Biobehavioral Pathways and Cancer Progression: Insights for Improving Well-Being and Cancer Outcomes.

The relationship between psychosocial factors and cancer has intrigued people for centuries. In the last several decades there has been an expansion of mechanistic research that has revealed insights regarding how stress activates neuroendocrine stress-response systems to impact cancer progression. Here, we review emerging mechanistic findings on key pathways implicated in the effect of stress on cancer progression, including the cellular immune response, inflammation, angiogenesis, and metastasis, with a primary focus on the mediating role of the sympathetic nervous system. We discuss converging findings from preclinical and clinical cancer research that describe these pathways and research that reveals how these stress pathways may be targeted via pharmacological and mind-body based interventions. While further research is required, the body of work reviewed here highlights the need for and feasibility of an integrated approach to target stress pathways in cancer patients to achieve comprehensive cancer treatment.

Light Therapy for Cancer-Related Fatigue in (Non-)Hodgkin Lymphoma Survivors: Results of a Randomized Controlled Trial.

PURPOSE: To evaluate the short- and long-term effects of light therapy on fatigue (primary outcome) and sleep quality, depression, anxiety, quality of life, and circadian rhythms (secondary outcomes) in survivors of (non-)Hodgkin lymphoma presenting with chronic cancer-related fatigue. METHODS: We randomly assigned 166 survivors (mean survival 13 years) to a bright white light intervention (BWL) or dim white light comparison (DWL) group. Measurements were completed at baseline (T0), post-intervention (T1), at three (T2), and nine (T3) months follow-up. A mixed-effect modeling approach was used to compare linear and non-linear effects of time between groups. RESULTS: There were no significant differences between BWL and DWL in the reduction in fatigue over time. Both BWL and DWL significantly (p < 0.001) improved fatigue levels during the intervention followed by a slight reduction in this effect during follow-up (EST0-T1 = -0.71; EST1-T3 = 0.15). Similar results were found for depression, sleep quality, and some aspects of quality of life. Light therapy had no effect on circadian rhythms. CONCLUSIONS: BWL was not superior in reducing fatigue compared to DWL in HL and DLBCL survivors. Remarkably, the total sample showed clinically relevant and persistent improvements on fatigue not commonly seen in longitudinal observational studies in these survivors.

The Impact of Yoga on Fatigue in Cancer Survivorship: A Meta-Analysis.

BACKGROUND: Mind-body approaches, particularly yoga, are used by cancer survivors to cope with treatment-related symptoms. Consistency of yoga-related effects on treatment-related symptoms are not known. This meta-analysis was designed to examine effects of yoga on pre- to postintervention improvements in fatigue among cancer patients. METHODS: PubMed and PsycINFO were searched for peer-reviewed articles of yoga randomized controlled trials including cancer survivors and reporting at least one fatigue measure. Twenty-nine studies met inclusion criteria (n = 1828 patients). Effect sizes (Hedge's g) were calculated for fatigue, depression, and quality of life. Patient-related and intervention-related characteristics were tested as moderators of outcomes. All statistical tests were two-sided. RESULTS: Yoga practice was associated with a small, statistically significant decrease in fatigue (g = 0.45, P = .013). Yoga type was a statistically significant moderator of this relationship (P = .02). Yoga was associated with a moderate decrease in depression (g = 0.72, P = .007) but was not associated with statistically significant changes in quality of life (P = .48). Session length was a statistically significant moderator of the relationship between yoga and depression (P = .004). Neither timing of treatment (during treatment vs posttreatment) nor clinical characteristics were statistically significant moderators of the effects of yoga on outcomes. The effect of yoga on fatigue and depression was larger when the comparator was a "waitlist" or "usual care" than when the control group was another active treatment (P = .036). CONCLUSIONS: Results suggest yoga may be beneficial as a component of treatment for both fatigue and depression in cancer survivors.

Light therapy as a treatment of cancer-related fatigue in (non-)Hodgkin lymphoma survivors (SPARKLE trial): study protocol of a multicenter randomized controlled trial.

