Psychological distress and physical symptoms in advanced cancer: cross-sectional study.

OBJECTIVES: Patients with advanced cancer experience varying physical and psychological symptoms throughout the course of their illness. Depression, anxiety and stress affect overall well-being. This study investigates the correlation between emotional distress and physical symptoms in a cohort of patients with advanced cancer. METHODS: There were 238 patients included in this study. Data from participants in two medicinal cannabis randomised controlled trials were analysed. Patients were aged over 18 years and had advanced cancer. Edmonton Symptom Assessment System, and Depression, Anxiety and Stress Scale (DASS-21) were assessed for all patients at baseline. RESULTS: Moderate-severe depression was reported in 29.8% and moderate-severe anxiety was reported in 47.9% of patients. The emotional subscales of DASS-21 (depression, anxiety, stress) correlated with total symptom distress score (p<0.001) and overall well-being (p<0.001). Depression was correlated with physical symptoms of fatigue, nausea, poor appetite and dyspnoea. Anxiety was correlated with fatigue and dyspnoea. Stress was correlated with fatigue, nausea and dyspnoea. CONCLUSIONS: Depression, anxiety and stress were common in this population. The relationship between physical and psychological well-being is complex. A holistic approach to symptom management is required to improve quality of life in patients with advanced cancer.

Medicinal Cannabis (MedCan 3): a randomised, multicentre, double-blind, placebo-controlled trial to assess THC/CBD (1:20) to relieve symptom burden in patients with cancer-a study protocol for a randomised controlled trial.

BACKGROUND: Distressing symptoms are common in advanced cancer. Medicinal cannabinoids are commonly prescribed for a variety of symptoms. There is little evidence to support their use for most indications in palliative care. This study aims to assess a 1:20 delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) cannabinoid preparation in the management of symptom distress in patients with advanced cancer undergoing palliative care. METHODS AND DESIGN: One hundred and fifty participants will be recruited across multiple sites in Queensland, Australia. A teletrial model will facilitate the recruitment of patients outside of major metropolitan areas. The study is a pragmatic, multicenter, randomised, placebo-controlled, two-arm trial of escalating doses of an oral 1:20 THC/CBD medicinal cannabinoid preparation (10 mg THC:200 mg CBD/mL). It will compare the efficacy and safety outcomes of a titrated dose range of 2.5 mg THC/50mgCBD to 30 mg THC/600 mg CBD per day against a placebo. There is a 2-week patient-determined titration phase, to reach a dose that achieves symptom relief or intolerable side effects, with a further 2 weeks of assessment on the final dose. The primary objective is to assess the effect of escalating doses of a 1:20 THC/CBD medicinal cannabinoid preparation against placebo on change in total symptom distress score, with secondary objectives including establishing a patient-determined effective dose, the effect on sleep quality and overall quality of life. Some patients will be enrolled in a sub-study which will more rigorously evaluate the effect on sleep. DISCUSSION: MedCan-3 is a high-quality, adequately powered, placebo-controlled trial which will help demonstrate the utility of a THC:CBD 1:20 oral medicinal cannabis product in reducing total symptom distress in this population. Secondary outcomes may lead to new hypotheses regarding medicinal cannabis' role in particular symptoms or in particular cancers. The sleep sub-study will test the feasibility of using actigraphy and the Insomnia Severity Index (ISI) in this cohort. This will be the first large-scale palliative care randomised clinical trial to utilise the teletrial model in Australia. If successful, this will have significant implications for trial access for rural and remote patients in Australia and internationally. TRIAL REGISTRATION: ANZCTR ACTRN12622000083796 . Protocol number 001/20. Registered on 21 January 2022. Recruitment started on 8 August 2022.

Cannabidiol oil or placebo in advanced cancer-disease progression and survival: a secondary analysis.

