Introduction

Cachexia is a multifactorial wasting syndrome characterized by involuntary weight loss through the ongoing loss of muscle mass, with or without loss of adipose tissue.1-3 It is a life-threatening aspect of advanced chronic disease, including cancer. Cancer-associated cachexia (CAC) is driven by tumour-host interactions resulting in progressive physical deterioration and functional impairment.4-6 It is associated with decreased quality of life (QoL) and tolerance to treatment and increased morbidity and mortality.2, 7-9 Attempts to define cachexia are relatively recent; therefore, estimates of prevalence vary considerably,10 particularly in cancer patients depending on tumour type and stage.11 A lack of consensus on definition and diagnostic criteria also makes it difficult to interpret research on the effectiveness of interventions and to compare studies.2, 3, 12

There are no standard treatments or guidelines to manage CAC,8 but an effective strategy should aim to reduce or prevent wasting to favour survival in advanced cancer patients.13, 14 Numerous therapeutic approaches have been developed to target wasting, weight loss and anorexia, three hallmarks of cachexia, including anti-cytokine therapies and metabolic mediators to counter wasting (e.g. glucocorticoids, anabolic steroids, progestogens, and beta-adrenoreceptor agonists); caloric or nutrient supplementation to prevent weight loss and promote muscle and weight gain; and using appetite stimulants like megestrol acetate and cannabinoids to manage anorexia.15-17 The benefits of megestrol acetate for appetite, caloric intake, nutritional status, QoL, and reduced muscle wasting in cachexia are well documented,15, 18, 19 but the weight gain associated with this drug often reflects fat deposition with little or no muscle growth.17, 20, 21 The potential of cannabinoids to relieve symptom burden in chronic diseases is recognized,22, 23 but their effectiveness in CAC is unclear.

Cannabinoids mimic the effect of human endocannabinoids on metabolism and appetite by interacting with their receptors, CB1, and CB2,24 and may have therapeutic benefits for body weight and appetite. The most commonly studied cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Currently, only three cannabinoid-containing drugs are commercially available for clinical use. Both Marinol and Cesamet, also known as dronabinol and nabilone respectively, are synthetic analogs of THC indicated for chemotherapy-induced nausea and vomiting in the USA and Canada.23 Dronabinol is sometimes also prescribed for HIV/AIDS-associated wasting syndrome. Sativex is a cannabis extract buccal spray containing a mixed ratio of THC and CBD adjunctively indicated for neuropathic and cancer pain.25 None of the above are currently indicated for CAC.

Previous randomized controlled trials (RCTs) report that cannabinoids can induce improvements in body weight, appetite, physical functioning and QoL in cachectic patients with other chronic diseases including HIV infection and multiple sclerosis.26-28 However, this is not well studied in cancer patients. Most reports suggesting the benefits of cannabinoids for appetite in CAC are anecdotal or lack methodological homogeneity,29 and few RCTs and one meta-analysis are available.16 The latter suggested cannabinoids were associated with improvements to appetite but not to QoL and more adverse events compared with placebo. However, the authors included few studies, which were small and likely underpowered, provided a poor description of their methodology, and carried out no supplementary searching suggesting that studies might have been missed.

Non-randomized studies of interventions (NRSIs) on the effect of cannabinoids on outcomes of CAC are available. To our knowledge, NRSIs have not yet been considered in a systematic review and are often excluded due to their methodological variability and the potential for biases. However, the relatively small number of RCTs is likely to give an incomplete picture and result in missing outcomes.30, 31 Findings from NRSIs could provide additional evidence on these outcomes and encourage the feasibility of larger, higher quality RCTs.32

Given the difficulty for clinical practitioners to manage cachexia and its severe health implications for patients, it is important to evaluate all the existing evidence relevant to developing efficient therapies. This review aimed to consider NRSIs alongside RCTs for a comprehensive approach to the available evidence on cannabinoid interventions in CAC, in order to inform clinical decisions and future investigations.

Methods

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)33 and Cochrane Handbook for Systematic Reviews of Interventions34 guidelines. A protocol was developed prior to initiating the review, but not published. A research question was formulated using the PICO approach. The inclusion and exclusion criteria, outcomes, and search were planned to capture as many studies as possible. Prior to the start of the investigation, it was also agreed by the investigators that meta-analyses would be performed where possible and narrative syntheses generated for all other outcomes.