BACKGROUND: Cancer related fatigue (CRF) is one of the most prevalent and distressing long-term complaints reported by (non-) Hodgkin survivors. To date there has been no standard treatment for CRF in this population. A novel and promising approach to treat CRF is exposure to bright white light therapy. Yet, large scale randomized controlled trials testing its efficacy in these patients and research on potential mechanisms is lacking. The objective of the current study is to investigate the efficacy of light therapy as a treatment for CRF and to explore potential mechanisms. METHODS/DESIGN: In a multicenter, randomized controlled trial we are evaluating the efficacy of two intensities of light therapy in reducing CRF complaints and restrictions caused by CRF in survivors of Hodgkin lymphoma or diffuse large B-cell lymphoma. Secondary outcomes include sleep quality, depression, anxiety, quality of life, cognitive complaints, cancer worries, fatigue catastrophizing, self-efficacy to handle fatigue, biological circadian rhythms of melatonin, cortisol and activity, and biomarkers of inflammation. We will recruit 128 survivors, with fatigue complaints, from academic and general hospitals. Survivors are randomized to either an intervention (exposure to bright white light) or a comparison group (exposure to dim white light). The longitudinal design includes four measurement points at baseline (T0), post-intervention at 3.5 weeks (T1), 3 months post-intervention (T2) and 9 months post-intervention (T3). Each measurement point includes self-reported questionnaires and actigraphy (10 days). T0 and T1 measurements also include collection of blood and saliva samples. DISCUSSION: Light therapy has the potential to be an effective treatment for CRF in cancer survivors. This study will provide insights on its efficacy and potential mechanisms. If proven to be effective, light therapy will provide an easy to deliver, low-cost and low-burden intervention, introducing a new era in the treatment of CRF. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov on August 8th 2017( NCT03242902 ).

Programmed environmental illumination during autologous stem cell transplantation hospitalization for the treatment of multiple myeloma reduces severity of depression: A preliminary randomized controlled trial.

BACKGROUND: Over a third of multiple myeloma (MM) patients report clinical levels of depression during autologous stem cell transplant (ASCT) hospitalization. We report preliminary results from a randomized clinical trial investigating the effect of Programmed Environmental Illumination (PEI) of hospital rooms on depression. METHODS: Patients (N = 187) scheduled to receive an ASCT were assessed for eligibility. Those who met study eligibility criteria (n = 44) were randomly assigned to one of two PEI conditions involving delivery of either circadian active bright white light (BWL) or circadian inactive dim white light (DWL) throughout the room from 7 to 10 am daily during hospitalization. Patients completed the Center for Epidemiological Studies Depression Scale (CES-D) prior to hospitalization, at days 2 and 7 post-transplant, and on the third day of engraftment. RESULTS: General linear model analyses revealed no difference between the groups in CES-D total score at baseline (P = 0.7859). A longitudinal linear mixed model analysis revealed a significant interaction between time of assessment and light condition [F(3,107) = 2.90; P = 0.0386; ɳ2  = 0.08)], indicating that PEI prevented the development of depression during hospitalization, with effects reaching significance by the third day of engraftment. At the third day of engraftment, 68.4% of the participants in the DWL comparison condition met the criteria for clinically significant depression compared to 42.1% in the BWL condition. CONCLUSION: These findings demonstrate that PEI using BWL during MM ASCT hospitalization is effective in reducing the development of depression. Future studies should examine the mechanisms whereby PEI improves depression.

Changes in spiritual well-being and psychological outcomes in ovarian cancer survivors.

OBJECTIVE: Because of the poor prognosis of ovarian cancer and concomitant distress, understanding contributors to positive well-being is critical. This study examines spiritual growth as a domain of posttraumatic growth and its contribution to longitudinal emotional outcomes in ovarian cancer. METHODS: Ovarian cancer patients (N = 241) completed measures assessing spirituality (Functional Assessment of Chronic Illness Therapy-Spiritual Well-being-12; subscales: faith, meaning, and peace), depression (Center for Epidemiologic Studies Depression Scale), cancer-specific anxiety (Impact of Event Scale), and total mood disturbance (TMD; Profile of Mood States) prior to surgery and 1-year postsurgery. Stressful life events in the year after diagnosis were measured at 1-year postsurgery. Regressions examined the association between changes in spirituality and depression, anxiety, and TMD at 1-year postsurgery. Additionally, spiritual change was examined as a moderator of the effect of recent life events on mood. RESULTS: Increases in peace were related to lower depression (ß = -.40, P < .001), anxiety (ß = -.20, P = .004), and TMD (ß = -.41, P < .001) at 1 year. Changes in meaning and faith were unrelated to all outcomes. Additionally, changes in peace moderated the effect of stressful life events on depression (ß = -.14, P = .027), anxiety (ß = -.16, P = .05), and TMD (ß = -.17, P = .01), such that those with a high number of life events paired with a decrease in peace experienced the worst psychological outcomes at 1 year. CONCLUSION: These findings suggest that the quality of peace may be the most adaptive facet of spiritual growth in cancer patients. Furthermore, changes in peace appear to moderate the effect of life events on psychological well-being.

