Bo Angela Wan

Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies

Chemotherapy-induced neuropathic pain is a distressing and commonly occurring side effect of many commonly used chemotherapeutic agents, which in some cases may prevent cancer patients from being able to complete their treatment. Cannabinoid based therapies have the potential to manage or even prevent pain associated with this syndrome. Pre-clinical animal studies that investigate the modulation of the endocannabinoid system (endogenous cannabinoid pathway) are being conducted to better understand the mechanisms behind this phenomenon. Five recent pre-clinical studies identified from Medline published between 2013 and 2016 were selected for review. All studies evaluated the effect of small-molecule agonists or antagonists on components of the endocannabinoid system in rats or mice, using cisplatin or paclitax-el-induced allodynia as a model of chemotherapy-induced neuropathic pain. Activation of the cannabinoid receptor-2 (CB-2) receptor by AM1710 blocked paclitaxel-induced mechanical and cold allodynia in one study. Four studies investigating the activation of both cannabinoid receptor-1 (CB-1) and CB-2 receptors by dual-agonists (WIN55,21 and CP55,940), or by the introduction of inhibitors of endocannabinoid metabolisers (URB597, URB937, JZL184, and SA-57) showed reduction of chemotherapy-induced al-lodynia. In addition, their results suggest that anti-allodynic effects may also be mediated by additional receptors, including TRPV1 and 5-hydroxytryptamine (5-HT1A). Pre-clinical studies demon-strate that the activation of endocannabinoid CB-1 or CB-2 receptors produces physiological effects in animal models, namely the reduction of chemotherapy-induced allodynia. These studies also provide in-sight into the biological mechanism behind the therapeutic utility of cannabis compounds in managing chemotherapy-induced neuropathic pain, and provide a basis for the conduct of future clinical studies in patients of this population.

A review of patterns of practice and clinical guidelines in the palliative radiation treatment of uncomplicated bone metastases

BACKGROUND AND PURPOSE Single fraction radiation treatment (SFRT) is recommended for its equivalence to multiple-fraction (MF) RT in the palliation of uncomplicated bone metastases (BM). However, adoption of SFRT has been slow. MATERIALS AND METHODS Literature searches for studies published following 2014 were conducted using online repositories of gray literature, Ovid MEDLINE, Embase and Embase Classic, and the Cochrane Central Register of Controlled Trials databases. RESULTS A total of 32 articles detailing patterns of practice and clinical practice guidelines were included for final synthesis. The majority of organizations have released high level recommendations for SFRT use in treatment of uncomplicated BM, based on evidence of non-inferiority to MFRT. There are key differences between guidelines, such as varying strengths of recommendation for SFRT use over MFRT; contraindication in vertebral sites for SFRT; and risk estimation of pathologic fractures after SFRT. Differences in guidelines may be influenced by committee composition and organization mandate. Differences in patterns of practice may be influenced by individual center policies, payment modalities and consideration of patient factors such as age, prognosis, and performance status. CONCLUSION Although there is some variation between groups, the majority of guidelines recommend use of SFRT and others consider it to be a reasonable alternative to MFRT.

Patient Reported Outcomes After Radiation Therapy for Bone Metastases as a Function of Age: A Secondary Analysis of the NCIC CTG SC—Twenty-Three Randomized Trial:

Purpose: To explore the age difference in response and patient-reported outcomes in patients with cancer having bone metastases undergoing palliative radiotherapy. Methods: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life (QOL) Bone Metastases module (QLQ-BM22), EORTC QOL Core-15-Palliative (QLQ-C15-PAL), and Dexamethasone Symptom Questionnaire (DSQ) before a single 8-Gy radiation treatment, on days 10 and 42 after treatment. Patient demographics, performance status, analgesic consumption, BM22, C15, and DSQ were compared with multivariant analysis between patients under 75 years and 75 years and older. Multiple linear regression models were used to assess the differences between age-groups, adjusting for baseline demographics and primary disease sites. Results: There were 298 patients (170 male) with 209 (70%) less than 75 years of age. Most common primary cancer sites include lung, prostate, and breast. At baseline, younger patients had better performance status, consumed more analgesic, and reported worse scores in nausea, insomnia, and functional interference, while older patients more commonly had prostate cancer. There were no significant differences in the incidence of radiation-induced pain flare; response to radiation; changes from baseline for BM22, C15-PAL; and DSQ, nor overall survival at day 42 between the 2 groups. Responders to radiation in the elderly group reported better improvement in physical and emotional domains when compared with nonresponders. Conclusions: In patients with cancer having bone metastases undergoing palliative radiotherapy, there was no significant difference in general with age in response to radiation and patient-reported outcomes. Palliative radiotherapy should be offered to elderly patients when needed.

An update in symptom clusters using the Edmonton Symptom Assessment System in a palliative radiotherapy clinic

PurposeTo identify symptom clusters in advanced cancer patients attending a palliative radiotherapy clinic using the Edmonton Symptom Assessment System (ESAS).MethodsPrincipal component analysis (PCA), exploratory factor analysis (EFA), and hierarchical cluster analysis (HCA) were used to identify symptom clusters among the nine ESAS items using scores from each patient’s first visit.ResultsESAS scores from 182 patients were analyzed. The PCA identified three symptom clusters (cluster 1: depression-anxiety-well-being, cluster 2: pain-tiredness-drowsiness, cluster 3: nausea-dyspnea-loss of appetite). The EFA identified two clusters (cluster 1: tiredness-drowsiness-loss of appetite-well-being-pain-nausea-dyspnea, cluster 2: depression-anxiety). The HCA identified three clusters similar to the PCA with an exception of the loss of appetite item being classified under cluster 1 rather than 3. Two to three symptom clusters were identified using three analytical methods, with similar patterns reported in the literature. Particular groups of items co-occurred consistently across all three analyses: depression and anxiety; nausea and dyspnea; as well as pain, tiredness, and drowsiness.ConclusionThree similar symptom clusters were identified in our patient population using the PCA and HCA; whereas, the EFA produced two clusters: one physical and one psychological cluster. Given the implications of symptom clusters in the management of quality of life, clinicians should be aware of these clusters to aid in the palliative treatment of patients.

A selective review of medical cannabis in cancer pain management

Insufficient management of cancer-associated chronic and neuropathic pain adversely affects patient quality of life. Patients who do not respond well to opioid analgesics, or have severe side effects from the use of traditional analgesics are in need of alternative therapeutic op-tions. Anecdotal evidence suggests that medical cannabis has potential to effectively manage pain in this patient population. This review presents a selection of representative clinical studies, from small pilot studies conducted in 1975, to double-blind placebo-controlled trials conducted in 2014 that evaluated the efficacy of cannabinoid-based therapies containing tetrahydrocannabinol (THC) and cannabidiol (CBD) for reducing cancer-associated pain. A review of literature published on Medline between 1975 and 2017 identified five clinical studies that evaluated the effect of THC or CBD on controlling cancer pain, which have been reviewed and summarised. Five studies that evaluated THC oil capsules, THC:CBD oromucosal spray (nabiximols), or THC oromucosal sprays found some evidence of cancer pain reduction associated with these therapies. A variety of doses ranging from 2.7-43.2 mg/day THC and 0-40 mg/day CBD were administered. Higher doses of THC were correlated with increased pain relief in some studies. One study found that significant pain relief was achieved in doses as low as 2.7-10.8 mg THC in combination with 2.5-10.0 mg CBD, but there was conflicting evidence on whether higher doses provide superior pain relief. Some reported side effects include drowsiness, hypotension, mental clouding, and nausea and vomiting. There is evidence suggesting that medical cannabis reduces chronic or neu-ropathic pain in advanced cancer patients. However, the results of many studies lacked statistical power, in some cases due to limited number of study subjects. Therefore, there is a need for the conduct of further double-blind, placebo-controlled clinical trials with large sample sizes in order to establish the optimal dosage and efficacy of different cannabis-based therapies.