Eligibility criteria Participants

Although the existing criteria for recognition of CAC enables more efficient diagnosis,2, 3 it is under-recognized in clinical practice. To reflect diagnostic oversights, adult (>18 years) cancer patients, whose baseline characteristics were judged to describe cachexia, were eligible, including individuals of any gender, ethnicity, disease stage in any care setting, and undergoing chemotherapy or radiotherapy. Individuals with an eating disorder, undergoing treatment for appetite and weight loss, or with a history or current habit of marijuana use were excluded.

Intervention

Cannabinoid-based interventions included any smoked or ingested medical marijuana, plant-based cannabinoids (THC and CBD) and synthetic cannabinoids (dronabinol, nabilone, or any other pharmaceutical form).

Comparison

No restrictions on the comparisons were applied to allow inclusion of qualitative evidence. Treatment comparisons were any active or inactive control. Active control included nutritional interventions administered orally (food fortification, snacks, and nutrient/caloric supplementation), while pharmacological interventions and co-interventions involved the use of active drugs (appetite stimulants, anticytokines, and metabolic mediators), and other forms of cannabis. Inactive control included placebo, standard care or no treatment.

Outcome measures

Primary outcomes included changes in weight and appetite and secondary outcomes included performance status (PS), quality of life (QoL), adverse events (AEs), treatment-related side effects, and mortality. Outcomes could be patient-reported or clinician-reported, using continuous or discreet methods, including validated scales, questionnaires, and interviews. The rationale for selecting the above outcomes was guided by previous work16, 27 and these were selected to reflect how patients perceive the symptoms of cachexia.

Studies

No restrictions on study design were applied to permit a comprehensive evaluation of the outcomes in a population of advanced cancer patients, in which ethical concerns complicate methodological implementation, such as randomization or blinding. All RCTs and NRSIs were included (refer to Quality of studies and risk of bias).

Search strategy Electronic searches

To account for the lack of a standard definition of cachexia, the search strategy was designed to incorporate any terms associated with CAC, including wasting syndrome and weight loss, and cannabis-based interventions. The electronic databases Ovid MEDLINE, Ovid Embase, and PubMed were searched from inception to May 2020, combining keyword terms with medical subject headings (MeSH), or equivalent, where possible. The full search strategies are shown in Figure S1. No restrictions on language or publication date and status (i.e. published, unpublished, conference abstracts, awaiting assessment, and in progress) were applied to account for the expected scarcity of evidence in this field.

Supplementary searching

Databases of registered and ongoing studies and reviews were searched, including PROSPERO, the ISRCTN registry, and ClinicalTrials.gov. Additional studies were identified by reference checking and citation tracking from studies identified as eligible for inclusion. Clarification was sought from corresponding authors where necessary.

Data collection and analysis Selection of studies

All references were imported into and duplicates were removed using EndNote. One investigator independently conducted the first screening to identify eligible titles and abstracts. Studies were excluded where interventions did not involve cannabis, target CAC, or report on any given outcome of interest. Any study that did not meet the inclusion criteria was excluded, while in a second screening the full texts of potentially eligible studies for inclusion were reviewed and selected, including articles in English, French, and Spanish. Any uncertainties were discussed and resolved with at least one more co-investigator. The full text of some studies that met the eligibility criteria were unavailable online and these were not included as no response was received upon request for access and/or contacting the author. Because these may have been of value in the analysis, the description of these studies is available in Table S1.

Quality of evidence and risk of bias

Two different scales, both recommended Cochrane tools, were used to assess methodological quality and risk of bias regarding study participation and attrition, measurement of the prognostic factor and outcomes, confounding, statistical analysis and reporting. ‘Risk of bias’ (Rob2) was used to assess RCTs and ‘Risk of bias in non-randomized Studies-of Interventions’ (ROBINS-I) to assess NRSIs. Uncertainties were discussed and resolved and each aspect was rated. The results of both assessments were combined and summarized in a table where +, −, or ? indicated the level of risk as low, high, or unclear, respectively.

The overall quality of evidence for each outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The quality of evidence was downgraded for any significant study limitations (risk of bias), indirectness, important inconsistency or heterogeneity, imprecision, or potential publication bias, or upgraded for large magnitude or confounding effects, and dose–response gradient. Data from NRSIs started at low quality. The body of evidence for each outcome was judged as very low, low, moderate, or high and summarized narratively (Table S2). Reasons for down-grading or up-grading evidence are referred in the table's footnotes.