The embodied mind: A review on functional genomic and neurological correlates of mind-body therapies.

A broad range of mind-body therapies (MBTs) are used by the public today, and a growing body of clinical and basic sciences research has resulted in evidence-based integration of many MBTs into clinical practice. Basic sciences research has identified some of the physiological correlates of MBT practices, leading to a better understanding of the processes by which emotional, cognitive and psychosocial factors can influence health outcomes and well-being. In particular, results from functional genomics and neuroimaging describe some of the processes involved in the mind-body connection and how these can influence health outcomes. Functional genomic and neurophysiological correlates of MBTs are reviewed, detailing studies showing changes in sympathetic nervous system activation of gene transcription factors involved in immune function and inflammation, electroencephalographic and neuroimaging studies on MBT practices, and persistent changes in neural function and morphology associated with these practices. While the broad diversity of study designs and MBTs studied presents a patchwork of results requiring further validation through replication and longitudinal studies, clear themes emerge for MBTs as immunomodulatory, with effects on leukocyte transcription and function related to inflammatory and innate immune responses, and neuromodulatory, with effects on brain function and morphology relevant for attention, learning, and emotion regulation. By detailing the potential mechanisms of action by which MBTs may influence health outcomes, the data generated by these studies have contributed significantly towards a better understanding of the biological mechanisms underlying MBTs.

Effects of Healing Touch and Relaxation Therapy on Adult Patients Undergoing Hematopoietic Stem Cell Transplant: A Feasibility Pilot Study.

BACKGROUND: Stem cell transplant (SCT), considered the current standard of care for adults with advanced cancers, can lead to substantial deconditioning and diminished well-being. Attending to life quality of SCT recipients is now viewed as essential. OBJECTIVE: The objective of this study was to identify the feasibility and preliminary efficacy of healing touch (HT) and relaxation therapy (RT) with patients undergoing SCT. METHODS: A randomized prospective design compared 13 SCT patients who received HT daily while hospitalized to 13 similar SCT patients who received daily RT. The clinical outcomes of the 2 groups were also compared with retrospective clinical data of 20 patients who received SCT during the same year. RESULTS: The mean age of participants was 57 years, with 54% receiving autologous and 46% receiving allogeneic transplants. All patients assigned to the HT group completed the protocol. Only 60% of the relaxation group completed the intervention. Both interventions produced improvement in psychosocial measures and a shorter hospital length of stay (LOS) than the historical group. Differential results for LOS were related to the type of transplant received. The LOS differences were not statistically significant but could be clinically significant. CONCLUSIONS: Healing touch was a better tolerated modality by this population. Future research is needed to validate the LOS advantage of the HT and RT interventions, explore the differences in effect found with different transplant types, and identify patients who can tolerate RT. IMPLICATIONS FOR PRACTICE: The LOS reduction could result in decreased cost. Second, mood and function improvements support quality of life during SCT treatment.

Clinical Studies of Biofield Therapies: Summary, Methodological Challenges, and Recommendations.

Biofield therapies are noninvasive therapies in which the practitioner explicitly works with a client's biofield (interacting fields of energy and information that surround living systems) to stimulate healing responses in patients. While the practice of biofield therapies has existed in Eastern and Western cultures for thousands of years, empirical research on the effectiveness of biofield therapies is still relatively nascent. In this article, we provide a summary of the state of the evidence for biofield therapies for a number of different clinical conditions. We note specific methodological issues for research in biofield therapies that need to be addressed (including practitioner-based, outcomes-based, and research design considerations), as well as provide a list of suggested next steps for biofield researchers to consider.

