March 2019 Research Findings

Integrative Oncology Research Digest March 2019

Grant SJ, Hunter J, Seely D, Balneaves LG, Rossi E, Bao T. Integrative Oncology: International perspectives. Integr Cancer Ther 2019 Jan-Dec
Interest in integrative oncology (IO) is growing globally. Patients with cancer are actively using traditional complementary and integrative medicine (TCIM) as part of their cancer and survivorship care. Published studies from around the world report increasing use of TCIM by people living with cancer. This article summarizes the presentations that took place during a symposium titled, "Integrative Oncology: International Perspectives" at the International Research Congress on Integrative Medicine and Health in Baltimore, 2018. The purpose of the presentations was to examine whether cancer services across a variety of geographical regions, including Australia, Canada, the United States, and the European Union, were actively responding to cancer survivors' demand for TCIM. The presenters highlighted utilization rates and both facilitators and barriers to the provision of IO services in their respective countries and regions. The audience discussion following the presentations drew out many noteworthy perspectives.

El-Hashimi D, Gorey KM. Yoga-specific enhancement of quality of life among women with breast cancer: systematic review and exploratory meta-analysis of randomized controlled trials. J Ev Based Integ Med. 2019 Feb; 24:1-9
Physical activities during and after cancer treatment have favorable psychosocial effects. Increasingly, yoga has become a popular approach to improving the quality of life (QoL) of women with breast cancer. However, the extant synthetic evidence on yoga has not used other exercise comparison conditions. This meta-analysis aimed to systematically assess yoga-specific effects relative to any other physical exercise intervention (eg, aerobics) for women with breast cancer. QoL was the primary outcome of interest. Eight randomized controlled trials with 545 participants were included. The sample-weighted synthesis at immediate postintervention revealed marginally statistically and modest practically significant differences suggesting yoga’s potentially greater effectiveness: d = 0.14, P = .10. However, at longer term follow-up, no statistically or practically significant between-group difference was observed. This meta-analysis preliminarily demonstrated that yoga is probably as effective as other exercise modalities in improving the QoL of women with breast cancer. Both interventions were associated with clinically significant improvements in QoL. Nearly all of the yoga intervention programs, however, were very poorly resourced. Larger and better controlled trials of well-endowed yoga programs are needed.
Campbell G, Stockings E, Nielsen S. Understanding the evidence for medical cannabis and cannabis-based medicines for the treatment of chronic non-cancer pain. Eur Arch Psychiatry Clin Neurosci 2019 Feb;269(1):135-144 PMID 30635715

The use of medical cannabis and cannabis-based medicines has received increasing interest in recent years; with a corresponding surge in the number of studies and reviews conducted in the field. Despite this growth in evidence, the findings and conclusions of these studies have been inconsistent. In this paper, we outline the current evidence for medical cannabis and cannabis-based medicines in the treatment and management of chronic non-cancer pain. We discuss limitations of the current evidence, including limitations of randomised control trials in the field, limits on generalisability of previous findings and common issues such as problems with measurements of dose and type of cannabinoids. We discuss future directions for medicinal cannabinoid research, including addressing limitations in trial design; developing frameworks to monitor for use disorder and other unintended outcomes; and considering endpoints other than 30% or 50% reductions in pain severity.


Dikmen HA, Terzioglu F. Effects of Reflexology and Progressive Muscle Relaxation on Pain, Fatigue, and Quality of Life during Chemotherapy in Gynecologic Cancer Patients. Pain Manag Nurs 2019 Feb;20(1):47-53 PMID 29776873

PURPOSE: Our aim was to investigate the effect of reflexology and progressive muscle relaxation (PMR) exercises on pain, fatigue, and quality of life (QoL) of gynecologic cancer patients during chemotherapy. METHODS: Eighty participants were randomly assigned to one of four groups: reflexology, progressive muscle relaxation (PMR) exercises, both (reflexology + PMR), or a control group. Data were collected with a general data collection form, Brief Pain and Fatigue inventories, and Multidimensional Quality-of-Life Scale-Cancer. RESULTS: In reflexology and reflexology + PMR groups, a significant decrease in pain severity and fatigue and an increase in QoL were found (p .05). CONCLUSIONS: Reflexology and PMR exercises given to gynecologic cancer patients during chemotherapy were found to decrease pain and fatigue and increase QoL.