Data synthesis and statistical analysis

Data extraction was carried out using a data collection form designed on Microsoft Office Excel (Microsoft Corporation) for this review, and data input was reviewed by two investigators. The form included extracted data on study design, participants, intervention, publication details, and outcomes of interest from the eligible studies using a template designed for this review. Where numerical data were not addressed in the full text or supplementary material and was only reported in graphs, and when no response was received from corresponding authors, it was extracted using a ruler on a magnified version of the figure.

Studies were grouped according to their design (RCTs or NRSIs). Outcome data and trends were described in terms of the number of studies, relevant effects, and statistical significance (P < 0.05) reported on the outcome. Results were combined narratively or by meta-analysis where possible.

Studies only reported sufficient data to conduct meta-analyses for QoL and appetite, which were pooled using Review Manager (RevMan version 5.4; The Nordic Cochrane Center) using a continuous, inverse variance, random effects analysis. A random effects model was used because of variability in both study design and participants, and interventions. Mean change and standard deviations (SDs) were available for most studies. Otherwise baseline and end-of-study means, and P values, were used to calculate mean change and compute SDs. In one RCT comprising of two treatment arms, data from each arm was compared with half the number in the control group to avoid duplicate reporting.35 The standardized mean difference (SMD) was used to account for differences in tools or methods of data collection for similar outcomes.36, 37 The inconsistency (I2) statistic was used to assess heterogeneity, which was subsequently classified as I2 < 40%—low; 30 to 60%—moderate; 50 to 90%—substantial and >75%—considerable.38

Results

Eight hundred and seventy-five studies were identified from searches with 716 titles and abstracts screened for eligibility following deduplication. We obtained and scrutinized 64 full-text papers, of which 10 were included in this review (Figure 1). Studies were excluded if they: were unrelated or irrelevant, did not meet the inclusion criteria, were awaiting completion, or were a registered trial of an included study. Two records were trials registered on ClinicalTrials.gov. One39 was an ongoing study that begun in July 2020 and is awaiting completion in October 2021 (Table S3). One40 was the ClinicalTrials.gov record reported by an included study. Six studies (Table S1) were excluded because the full text could not be obtained online or retrieved physically.

Study selection process following the PRISMA guidelines.33 Characteristics of included studies

Ten studies were included in this review23, 35, 41-48 (Table 1). All participants were adult cancer patients, mean age ranging from 47.3 to 67 years. The presence of cachexia was confirmed as previously described, using guidance from existing criteria. Study duration varied from 18 days to 6 months, including both intervention and follow up. Two studies42, 48 were open-label continuation studies. Methods of outcome reporting varied and comprised a range of both validated scales and procedures as described in Tables S5–S8.

Table 1. Characteristics of included studies Summary of studies RCTs Study author, year Study design Duration and follow up Participant characteristics Sample size Intervention Route Comparator Outcome of interest Additional outcomes Brisbois et al., 201141 RCT, Canada 18 days; F/U: 30 days

12 male, 9 female; mean age (SD):

Intervention group: 67(10.9) years Comparator group: 65.5(8.0) years

Advanced cancer with decreased food intake

I: 24

C: 22

2.5 mg THC: once daily for 3 days; before bedtime for first 2 days and before supper on third day) twice daily on fourth day (1 before lunch, 1 before dinner) option to increase to 20 mg/day Oral 2.5 mg placebo: once daily for 3 days; before bedtime for first 2 days and before supper on third day) twice daily on fourth day (1 before lunch, 1 before dinner) option to increase to 20 mg/day Total calorie and macronutrient intake Nausea Food preference Chemosensory alterations Jatoi et al., 200242 RCT, United Kingdom open-label continuation; ‘patient continued on treatment for as long as they and their healthcare providers thought it beneficial or until toxic side effects prompted study withdrawal’

Intervention group: 65% male, 35% female; mean age (SD): 65(11) years

Comparator group: 66% male, 34% female; mean age (SD): 67(10)

Advanced cancer with self-reported weight loss >5 lbs (2.3 kg) in last 2 months, loss of appetite, <20 kcal/kg intake per day, and 0–2 PS score