Multimodal intervention improves fatigue and quality of life in subjects with progressive multiple sclerosis: a pilot study.

BACKGROUND: Fatigue is a disabling symptom of multiple sclerosis (MS) and reduces quality of life. The aim of this study was to investigate the effects of a multimodal intervention, including a modified Paleolithic diet, nutritional supplements, stretching, strengthening exercises with electrical stimulation of trunk and lower limb muscles, and stress management on perceived fatigue and quality of life of persons with progressive MS. METHODS: Twenty subjects with progressive MS and average Expanded Disability Status Scale (EDSS) score of 6.2 (range: 3.5-8.0) participated in the 12-month phase of the study. Assessments were completed at baseline and at 3 months, 6 months, 9 months, and 12 months. Safety analyses were based on monthly side effects questionnaires and blood analyses at 1 month, 3 months, 6 months, 9 months, and 12 months. RESULTS: Subjects showed good adherence (assessed from subjects' daily logs) with this intervention and did not report any serious side effects. Fatigue Severity Scale (FSS) and Performance Scales-fatigue subscale scores decreased in 12 months (P<0.0005). Average FSS scores of eleven subjects showed clinically significant reduction (more than two points, high response) at 3 months, and this improvement was sustained until 12 months. Remaining subjects (n=9, low responders) either showed inconsistent or less than one point decrease in average FSS scores in the 12 months. Energy and general health scores of RAND 36-item Health Survey (Short Form-36) increased during the study (P<0.05). Decrease in FSS scores during the 12 months was associated with shorter disease duration (r=0.511, P=0.011), and lower baseline Patient Determined Disease Steps score (r s=0.563, P=0.005) and EDSS scores (r s=0.501, P=0.012). Compared to low responders, high responders had lower level of physical disability (P< 0.05) and lower intake of gluten, dairy products, and eggs (P=0.036) at baseline. High responders undertook longer duration of massage and stretches per muscle (P<0.05) in 12 months. CONCLUSION: A multimodal intervention may reduce fatigue and improve quality of life of subjects with progressive MS. Larger randomized controlled trials with blinded raters are needed to prove efficacy of this intervention on MS-related fatigue.

Focal adhesion kinase: an alternative focus for anti-angiogenesis therapy in ovarian cancer.

This investigation describes the clinical significance of phosphorylated focal adhesion kinase (FAK) at the major activating tyrosine site (Y397) in epithelial ovarian cancer (EOC) cells and tumor-associated endothelial cells. FAK gene amplification as a mechanism for FAK overexpression and the effects of FAK tyrosine kinase inhibitor VS-6062 on tumor growth, metastasis, and angiogenesis were examined. FAK and phospho-FAK(Y397) were quantified in tumor (FAK-T; pFAK-T) and tumor-associated endothelial (FAK-endo; pFAK-endo) cell compartments of EOCs using immunostaining and qRT-PCR. Associations between expression levels and clinical variables were evaluated. Data from The Cancer Genome Atlas were used to correlate FAK gene copy number and expression levels in EOC specimens. The in vitro and in vivo effects of VS-6062 were assayed in preclinical models. FAK-T and pFAK-T overexpression was significantly associated with advanced stage disease and increased microvessel density (MVD). High MVD was observed in tumors with elevated endothelial cell FAK (59%) and pFAK (44%). Survival was adversely affected by FAK-T overexpression (3.03 vs 2.06 y, P = 0.004), pFAK-T (2.83 vs 1.78 y, P<0.001), and pFAK-endo (2.33 vs 2.17 y, P = 0.005). FAK gene copy number was increased in 34% of tumors and correlated with expression levels (P<0.001). VS-6062 significantly blocked EOC and endothelial cell migration as well as endothelial cell tube formation in vitro. VS-6062 reduced mean tumor weight by 56% (P = 0.005), tumor MVD by 40% (P = 0.0001), and extraovarian metastasis (P<0.01) in orthotopic EOC mouse models. FAK may be a unique therapeutic target in EOC given the dual anti-angiogenic and anti-metastatic potential of FAK inhibitors.

