Has medicinal cannabis found a role in oncology/palliative care?

Following sustained public pressure and despite a paucity of evidence to support medical benefit, medicinal cannabis (MC) was legalised in Australia in 2016 for use in resistant childhood epilepsy, chemotherapy-induced nausea and vomiting (CINV), spasticity associated with multiple sclerosis, chronic non-cancer pain and ‘palliative care’.¹ Over subsequent years, there has been an exponential rise in the number of prescriptions approved² and an associated ‘indication creep’. Most common Special Access Scheme applications to the Therapeutic Goods Administration are for pain, anxiety, sleep disorders and cancer symptoms.³ Popular brands include those with tetrahydrocannabinol (THC), the most common psychoactive cannabinoid. This is despite the fact that THC is associated with significant side effects, and it is illegal to drive while taking THC in most states.

Cannabis remains popular amongst cancer patients. A recent review reports that one-quarter of adults receiving cancer treatment at a cancer clinic in the United States had used cannabis in the past 30 days in an attempt to fight cancer or ameliorate the symptoms related to the disease or its treatment.⁴ The most common reasons given by over 1000 cancer patients and survivors in South Carolina were difficulty in sleeping, stress/anxiety/depression and pain.⁵ The ongoing interest is not surprising when uncontrolled trials continually report significant benefits, supported by strong media bias towards positive results.⁶ A fake news story claiming that cannabis cured cancer received 100-fold more media attention than the evidence-based story debunking the theory.⁷

Over recent years, much research has been undertaken to answer many of the unknowns around cannabis (e.g. what combination of cannabinoids is best, at what dose and by what schedule) and to explore where it might be most effective. Uncontrolled studies and case reports continue to report benefit for a range of conditions.⁸ Randomised controlled trials (RCTs) do not.⁹ So, what is the hard evidence to date in oncology/palliative care?

There is considerable in vitro work pointing to a potential anti-neoplastic activity of cannabinoids¹⁰ but sparse clinical evidence. Schloss et al. reported on safety and quality-of-life benefits of cannabis in an RCT of two different cannabidiol (CBD)/THC combination products.¹¹ A small phase 1b study of the tolerability and safety of nabiximol and dose-intense temozolamide in relapsed patients with glioblastoma confirmed the safety and tolerability of nabiximol (1:1 THC/CBD).¹² The study was not powered for efficacy, but a survival benefit suggests that further research is warranted. Less well known is that cannabis contains most of the major carcinogens of tobacco and that several cancers have been epidemiologically linked with THC or CBD exposure.¹³ American Society of Clinical Oncology guidelines give a strong recommendation against the use of cannabinoids in place of cancer-directed treatment and that any use of cannabis to augment cancer-directed treatment should be done in the context of a clinical trial.¹⁴

The cytochrome P450 system, specifically subfamilies 2C, 1A, 3A and 2D, plays a prominent role in cannabinoid metabolism. The CYP3A and CYP2C enzymes are involved in the metabolism of many prescribed medications, creating the opportunity for a range of cannabinoid/drug interactions. As a potent CYP3AA inhibitor, for example, CBD has the potential to increase the levels of ribociclib, resulting in an increased risk of adverse effects in women receiving this drug for the treatment of breast cancer.¹⁵ The issue of whether cannabis should be used in conjunction with immunotherapy remains controversial. Deleterious effects with respect to response, time to progression and overall survival have been reported, but in cohort studies only.^{16, 17}

Pain is one of the most common reasons given by people who take cannabinoids. Most systematic reviews of cannabis in chronic pain of mixed aetiologies point to a small benefit of questionable clinical significance.¹⁸ It has been more difficult to demonstrate this for cancer pain. A Cochrane Review concludes that THC-containing products are ‘ineffective in relieving moderate to severe opioid refractory cancer pain’.⁹ The Multinational Association of Supportive Care in Cancer (MASCC) guidance recommends against the use of cannabinoids as an adjuvant analgesic for cancer pain and suggests that the potential risk of harm and adverse events be carefully considered for all cancer patients.¹⁹ Despite many pre-clinical data supporting an opioid-sparing effect, this has been very difficult to demonstrate in clinical studies.²⁰

Synthetic THC products (dronabinol and nabilone) have been recognised for many years as being effective anti-nausea medications but had never been tested against modern antiemetics. A recent placebo-controlled study from Sydney²¹ that followed a promising phase II cross-over study²² confirmed the efficacy of low-dose THC/CBD in patients with refractory CINV but at the expense of greater toxicity (sedation, dizziness and anxiety). The RCT was terminated early because of difficulty in recruitment. Driving restrictions were a factor, and many patients were already using cannabis or had an aversion to it. The authors conclude that ‘drug availability, cultural attitudes, legal status and preferences may affect implementation’ in the future. MASCC guidance quotes insufficient evidence to recommend cannabinoids for the management of nausea from advanced cancer, cancer-associated anorexia-cachexia and taste disturbance.²³

Very few quality studies have addressed psychological symptoms (anxiety, stress and depression) as primary outcome measures in cancer patients.^{24, 25} With current evidence, cannabis cannot be recommended for the management of these symptoms and an increased likelihood of increased anxiety events has been associated with higher-dose THC.²⁶ Small benefits in sleep have been demonstrated in people with chronic pain, not specifically in cancer.¹⁸

MC has been recommended for use in palliative care,^{26, 27} but generally because of a ‘nothing to lose’ scenario rather than because it has shown to be of benefit. Our group has elected to study total symptom burden (a summated symptom score) as a holistic approach when exploring the potential benefits of cannabis. We have found both CBD alone²⁸ and a 1:1 CBD/THC combination oil²⁹ to be no better than palliative care in reducing symptoms related to advanced cancer, although a small improvement in pain was shown with the addition of THC.

Although CBD is generally very well tolerated, THC has been associated with many side effects, most commonly gastrointestinal (nausea/vomiting, diarrhoea), dizziness and somnolence.^{18, 26} Concern has been raised regarding worsening psychotic symptoms (particularly with THC) and a potential deleterious effect of CBD on liver function.¹⁴

So, how has the dust settled? MC has proven to be an effective antiemetic for resistant CINV (subject to patient choice and with the caveats of increased toxicity) and may help some patients' pain and sleep. It remains expensive and it is difficult to see how a government subsidy can be justified based on current knowledge. At this stage, clinicians need not feel pressured to prescribe, and current research findings and specialty society guidelines are available to assist when counselling patients who request it. Patients should be encouraged to enter trials of MC if available, and those prescribing should ensure follow-up for assessment of benefit and/or harms.