I: 152

C: 159

2.5 mg dronabinol capsules twice daily plus liquid placebo Oral 800 mg megestrol acetate liquid suspension daily plus capsule placebos Strasser et al., 200635 RCT, Germany 6 weeks; F/U at week 2, week 4 and week 6

54% men, 46% women; mean age: 61 years

Advanced cancer with involuntary weight loss >5% in last 6 months, anorexia, and <2 PS score

I: 100 (THC); 95 (cannabis extract, CE)

C: 48

THC: 2.5 mg THC capsulesCE: 2.5 mg: 1 mg THC:CBD capsules

Three times 2-weeks supply taken twice daily (1 hour before lunch and dinner, or at bedtime), preferably with milk

Oral

Placebo capsules containing a standardization medium

Three times 2-weeks supply taken twice daily (1 hour before lunch and dinner, or at

Body weight Appetite change QoL change Adverse events Other symptoms Functional domains of QoL Turcott et al., 201843 RCT, Mexico 8 weeks; F/U at week 2, 4 and 8

Intervention group: 3 male (21.4%), 11 female (78.6%); mean age (SD): 61.1(10.6) years; 6 moderately malnourished, 8 severely malnourished

Comparator group: 4 male (21.1%), 15 female (78.9%); mean age (SD): 52.6(11.8) years mean age; 6 moderately malnourished, 13 severely malnourished

Confirmed NSCLC with anorexia and <2 PS score

47 (33 included in analysis)

0.5 mg nabilone (CESAMET) for 2 weeks

Increased to 1 mg for next 6 weeks

Oral

0.5 mg placebo for 2 weeks

Increased to 1 mg for next 6 weeks

Weight change Appetite change HRQL Biochemical parameters Nutritional consumption Non-RCTs Bar-Sela et al., 201944 Pilot study 6 months

62.5% male, 38.5% female; median age: 66; median weight: 65.5 kg

Advanced cancer with weight loss of >5% in last 2 months, loss of appetite and <3 PS score

11

10 mg THC:CBD (9.5:0.5)

or

5 mg THC:CBD (4.75:0.25) cannabis capsules

Once daily for 2 weeks, then twice daily (first in the morning, then after 8 hours)

Oral None Tolerance to cannabis dosage Kasvis et al., 201945 Retrospective observational study 120 days; F/U at 30–75 days and 75–120 days (clinic visits)

Cancer patients referred to the Cannabis Pilot Project from McGill University Health Centre

Mean age (SD): 61 (11) years; 49% male, 51% female; 43% anorexia

37 medical cannabis treatment based on individual assessment by multidisciplinary team Not specified None Weight improvement Appetite improvement Kasvis et al., 201946 Retrospective chart review 3 months Mean age (SD): 47.3(16.1) years; 34 male (63%), 20 female (37%); 23 cancer (42.6%), 31 non-cancer (57.4%); 54 (51 included in analysis)

cannabinoid therapy (number of participants):

THC/CBD (1:1):

6 total participants with SC: 2 participants no SC: 4 participants

THC-rich:

17 total participants with SC: 8 participants no SC:9 participants

CBD-rich:

combined therapies:

THC/CBD and THC-rich:

17 total participants with SC: 7 participants no SC: 10 participants

THC/CBD and CBD-rich:

with SC:3 participants

THC- and CBD-rich:

17 total participants with SC: 8 participants no SC: 9 participants

THC/CBD, THC-rich, CBD-rich:

1 total participant with SC: 0 participants no SC: 1 participant 20.4% oral, 25.9% inhaled, 53.7% combined oral and inhaled None Nelson et al., 199447 Phase II trial 28 days: F/U at week 2 and 4

13 male, 6 female; mean age: 65.12 years, median (range) age 64(52–81) years; median (range) PS: 2(0–3); median (range) mini-mental status exam score: 29 (13–30);

Advanced cancer patients

10

THC 2.5 mg p.o. t.i.d. one hour after meals

2.5 mg b.i.d. for 3 days if >65 years

Oral None Unclear Plasse et al., 199123 Non-RCT 3 and 6 weeks

33 male, 9 female; Karfnofsky performance status (median, range): 80 (60–100); previous THC exposure: 4