Djalilova DM, Schulz PS, Berger AM, Case AJ, Kupzyk KA, Ross AC. Impact of Yoga on Inflammatory Biomarkers: A Systematic Review. Biol Res Nurs 2019 Mar;21(2):198-209 PMID 30572710

BACKGROUND:: Many chronic conditions, including heart disease, cancer, and rheumatoid arthritis, are associated with underlying chronic inflammatory processes. Literature reviews have analyzed a variety of integrative therapies and their relationships with chronic inflammation. This systematic review is unique in reporting solely on yoga's relationship with inflammation. Its purpose was to synthesize current literature examining the impact of yoga interventions on inflammatory biomarkers in adults with chronic inflammatory-related disorders. METHOD:: Searches of several electronic databases were conducted. Inclusion criteria were (a) English language, (b) sample age >18 years old, (c) yoga interventions involving postures with or without yoga breathing and/or meditation, and (d) measured inflammatory biomarkers. RESULTS:: The final review included 15 primary studies. Of these, seven were rated as excellent and eight as average or fair. There was considerable variability in yoga types, components, frequency, session length, intervention duration, and intensity. The most common biomarkers measured were interleukin-6 ( n = 11), C-reactive protein ( n = 10), and tumor necrosis factor ( n = 8). Most studies reported positive effects on inflammatory biomarkers ( n = 11) from baseline to post yoga intervention. Analysis of the dose showed higher total dose (>1,000 min) resulted in greater improvements in inflammation. CONCLUSION:: This review suggests that yoga can be a viable intervention to reduce inflammation across a multitude of chronic conditions. Future studies with detailed descriptions of yoga interventions, measurement of new and well-established inflammatory biomarkers, and larger sample sizes are warranted to advance the science and corroborate results.


Duggan KJ, Wiltshire J, Strutt R, Boxer MM, Berthelsen A, Descallar J, et al. Palliative care and psychosocial care in metastatic non-small cell lung cancer: factors affecting utilisation of services and impact on patient survival. Support Care Cancer 2019 Mar;27(3):911-919 PMID 30066201

BACKGROUND: Palliative care (PC) and psychosocial care (PSC) are essential services, which can positively impact on quality of life in patients with metastatic lung cancer, when advanced disease and poor prognosis preclude the use of curative therapies. The aims of this study were to describe patterns of PC and PSC and identify factors associated with service utilisation and overall patient survival. METHOD: A retrospective Australian cohort of South Western Sydney residents with newly diagnosed stage IV non-small cell lung cancer (NSCLC) in 2006-2012 was identified from the Local Health District Clinical Cancer Registry. Supplemental information was sourced from the area PC database and hospital medical records. Cox regression models with robust variance identified factors associated with PC and PSC and examined patient survival. RESULTS: A total of 923 patients were identified. Eighty-three per cent of patients were seen by PC, with 67% seen within 8 weeks of diagnosis. PSC utilisation was 82%. Radiotherapy treatment and residential area were associated with both PC and PSC. Increasing age was associated with early PC referral. Median overall survival was 4 months. PC was associated with patient survival; however, the effect varied over time. CONCLUSION: The rate of PC and PSC in our metastatic NSCLC population was high when compared with published data. Despite this, there were gaps in PC and PSC provision in this population, notably with patients not receiving active treatment, and those receiving systemic therapy utilising these services less frequently. PSC and PC contact were not convincingly associated with improved patient survival.