A multimodal intervention for patients with secondary progressive multiple sclerosis: feasibility and effect on fatigue.

BACKGROUND: Multiple sclerosis is an autoimmune disease influenced by environmental factors. OBJECTIVES: The feasibility of a multimodal intervention and its effect on perceived fatigue in patients with secondary progressive multiple sclerosis were assessed. DESIGN/SETTING: This was a single-arm, open-label intervention study in an outpatient setting. INTERVENTIONS: A multimodal intervention including a modified paleolithic diet with supplements, stretching, strengthening exercises with electrical stimulation of trunk and lower limb muscles, meditation, and massage was used. OUTCOME MEASURES: Adherence to each component of the intervention was calculated using daily logs. Side-effects were assessed from a monthly questionnaire and blood analyses. Fatigue was assessed using the Fatigue Severity Scale (FSS). Data were collected at baseline and months 1, 2, 3, 6, 9, and 12. RESULTS: Ten (10) of 13 subjects who were enrolled in a 2-week run-in phase were eligible to continue in the 12-month main study. Of those 10 subjects, 8 completed the study and 6 subjects fully adhered to the study intervention for 12 months. Over a 12-month period, average adherence to diet exceeded 90% of days, and to exercise/muscle stimulation exceeded 75% of days. Nutritional supplements intake varied among and within subjects. Group daily average duration of meditation was 13.3 minutes and of massage was 7.2 minutes. No adverse side-effects were reported. Group average FSS scores decreased from 5.7 at baseline to 3.32 (p=0.0008) at 12 months. CONCLUSIONS: In this small, uncontrolled pilot study, there was a significant improvement in fatigue in those who completed the study. Given the small sample size and completer rate, further evaluation of this multimodal therapy is warranted.

Slowing progression of early stages of AD with alternative therapies: a feasibility study.

This pilot study identified the feasibility and efficacy of the effect of combining healing touch (HT) and body talk cortices (BTC) on the progression of Alzheimer's disease (AD). Both HT and BTC elicit the relaxation response and support cognitive function from two different perspectives. A two-group, repeated measures design was used. Subjects (n = 22), 65 or older with early stage (less than four) AD, residing in the community (n = 2) or in care agencies (n = 20), were assigned to either the HT-BTC group (n = 12) or the control group (n = 10) randomized by residence. The treatment group received, 6 months of weekly HT and performed the BTC technique daily. The usual medical regimen for all subjects was continued. The control group had no additional interventions. Both groups were assessed at baseline, 3 and 6 months. The groups did not differ significantly at baseline on cognitive reserve, age, gender, and ethnicity, nor on the outcome variables (cognitive function, mood, & depression). Adherence (76%) to the BTC protocol, the major feasibility problem, related to memory deficits. Significant interactions occurred regarding cognitive function and mood. Significant improvements in cognitive function (p = .008), mood (p = .001), and depression (p = .028) were observed in the treatment group which is not the usual course of AD. A decline in cognitive function occurred in the control group typical of AD's usual course. Although the number of subjects in this pilot study was small, and there were feasibility challenges with recruitment and adherence, important trends were noted suggesting areas for future study.

The effect of healing touch on the pain and mobility of persons with osteoarthritis: a feasibility study.

The aims of this pilot study were to investigate the effects of Healing Touch (HT) on the pain level, joint function, mobility, and depression in persons with osteoarthritis (OA) of the knee joint(s). A randomized controlled trial using a repeated measures design was used. Cognitively intact persons (institutionalized and community) with a diagnosis of OA of the knee joint(s) received either HT sessions three times per week for 6 weeks (n = 12) or weekly friendly visits (FV) (n = 7). The HT sessions were delivered by a team of two nurses certified as HT practitioners and the FV was conducted by a nurse. All subjects continued to receive their standard care including the methods they had been using to relieve their joint pain. The two groups were similar regarding demographic variables, number of knees affected, co-morbidities, pain medications used and outcome variables at baseline. Two pain outcome measures (intensity and life interference) produced significant interaction effects. Two joint outcome measures (extension and extensor lag) also produced significant interaction effects. Furthermore, the HT group demonstrated significant improvements in 9 of the 12 outcome variables (75%) while no significant improvements occurred in the FV group. The HT group exhibited sustained effects (3 weeks post treatments) in three outcome variables. The reduction in joint pain and improvement in joint function suggest that biofield therapies could be effective non-pharmacological adjuncts to treatment of OA.