Cancer patients

42

I: dronabinol treatment, 4 groups;

group 1: 2.5 mg q.d. group 2: 2.5 mg b.i.d. group 3: 5 mg q.d. group 4: 5 mg b.i.d.

study 1: group 3 received dose before breakfast;

study 2: group 3 received dose before dinner;

Oral None Weight change Appetite (visual analog scales and scores) Walsh et al., 200548 Case series Open continuation; F/U biweekly or at every outpatient clinic visit until considered stable, then per routine clinical practice Patients treated chronically with escalating dronabinol doses for cancer-related anorexia 6 dronabinol was titrated from 7.5 to 15 mg daily in 5 patients, 1 patient remained on initial dose; Oral None Weight change Self-reported appetite Self-reported food intake Efficacy Side effects Abbreviations: b.i.d., twice daily; C, comparison; CBD, cannabidiol; CE, cannabis extract;; F/U, follow up; HRQL, health-related quality of life; I, intervention; NSCLC, non-small cell lung cancer; p.o., oral; PS, performance status; q.d., daily; QoL, quality of life; RCT, randomized controlled trial; SC, synthetic cannabinoid; SD, standard deviation; THC, tetrahydrocannabinol; t.i.d., three times daily.

Four studies were RCTs (n = 647) assessing the effect of cannabinoids on at least one outcome (appetite, weight, or QoL) in advanced cancer patients and two41, 43 were pilot studies. Three multi-centre trials35, 41, 42 used dronabinol and one study43 used nabilone. Three RCTs35, 41, 43 used a placebo as the control. The remaining study, a large RCT,42 used megestrol acetate plus placebo as the standard treatment arm, dronabinol capsules plus liquid placebo as the intervention arm, and a combination of both dronabinol and megestrol acetate in a third intervention arm. Only the standard treatment and first intervention arm were included in this analysis, because they both included placebo and were most comparable. One study35 included a third intervention arm with cannabis extract (CE) to compare with THC, which were individually compared with the comparison arm (placebo). Two RCTs35, 42 prescribed 2.5 mg THC doses twice daily for the entire treatment and two41, 43 prescribed increasing doses (from 0.5 mg to 20 mg per day maximum).

The remaining six studies were NRSI (n = 157) assessing the effects of cannabis or cannabinoid treatment on appetite and weight in cancer patients. Participants' physical status and disease stage, and study design, varied. Where specified, treatment was administered orally. Two were retrospective studies45, 46 one of which one45 was only reported as a conference abstract. The other46 was a retrospective chart review where one of the following cannabinoid therapies were either taken orally or inhaled: 1:1 THC/CBD, THC-rich, CBD-rich, 1:1 THC/CBD + THC-rich, 1:1 THC/CBD + CBD-rich, THC- + CBD-rich, or all three. Two were single-arm intervention studies23, 44 one of which included two consecutive studies (lasting 3 and 6 weeks, respectively). In this study, patients were assigned to one of four treatment groups: 2.5 mg once or twice daily or 5 mg once or twice daily. Patients on 5 mg once daily received their dose before breakfast in the first 3 weeks, then before dinner until the end of the 6 weeks. One was a Phase-II trial47 and one was a case series48 both of which specifically aimed to treat cancer-related anorexia.

Risk of bias and quality assessment

Risk of bias was assessed for all outcomes of interest for which both objective and subjective measures were used in data collection methods (Figure 2). Risk of bias was determined as unclear by the author wherever information was lacking or vague. All four RCTs were at low risk of selection and reporting bias due to appropriate randomization, allocation, and analyses methods. One35 was at high risk of performance bias due to major protocol violations by 84 participants, and one was unclear43 because allocation was carried out by the protocol coordinator. Low or unclear risk of bias in the remaining three domains was determined primarily due to uncertainties concerning how missing data, and withdrawals were handled.

Risk of bias summary: review authors' judgements of risk of bias for each included study key: + low risk; − high risk; ? unclear risk of bias (Review Manager 5.4).

The remaining studies were at unclear risk of performance or reporting bias due to uncertainties. They also all had unclear risk of confounding for not controlling for pre-conceptions associated with cannabis intake (i.e., cravings, relaxation and sleepiness related to the THC-induced high, a bad trip or other associated side effects), recall bias, and no controls.

Risk of classification of intervention was judged to be low23, 44, 47, 48 or unclear