Hohmann T, Feese K, Ghadban C, Dehghani F, Grabiec U. On the influence of cannabinoids on cell morphology and motility of glioblastoma cells. PLoS One 2019 Feb 12;14(2):e0212037 PMID 30753211

The mechanisms behind the anti-tumoral effects of cannabinoids by impacting the migratory activity of tumor cells are only partially understood. Previous studies demonstrated that cannabinoids altered the organization of the actin cytoskeleton in various cell types. As actin is one of the main contributors to cell motility and is postulated to be linked to tumor invasion, we tested the following hypothesizes: 1) Can cannabinoids alter cell motility in a cannabinoid receptor dependent manner? 2) Are these alterations associated with reorganizations in the actin cytoskeleton? 3) If so, what are the underlying molecular mechanisms? Three different glioblastoma cell lines were treated with specific cannabinoid receptor 1 and 2 agonists and antagonists. Afterwards, we measured changes in cell motility using live cell imaging and alterations of the actin structure in fixed cells. Additionally, the protein amount of phosphorylated p44/42 mitogen-activated protein kinase (MAPK), focal adhesion kinases (FAK) and phosphorylated FAK (pFAK) over time were measured. Cannabinoids induced changes in cell motility, morphology and actin organization in a receptor and cell line dependent manner. No significant changes were observed in the analyzed signaling molecules. Cannabinoids can principally induce changes in the actin cytoskeleton and motility of glioblastoma cell lines. Additionally, single cell motility of glioblastoma is independent of their morphology. Furthermore, the observed effects seem to be independent of p44/42 MAPK and pFAK pathways.


Jeong S, Yun HK, Jeong YA, Jo MJ, Kang SH, Kim JL, et al. Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells. Cancer Lett 2019 Apr 10;447:12-23 PMID 30660647

Cannabidiol (CBD), one of the compounds present in the marijuana plant, has anti-tumor properties, but its mechanism is not well known. This study aimed to evaluate the apoptotic action of CBD in colorectal cancer (CRC) cells, and focused on its effects on the novel pro-apoptotic Noxa-reactive oxygen species (ROS) signaling pathway. CBD experiments were performed using the CRC cell lines HCT116 and DLD-1. CBD induced apoptosis by regulating many pro- and anti-apoptotic proteins, of which Noxa showed significantly higher expression. To understand the relationship between Noxa and CBD-induced apoptosis, Noxa levels were downregulated using siRNA, and the expression of apoptosis markers decreased. After ROS production was blocked, the level of Noxa also decreased, suggesting that ROS is involved in the regulation of Noxa, which along with ROS is a well-known pro-apoptotic signaling agents. As a result, CBD induced apoptosis in a Noxa-and-ROS-dependent manner. Taken together, the results obtained in this study re-demonstrated the effects of CBD treatment in vivo, thus confirming its role as a novel, reliable anticancer drug.

Kosgodage US, Uysal-Onganer P, MacLatchy A, Mould R, Nunn AV, Guy GW, et al. Cannabidiol Affects Extracellular Vesicle Release, miR21 and miR126, and Reduces Prohibitin Protein in Glioblastoma Multiforme Cells. Transl Oncol 2019 Mar;12(3):513-522 PMID 30597288

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary malignant brain tumor in adults, with poor prognosis. Extracellular vesicles (EVs) are key-mediators for cellular communication through transfer of proteins and genetic material. Cancers, such as GBM, use EV release for drug-efflux, pro-oncogenic signaling, invasion and immunosuppression; thus the modulation of EV release and cargo is of considerable clinical relevance. As EV-inhibitors have been shown to increase sensitivity of cancer cells to chemotherapy, and we recently showed that cannabidiol (CBD) is such an EV-modulator, we investigated whether CBD affects EV profile in GBM cells in the presence and absence of temozolomide (TMZ). Compared to controls, CBD-treated cells released EVs containing lower levels of pro-oncogenic miR21 and increased levels of anti-oncogenic miR126; these effects were greater than with TMZ alone. In addition, prohibitin (PHB), a multifunctional protein with mitochondrial protective properties and chemoresistant functions, was reduced in GBM cells following 1 h CBD treatment. This data suggests that CBD may, via modulation of EVs and PHB, act as an adjunct to enhance treatment efficacy in GBM, supporting evidence for efficacy of cannabinoids in GBM.


