Medicinal cannabis for chemotherapy-induced nausea and vomiting: prescribing with limited evidence

Although medicinal cannabis can now be prescribed for CINV, high quality clinical trial evidence is required to determine its efficacy and safety

Access to medicinal cannabis in Australia is a rapidly evolving and controversial field that is relevant to clinicians across a range of medical disciplines. There is widespread community interest in allowing access to medicinal cannabis for a variety of unapproved indications, despite a lack of high level evidence of efficacy.1 Legal and regulatory constraints make this access challenging; however, state and federal governments have now passed legislation enabling prescription by medical practitioners of medicinal cannabis in defined circumstances.2 In recognition of the lack of high level evidence supporting the use of medicinal cannabis for indications including but not limited to cancer pain, refractory paediatric epilepsy and palliative care, combined with the lack of formalised teaching in medical training programs, the Australian Government Therapeutics Goods Administration, in conjunction with state and territory governments, has commissioned a systematic review into the efficacy of medicinal cannabis, and has developed guidance documents for indications in which the evidence base is strongest to assist clinicians in appropriate prescribing of cannabis-based products.3 Despite these initiatives, willingness by medical practitioners to prescribe remains a significant barrier, with only 34 registered prescribers as of 31 July 2018.4

One indication for which medicinal cannabis can now be prescribed is the prevention and management of chemotherapy-induced nausea and vomiting (CINV).

Historically, trials using tetrahydrocannabidiol (THC)-rich products demonstrate limited anti-emetic effect and significant adverse events, and study designs were compromised by small sample sizes and outdated anti-emetic control arms.5,6 A preliminary trial in a small number of patients using nabiximols, a cannabidiol (CBD)-rich cannabis extract containing THC and CBD in a 1:1 ratio administered as a buccal spray, in combination with contemporary guideline-consistent prophylactic anti-emetic regimens for CINV, showed a promising efficacy signal and tolerable psychological adverse event profile; although of some concern, one of the seven patients who received nabiximols in this study withdrew due to transient psychotic symptoms.7 These preliminary results justify further study and community interest in the use of this class of drug for this indication, and highlight the need for more safety data. However, no adequately powered trials have been conducted using more tolerable cannabis preparations and rigorous study design, nor has the potential economic impact of incorporating such regimens into the Australian health care system been established.

The most recent evidence-based guidelines for the prevention and management of CINV by leading global and Australian bodies provide very limited support for use of medicinal cannabis. The National Comprehensive Cancer Network (NCCN) guideline suggests a limited role for dronabinol or nabilone for breakthrough anti-emesis (category 2A: based on lower level evidence, there is uniform NCCN consensus that the intervention is appropriate), but makes no recommendation for the use of cannabinoids for the prevention of CINV.8 Recent guidelines by the Multinational Association of Supportive Care in Cancer and the European Society of Medical Oncology9 and Cancer Institute NSW (eviQ)10 offer no recommendations regarding medicinal cannabis. The most recent American Society of Clinical Oncology guidelines conclude that the evidence regarding treatment with medicinal cannabis, including the United States Food and Drug Administration-approved cannabinoids dronabinol and nabilone remains insufficient for a positive recommendation.11 The Therapeutics Goods Administration guidance documents conclude that use of medicinal cannabis for CINV is experimental, and should only be considered for the management of intractable symptoms where standard therapies are ineffective.3

Importantly, the antipsychotic olanzapine has been recommended by the most recent American Society of Clinical Oncology guidelines for CINV prophylaxis in patients receiving highly emetogenic chemotherapy, in addition to the existing three-drug combination of a neurokinin-1 receptor antagonist, a serotonin (5-HT₃) receptor antagonist and dexamethasone.11 The recommendation for olanzapine arises from a recently published phase 3, placebo-controlled randomised trial in which patients receiving anthracycline or cisplatin-containing chemotherapy regimens were randomised to olanzapine 10 mg orally daily from Day 1 to 4 or placebo, in addition to standard anti-emetic therapy. Patients receiving olanzapine experienced significantly less chemotherapy-induced nausea over the acute (0–24 hours), delayed (24–120 hours) and overall (0–120 hours) phases of their chemotherapy cycle, and lower rates of emesis and use of rescue anti-emetic medications.12 Some patients receiving olanzapine suffered increased sedation, which has limited the use of olanzapine in clinical practice for prevention of CINV and raised questions about the optimal dose of olanzapine for this indication.

We argue that evidence from high quality trials similar in design to the olanzapine trial, demonstrating the efficacy and safety of medicinal cannabis for the prevention and management of CINV, is needed before most clinicians are willing to prescribe this class of medications widely in Australian clinical practice. The CannabisCINV trial (ACTRN12616001036404) is an ongoing New South Wales-based randomised trial that has been specifically designed to definitively assess the efficacy, safety and cost-effectiveness of the addition of an oral CBD-rich THC–CBD extract to guideline-consistent anti-emetics for secondary prevention and management of CINV. The pilot crossover randomised phase 2 trial (n = 80) is currently recruiting, with a planned definitive parallel phase 3 randomised trial (n = 250) to proceed if the pilot study meets its preliminary efficacy endpoint.

Recent legislation has allowed the prescription of medicinal cannabis by medical practitioners in Australia for the prevention and management of CINV, and a range of other indications. In contrast, current international and national clinical practice guidelines for prevention and management of CINV — representing the highest level of synthesised evidence available — conclude that there is currently insufficient quality evidence to recommend medicinal cannabis for routine use in this indication. These developments illustrate the challenges of managing community demand for access to such products, and highlight the importance of conducting appropriately designed clinical trials. The results of such clinical trials will provide guidance to clinicians regarding appropriate use in specific indications, product selection, dosage and titration, and appropriate monitoring of both efficacy and safety.