OBJECTIVES: Medical cannabinoids have become increasingly popular over the last decade. Preclinical trials suggest cannabinoids, for example, cannabidiol (CBD), may provide an anticancer effect; however, good-quality clinical information supporting this is lacking. We assessed the effect of CBD treatment on disease progression and survival in patients enrolled in a study of CBD versus placebo for symptom management in patients with advanced cancer (MEDCAN-1). METHODS: We reviewed the clinical records of all patients enrolled in the MEDCAN-1 Study (CBD vs placebo) at days 14, 28 and 56 of study follow-up, for evidence of disease progression. The proportion of participants with disease progression by treatment arm at each time point was compared, as was survival between both groups from study entry to the censor date (end of study period) and the effect of treatment arm and disease progression status on survival. RESULTS: Of the 135 patient records assessed, 128 were included in the final analysis. 36% (n=46) had progressive disease documented at day 28, rising to 49.2% (n=63) by day 56. No significant difference in disease progression was noted between the two groups at days 14 (p=0.33), 28 (p=0.67) or 56 (p=0.50). There was no difference in survival between both groups from study entry to censor date (p=0.38). Disease progression at day 14 was highly predictive of mortality (p<0.001). CONCLUSIONS: In this substudy analysis, treatment with CBD oil did not affect disease progression or survival over the course of 56 days in patients with advanced cancer.

Exploring potential anti-inflammatory effects of medicinal cannabis.

PURPOSE: Inflammation is thought to play a key role in malignant disease and may play a significant part in the expression of cancer-related symptoms. Cannabidiol (CBD) is a bioactive compound in cannabis and is reported to have significant anti-inflammatory properties. METHOD: Serial C-reactive protein (CRP) levels were measured in all participants recruited to a randomised controlled trial of CBD versus placebo in patients with symptoms related to advanced cancer. A panel of inflammatory cytokines was measured over time in a subset of these patients. RESULTS: There was no difference between the two arms in the trajectory of CRP or cytokine levels from baseline to day 28. CONCLUSION: We were unable to demonstrate an anti-inflammatory effect of CBD in cancer patients. TRIAL REGISTRATION: ANZCTR 26180001220257, registered 20/07/2018.

Drug dependence epidemiology in palliative care medicinal cannabis trials.

OBJECTIVES: Drug dependence is becoming increasingly common and meeting palliative care patients with substance use disorders is inevitable. However, data on substance use in these patients are lacking. This study aims to evaluate the prevalence of drug dependence in palliative care patients with advanced cancer and correlate with symptom distress and opioid use. METHODS: Palliative care patients with advanced cancer interested in participation in a medicinal cannabis trial were required to complete Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), Edmonton Symptom Assessment Scale (ESAS) and record of concomitant medications including baseline opioid use as part of the eligibility screen. RESULTS: Of the 182 participants, 167 (92%) reported lifetime alcohol and 132/182 (73%) lifetime tobacco use. No participant reached the threshold criteria for high risk of drug dependence with majority being low risk. There was no correlation between ASSIST score, ESAS and oral morphine equivalent. CONCLUSION: This study identified alcohol and tobacco as the main substances used in this group of patients and that most were of very low risk for drug dependence. This suggests routine drug screening for palliative care patient may not be justified, but the high possibility of questionnaire bias is acknowledged.

Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD).