Majeed MH, Ali AA, Sudak DM. Psychotherapeutic interventions for chronic pain: Evidence, rationale, and advantages. Int J Psychiatry Med 2019 Mar;54(2):140-149 PMID 30091372

BACKGROUND: Long-term use of opioids to treat chronic pain incurs serious risks for the individual-including misuse, abuse, addiction, overdose and death-as well as creating economic, social, and cultural impacts on society as a whole. Chronic pain and substance use disorders are often co-morbid with other medical problems and at the present time, primary care clinicians serve most of this population. Primary care clinicians would benefit from having alternatives to opioids to employ in treating such patients. METHOD: We electronically searched different medical databases for studies evaluating the effect of nonpharmacological treatments for chronic pain. We describe alternative approaches for the treatment of chronic pain and cite studies that provide substantial evidence in favor of the use of these treatments. RESULTS: Cognitive behavioral therapy, acceptance and commitment therapy, and mindfulness-based programs have well-documented effectiveness for the treatment of chronic nonmalignant pain. Integration of such behavioral health therapies into primary care settings may optimize health resources and improve treatment outcomes. CONCLUSION: Evidence-based psychotherapy for chronic pain has established efficacy and safety and improves quality of life and physical and emotional functioning. Such interventions may be used as an alternative or adjunct to pharmacological management. Chronic opioid use should be reserved for individuals undergoing active cancer treatment, palliative care, or end-of-life care.


Miller KR, Patel JN, Symanowski JT, Edelen CA, Walsh D. Acupuncture for Cancer Pain and Symptom Management in a Palliative Medicine Clinic. Am J Hosp Palliat Care 2019 Apr;36(4):326-332 PMID 30286611

OBJECTIVE:: Studies suggest acupuncture improves cancer-related symptoms; however, it is unclear whether patient characteristics predict pain response. This study determined acupuncture's effect on cancer-related pain and identified variables associated with pain response. METHODS:: A retrospective chart review included adult patients with cancer referred to palliative medicine and received acupuncture for pain management. Paired t tests compared differences in pain scores from pre- to postacupuncture. Clinically meaningful pain improvement was defined as >/=2-point reduction in pain score. Logistic regression was used to evaluate associations between patient characteristics and pain improvement. RESULTS:: One hundred seventy acupuncture treatments from 68 individual patients were studied. Significant reductions in mean pain scores were observed after the first treatment (-1.9 +/- 1.8; P < .001) and across all treatments (-1.7 +/- 1.9; P < .001). Multivariable analysis demonstrated clinically meaningful pain improvement with higher baseline pain scores (odds ratio [OR]: 1.79, 95% confidence interval [CI]: 1.44-2.22; P < .001) and stage III/IV disease (OR: 3.23, 95% CI: 1.11-9.40; P < .001). There were significant improvements in anxiety, depression, drowsiness, dyspnea, fatigue, nausea, and well-being after the first treatment and across all treatments ( P < .001). CONCLUSIONS:: Acupuncture improved cancer-related pain and other symptoms. Those with higher baseline pain scores and advanced disease were more likely to achieve significant pain reduction. Improved depression and fatigue were closely related to pain reduction. Further studies are needed to confirm pain response variables, establish durability, and develop a personalized approach to acupuncture.