Genetic biomarkers associated with response to palliative radiotherapy in patients with painful bone metastases

BACKGROUND Palliative radiotherapy (RT) is effective in patients with painful bone metastases. Genetic factors may identify subgroup of patients who responded to RT. To identify DNA biomarkers associated with response to palliative RT. METHODS Patients who received a single 8 Gy dose of RT for painful bone metastases were categorised into responders (n=36), non-responders (NR) (n=71). Saliva samples were sequenced to identify single-nucleotide variants (SNVs) in genes with known disease-causing variants from inflammation, radiation response, and DNA damage pathways. In univariate analysis, Cochran-Armitage trend tests were used to identify SNVs that associated with pain response (P<0.005), and the Penalized LASSO method with minimum Bayesian Information Criterion was used to identify multi-SNVs that jointly predict pain response to RT. The corresponding estimated effect of the multi-SNVs were used to drive the prognostic score for each patient. Based on it, patients were divided into 3 equal size risk groups. RESULTS Forty-one significant variants were identified in univariate analysis. Multivariable analysis selected 14 variants to generate prognostic scores, adjusting for gender and primary cancer site. Eighty-nine percent of patients in the high prognostic group responded to palliative radiation therapy (P=0.0001). Estimated effect sizes of the variants ranged from 0.108-2.551. The most statistically significant variant was a deletion at position 111992032 in the ataxin gene ATXN2 (P=0.0001). Five variants were non-synonymous, including AOAH rs7986 (P=0.0017), ZAN rs539445 (P=0.00078) and rs542137 (P=0.00078), RAG1 rs3740955 (P=0.0014), and GBGT1 rs75765336 (P=0.0026). CONCLUSIONS SNVs involved in mechanisms including DNA repair, inflammation, cellular adhesion, and cell signalling have significant associations with radiation response. SNVs with predictive power may stratify patient populations according to likelihood of responding to treatment, therefore enabling more efficient identification of beneficial strategies for pain management and improved resource utilisation.

Gender differences in pain and patient reported outcomes: a secondary analysis of the NCIC CTG SC. 23 randomized trial

BACKGROUND Gender differences may contribute to variations in disease presentations and health outcomes. To explore the gender difference in pain and patient reported outcomes in cancer patients with bone metastases undergoing palliative radiotherapy on the National Cancer Institute of Canada (NCIC) SC.23 randomized trial. METHODS Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) bone metastases module (QLQ-BM22) and EORTC QOL Core-15-Palliative (QLQ-C15-PAL) before treatment and at days 10 and 42 after a single 8 Gy radiation treatment. Patient demographics, performance status, analgesic consumption, BM22 and C15 were compared between males and females using the 2-sample t-test for continuous variables or the Chi-squared test for categorical variables. Multiple linear regression models were used to check the difference between gender groups adjusting for the baseline demographics and primary disease sites. RESULTS There were 298 patients (170 male, 128 female) with median age of 69 years. The most common primary cancer sites were lung, prostate and breast. At baseline, there were no differences in BM22 and C15 scores, except a worse nausea and vomiting score (P=0.03) in females on the C15. In patients with moderate baseline worst pain scores (WPS), females reported worse scores in painful sites of BM22. At day 42, there was no significant difference in response to radiotherapy. Among the responders, females reported better improvement in emotional aspect. CONCLUSIONS In cancer patients with bone metastases undergoing palliative radiotherapy, the majority of symptom presentations, patient reported outcomes, and response to radiation was not significantly different between genders. TRIAL REGISTRATION NCT01248585.