Psychoneuroimmunology and cancer: a decade of discovery, paradigm shifts, and methodological innovations.

This article introduces the supplement Advances in Cancer and Brain, Behavior, and Immunity and outlines important discoveries, paradigm shifts, and methodological innovations that have emerged in the past decade to advance mechanistic and translational understanding of biobehavioral influences on tumor biology, cancer treatment-related sequelae, and cancer outcomes. We offer a heuristic framework for research on biobehavioral pathways in cancer. The shifting survivorship landscape is highlighted, and we propose that the changing demographics suggest prudent adoption of a life course perspective of cancer and cancer survivorship. We note opportunities for psychoneuroimmunology (PNI) research to ameliorate the long-term, unintended consequences of aggressive curative intent and call attention to the critical role of reciprocal translational pathways between animal and human studies. Lastly, we briefly summarize the articles included in this compilation and offer our perspectives on future research directions.

The use of healing touch in integrative oncology.

The use of complementary therapies by patients with cancer has become increasingly prevalent; as a result, oncology nurses find themselves needing to understand those therapies and the evidence-based support for their use. This article describes the integrative use of the biofield therapy healing touch in conjunction with the chemoradiation received by patients with cervical cancer (stages IB1 to IVA) as reported in a 2010 research study. Findings indicated effects on the immune response and depression in healing touch recipients compared to patients receiving relaxation or standard care. Specifically, healing touch recipients demonstrated a minimal decrease in natural killer cell cytotoxicity over the course of treatment, whereas the cytotoxicity of patients receiving relaxation therapy and standard care declined sharply during radiation. Healing touch recipients also showed decreases in depressed mood compared to relaxation therapy and standard care recipients. The findings suggest that appropriate integration of complementary modalities into oncology care can enhance the impact of conventional care by putting patients in the best condition to use their innate healing resources.

Impact of stress on cancer metastasis.

The influence of psychosocial factors on the development and progression of cancer has been a longstanding hypothesis since ancient times. In fact, epidemiological and clinical studies over the past 30 years have provided strong evidence for links between chronic stress, depression and social isolation and cancer progression. By contrast, there is only limited evidence for the role of these behavioral factors in cancer initiation. Recent cellular and molecular studies have identified specific signaling pathways that impact cancer growth and metastasis. This article provides an overview of the relationship between psychosocial factors, specifically chronic stress, and cancer progression.

Preservation of immune function in cervical cancer patients during chemoradiation using a novel integrative approach.

Patients receiving chemoradiation for cervical cancer are at risk for distress, chemoradiation-related side-effects, and immunosuppression. This prospective randomized clinical trial examined effects of a complementary therapy, Healing Touch (HT), versus relaxation training (RT) and usual care (UC) for (1) supporting cellular immunity, (2) improving mood and quality of life (QOL), and (3) reducing treatment-associated toxicities and treatment delay in cervical cancer patients receiving chemoradiation. Sixty women with stages IB1 to IVA cervical cancer were randomly assigned to receive UC or 4 ×/weekly individual sessions of either HT or RT immediately following radiation during their 6-week chemoradiation treatment. Patients completed psychosocial assessments and blood sampling before chemoradiation at baseline, weeks 4 and 6. Multilevel regression analyses using orthogonal contrasts tested for differences between treatment conditions over time. HT patients had a minimal decrease in natural killer cell cytotoxicity (NKCC) over the course of treatment whereas NKCC of RT and UC patients declined sharply during chemoradiation (group by time interaction: p = 0.018). HT patients showed greater decreases in two different indicators of depressed mood (CES-D depressed mood subscale and POMS depression scale) compared to RT and UC (group by time interactions: p<0.05). No between group differences were observed in QOL, treatment delay, or clinically-rated toxicities. HT may benefit cervical cancer patients by moderating effects of chemoradiation on depressed mood and cellular immunity. Effects of HT on toxicities, treatment delay, QOL, and fatigue were not observed. Long-term clinical implications of findings are not known.