more often outside of group, and used it to manage other symptoms in addition to pain. CONCLUSION: These results augment the growing literature supporting the use of hypnosis as an adjunctive treatment for medical patients experiencing pain.

Tai Chi Chuan for breast cancer survivors.

BACKGROUND/AIMS: Treatment for breast cancer produces side effects that diminish functional capacity and quality of life (QOL) among survivors. Tai Chi Chuan (TCC) is a moderate form of exercise that may improve functional capacity and QOL in these individuals. Women who completed treatment for breast cancer were randomized to receive TCC or psychosocial support therapy for 12 weeks (60 min; three times weekly). RESULTS: The TCC group demonstrated significant improvements in functional capacity, including aerobic capacity, muscular strength, and flexibility, as well as QOL; the psychosocial support therapy group showed significant improvements only in flexibility, with declines in aerobic capacity, muscular strength, and QOL. CONCLUSIONS: The TCC group exhibited significant improvements in functional capacity and QOL. These data suggest that TCC may enhance functional capacity and QOL among breast cancer survivors.

Behavioral interventions in treating anticipatory nausea and vomiting.

Anticipatory nausea and vomiting (ANV) is associated with a significant reduction in the quality of life for many chemotherapy patients. The use of 5-hydroxytryptamine type 3 receptor antagonists provides some relief for chemotherapy-induced nausea and vomiting, but does not seem to control ANV. Nonpharmacologic approaches, which include behavioral interventions, may provide the greatest promise in relieving symptoms. Little evidence supports the use of complementary and alternative methods, such as acupuncture and acupressure, in relieving ANV. Behavioral interventions, especially progressive muscle relaxation training and systematic desensitization, should be considered important methods for preventing and treating ANV.