Impact of radiation-induced nausea and vomiting on quality of life

PurposeRadiotherapy-induced nausea and vomiting is a common side effect of radiotherapy. It is well-established that nausea and vomiting have a negative impact on quality of life, but the relative influence of each of symptom is infrequently reported. This study aimed to compare the effects of nausea and vomiting on quality of life in cancer patients receiving palliative radiotherapy.MethodsThe Functional Living Index-Emesis (FLIE) is a quality of life questionnaire developed in the chemotherapy-induced nausea and vomiting setting. The FLIE consists of 18 questions, half of which address nausea and half of which address vomiting. Three prospective studies on the efficacy of various anti-emetic medications conducted at our center used the FLIE to assess radiotherapy-induced nausea and vomiting at various time points during and after palliative radiotherapy. FLIE data from these three studies were combined for the present analysis. Univariate and multivariate analyses were conducted to assess the relationships between nausea and vomiting, time of FLIE completion, and patient-reported quality of life.ResultsNausea and vomiting scores both decreased patients’ quality of life. Multivariate modeling showed that both symptoms significantly influenced patients’ ability to enjoy meals. Nausea was also associated with increased hardship for the patient, while vomiting imposed more difficulty on the patients’ loved ones.ConclusionsNausea and vomiting both significantly influence quality of life. Nausea seems to impact the patient more directly, whereas vomiting affects those closest to the patient.

Symptom clusters using the EORTC QLQ-C15-PAL in palliative radiotherapy

BACKGROUND Patients with advanced cancer often experience a multitude of symptoms. Due to the potential interrelation of symptoms, symptom clusters of 2 or more concurrent symptoms have been advocated for use in the palliative setting to provide better management of symptoms. METHODS The principal component analysis (PCA), exploratory factor analysis (EFA) and hierarchal cluster analysis (HCA) were conducted on responses to items 1-14 in the European Organisation for Research and Treatment of Cancer Quality of Life-C15-Palliative (EORTC QLQ-C15-PAL) at baseline and days 5 and 10 following RT. RESULTS There was complete data for 109, 90 and 87 patients at baseline, day 5 and day 10 respectively. The average age was 72 years. The most common site of primary was the prostate (36.7%), and almost all patients presented with bone metastases (95.4%). Analyses identified 2-4 clusters at each interval. From baseline to day 10 follow-up, across all analyses, items associated with physical functioning clustered consistently with shortness of breath. Pain and pain interference clustered with nausea at baseline; and with sleep at both follow-up intervals. Cronbachs alpha values for the clusters ranged from 0.53 to 0.90. CONCLUSIONS Fluctuation of symptom clusters was observed in a short time frame following palliative RT. Although clusters were dynamic, several items tended to cluster together. Further research is required to validate these clusters.

A pilot study with palonosetron in the prophylaxis of radiation-induced nausea and vomiting

BACKGROUND Palonosetron is an effective antiemetic in chemotherapy-induced nausea and vomiting (CINV), but has yet to be studied in the radiation setting. The purpose of the present study was to investigate the efficacy and safety of palonosetron in the prophylaxis of radiation-induced nausea and vomiting (RINV). METHODS Patients without existing nausea and vomiting undergoing palliative radiotherapy to sites with emetic risk were prescribed palonosetron 0.5 mg orally before the start of radiation treatment, and every other day until completion of treatment. Patients were followed up in acute (day 1 of treatment to day 1 after treatment) and delayed phases (days 2-10 after treatment). The primary endpoint was control of vomiting. Complete control was defined as no use of rescue medication and no episodes of nausea or vomiting. Secondary endpoints included control of nausea and quality of life (QOL). QOL was assessed with the Functional Living Index-Emesis and the European Organisation for Research and Treatment of Cancer QOL Questionnaire-Core 15 Palliative (C15-PAL). RESULTS In all evaluable patients (n=75), complete control of vomiting was 93.3% in the acute phase and 93.2% in the delayed phase. Complete control of nausea was 74.7% in the acute phase and 74.0% in the delayed phase. CONCLUSIONS Results suggest improved control in RINV compared to historical reports with first generation serotonin receptor antagonists (RA). A randomized study will be needed to confirm this finding.