Nourmohammadi H, Motaghi M, Borji M, Tarjoman A, Soltany B. The Effects of Reflexology on Fatigue Severity of Patients with Cancer. Asian Pac J Cancer Prev 2019 Feb 26;20(2):391-394 PMID 30803197

Introduction: Breast cancer is a major threat to women's health and a common factor that can reduce their life expectancy. Complementary medicine such as reflexology is known to reduce fatigue severity in cancer patients. The present study aimed to cultivate the effect of reflexology on fatigue severity of patients with breast cancer. Methods: The present pre-post clinical trial recruited 57 patients with breast cancer and involved an experimental and a control group. All patients were livening in Ilam, Iran. Patients were randomly assigned to two groups of experimental (N=27) and control (N=30). The experimental group received reflexology for 4 sessions. Data were collected using Fatigue severity scale (FSS) and demographic information questionnaire. FSS was completed by the patients twice; before the intervention and 2 months after the intervention. Data were analyzed using SPSS and running t-test and ANOVA. Results: Results showed no significant difference in fatigue severity between experimental (45.44+/-5.30) and control (43.66+/-7.68) groups prior to the intervention (p>0.05). However, after conducting the intervention, a significant difference in fatigue severity was seen between the experimental (20.66+/-4.54) and control (40.36+/-9.58) groups (p=0.000). Conclusion: The present study showed that reflexology decrease fatigue severity in patients with breast cancer and community health nursing can to use of these complementary medicine to increase patients health conditions.


Pene CTH, Kissane D. Communication in cancer: its impact on the experience of cancer care: communicating with the angry patient and the patient in denial. Curr Opin Support Palliat Care 2019 Mar;13(1):46-52 PMID 30632988

PURPOSE OF REVIEW: This review aims to describe the recent literature on communication between cancer care clinicians and angry patients and patients in denial. RECENT FINDINGS: Clinicians had improved perceived self-efficacy in responding to patient anger after completing anger management training, with a focus on reframing anger as a normative response to unmet needs. Psychosocial and mindfulness programmes for cancer patients were found to be useful for modifying anger response to stressors. Existing clinician communication guidelines may not meet the complex needs of adolescents and individuals with anger-prone personality expressing anger. The detrimental effects of avoiding communication about cancer and dying in patients and families include increased stress and emotional burden, patient depression and anxiety and regret in bereaved family members. Further understanding of the complex interplay between the expression of instrumental and emotional concerns of patients may lead to improved clinician communication. SUMMARY: Anger and maladaptive denial in patients with cancer have detrimental effects that can be seen across a wide range of cultural contexts, in not only the patient but also in their families and the involved clinicians. Training interventions for both patients and clinicians can benefit patient emotional response and perceived clinician self-efficacy.

Turgeman I, Bar-Sela G. Cannabis for cancer - illusion or the tip of an iceberg: a review of the evidence for the use of Cannabis and synthetic cannabinoids in oncology. Expert Opin Investig Drugs 2019 Mar;28(3):285-296 PMID 30572744

INTRODUCTION: A flowering plant of variegated ingredients and psychoactive qualities, Cannabis has long been used for medicinal and recreational purposes. Regulatory approvals have been gained across a broad range of palliative and therapeutic indications, and in some cases, included in standard treatment guidelines. Areas covered: The use of Cannabis and cannabinoid-based-medicines in oncology is summarized in this article. Cannabinoids are classified according to natural and synthetic subtypes and their mechanisms of action expounded. The variability of available products is discussed in the clinical context and data regarding chemotherapy-induced nausea and vomiting, cancer-related pain, anorexia, insomnia, and anxiety are presented. Moreover, immunological and antineoplastic effects in preclinical and clinical trials are addressed. Concepts such as synergism or opposition with conventional treatment modalities, the sequence of administration and dosage, molecular cross-talk and malignancy-cannabinoid congruence, are explored. Finally, side-effects, limitations in trial design and legislation barriers are related. Expert opinion: Sufficient evidence supports the use of Cannabis for palliative indications in oncology; however, patients should be carefully selected, guided and followed. Promising research suggests the potent antineoplastic activity, but more data must be accrued before conclusions can be drawn.