PURPOSE: To determine whether cannabidiol (CBD) oil can improve symptom distress in patients with advanced cancer receiving palliative care. METHODS: Participants were adults with advanced cancer and symptom distress (Edmonton Symptom Assessment Scale [ESAS] total score of ≥ 10/90) who received titrated CBD oil 100 mg/mL, 0.5 mL once daily to 2 mL three times a day, or matched placebo for 28 days. The primary outcome was ESAS total symptom distress score (TSDS) at day 14. Response was defined as a decrease in TSDS by ≥ 6 at day 14. Secondary outcomes were ESAS TSDS over time, individual symptom scores, patient-determined effective dose, opioid use, Global Impression of Change, depression, anxiety, quality of life, and adverse events. RESULTS: Of the 144 patients randomly assigned, the planned sample size of 58 participants on CBD and 63 on placebo reached the primary analysis point (day 14). The unadjusted change in TSDS from baseline to day 14 was -6.2 (standard deviation, 14.5) for placebo and -3.0 (standard deviation, 15.2) for CBD with no significant difference between arms (P = .24). Similarly, there was no detected difference in proportion of responders (placebo: 37 of 63 [58.7%], CBD: 26 of 58 [44.8%], P = .13). All components of ESAS improved (fell) over time with no difference between arms. The median dose of participant-selected CBD was 400 mg per day with no correlation with opioid dose. There was no detectable effect of CBD on quality of life, depression, or anxiety. Adverse events did not differ significantly between arms apart from dyspnea that was more common with CBD. Most participants reported feeling better or much better at days 14 (53% CBD and 65% placebo) and 28 (70% CBD and 64% placebo). CONCLUSION: CBD oil did not add value to the reduction in symptom distress provided by specialist palliative care alone.

Medicinal cannabis in palliative medicine: lessons learnt from randomised controlled trials.

OBJECTIVES: To detail important lessons learnt while conducting several large, medicinal cannabis (MC) randomised clinical trials in a palliative cancer population. METHODS: Investigators involved in these trials had several meetings to agree on the major lessons learnt and how the various challenges could be mitigated in the future. RESULTS: The lessons were sorted into separate categories: patient confidentiality, family dynamics, driving, cost, unfounded beliefs, accessing specific MC products, trial funding, telehealth and COVID-19, and miscellaneous issues. CONCLUSION: Using MC as the intervention arm in such trials entails some unique regulatory, logistical and other challenges. This short report presents key lessons learnt in conducting these randomised controlled trials in a palliative care population for the benefit of future investigators planning similar trials in a similar patient population.

Using a qualitative sub-study to inform the design and delivery of randomised controlled trials on medicinal cannabis for symptom relief in patients with advanced cancer.

BACKGROUND: Recruitment for randomised controlled trials in palliative care can be challenging; disease progression and terminal illness underpin high rates of attrition. Research into participant decision-making in medicinal cannabis randomised controlled trials (RCTs) is very limited. Nesting qualitative sub-studies within RCTs can identify further challenges to participation, informing revisions to study designs and recruitment practices. This paper reports on findings from a qualitative sub-study supporting RCTs of medicinal cannabis for symptom burden relief in patients with advanced cancer in one Australian city. METHODS: Semi-structured qualitative interviews were conducted with 48 patients with advanced cancer, eligible to participate in a medicinal cannabis RCT (n=28 who consented to participate in an RCT; n=20 who declined). An iterative and abductive approach to thematic analysis and data collection fostered exploration of barriers and enablers to participation. RESULTS: Key enablers included participants' enthusiasm and expectations of medicinal cannabis as beneficial (to themselves and future patients) for symptom management, especially after exhausting currently approved options, and a safer alternative to opioids. Some believed medicinal cannabis to have anti-cancer effects. Barriers to participation were the logistical challenges of participating (especially due to driving restrictions and fatigue), reluctance to interfere with an existing care plan, cost, and concerns about receiving the placebo and the uncertainty of the benefit. Some declined due to concerns about side-effects or a desire to continue accessing cannabis independent of the study. CONCLUSIONS: The findings support revisions to subsequent medicinal cannabis RCT study designs, namely, omitting a requirement that participants attend weekly hospital appointments. These findings highlight the value of embedding qualitative sub-studies into RCTs. While some challenges to RCT recruitment are universal, others are context (population, intervention, location) specific. A barrier to participation found in research conducted elsewhere-stigma-was not identified in the current study. Thus, findings have important implications for those undertaking RCTs in the rapidly developing context of medical cannabis.