A randomized, placebo-controlled, two-stage phase II/III trial has found that an oral cannabis extract containing tetrahydrocannabinol (THC) and cannabidiol (CBD) is effective as an adjunct treatment for chemotherapy-induced nausea and vomiting (CINV) that is refractory to standard antiemetic prophylaxis. The study, conducted across 17 sites in Australia, was funded by the Department of Health, New South Wales Government, with study treatments supplied by Tilray. The results were published in the Journal of Clinical Oncology on August 16, 2024.
The trial aimed to determine the efficacy of oral THC:CBD capsules in adults experiencing refractory nausea and/or vomiting during moderately or highly emetogenic intravenous chemotherapy, despite receiving guideline-consistent antiemetic prophylaxis. The study recruited 147 evaluable participants out of a planned 250 between 2016 and 2022. Participants were randomized to receive either oral THC:CBD capsules or matching placebo, taken three times daily from the day before chemotherapy to 5 days after, in addition to standard antiemetics.
Inclusion criteria required participants to be 18 years or older with a solid tumor or hematologic malignancy of any stage, undergoing intravenous chemotherapy of moderate or high emetogenic risk, and scheduled for at least two more consecutive cycles of the same chemotherapy. Importantly, patients must have experienced refractory CINV in an earlier treatment cycle despite guideline-consistent antiemetic prophylaxis. Exclusion criteria included Eastern Cooperative Oncology Group performance status >2, contraindications to medicinal cannabis, disease-related nausea or vomiting, oral chemotherapy, or radiotherapy to the brain or GI tract during the study period.
The study population had a median age of 56 years (range 25-80), with 78% being female. About 39% reported previous cannabis use, and 65% were being treated with curative intent. The chemotherapy regimens were classified as highly emetogenic in 53% of cases and moderately emetogenic in 47%. All participants had received at least one cycle of the same chemotherapy before enrollment, with 46% having received two or more cycles.
The primary outcome measure was the difference in the proportions of participants with no vomiting or retching and no use of rescue medications (a complete response) during the first 120 hours after the first cycle of chemotherapy on study. The results showed a significant improvement in the complete response rate for those receiving THC:CBD compared to placebo (24% vs 8%, absolute difference 16%, 95% CI 4-28, P=0.01). Similar beneficial effects were observed for absence of significant nausea, use of rescue medications, daily vomits, and the nausea scale on the Functional Living Index-Emesis quality-of-life questionnaire.
However, the THC:CBD group experienced more frequent bothersome adverse events, including sedation (18% vs 7%), dizziness (10% vs 0%), and transient anxiety (4% vs 1%). No serious adverse events were attributed to THC:CBD. The most frequently titrated dose was 5 mg of THC with 5 mg of CBD three times daily.
The study had several limitations. Recruitment was stopped early due to slow accrual, which reduced the power to detect differences between groups. Only 10% of participants were treated with olanzapine, which has recently been added to clinical practice guidelines for antiemetic prophylaxis in highly emetogenic chemotherapy. The trial did not provide information on longer-term efficacy over multiple chemotherapy cycles.
The authors concluded that oral THC:CBD is an effective adjunct for chemotherapy-induced nausea and vomiting despite standard antiemetic prophylaxis, albeit with additional adverse events. They noted that drug availability, cultural attitudes, legal status, and preferences may affect implementation.
The potential clinical impact of this study is significant. It provides evidence for a new option in managing refractory CINV, which remains a challenging side effect of cancer treatment. The absolute improvement of 16% in complete response rates exceeds the 10% threshold considered sufficient to warrant changing recommendations in antiemetic guidelines. However, the implementation of THC:CBD in clinical practice may face barriers, including adverse effects, cultural attitudes, and legal restrictions on cannabis use. The driving restrictions associated with THC use pose a particular challenge, especially in areas with limited public transport.
Future research directions suggested by this study include evaluating alternative cannabinoid formulations, sequencing, and combinations with other antiemetics; comparing cannabinoids to olanzapine; and investigating the use of cannabinoids as primary prevention of CINV. The authors also noted the potential for research on THC:CBD use in managing nausea, vomiting, and anorexia associated with oral anticancer treatments, as well as its role in pain management.
In conclusion, this study provides important evidence for the efficacy of oral THC:CBD in managing refractory CINV. While it offers a new treatment option, clinicians will need to carefully consider the potential benefits against the risks and practical challenges of implementation when making treatment decisions for individual patients.
References
Grimison P, Mersiades A, Kirby A, et al. Oral Cannabis Extract for Secondary Prevention of Chemotherapy-Induced Nausea and Vomiting: Final Results of a Randomized, Placebo-Controlled, Phase II/III Trial. J Clin Oncol. 2024;42(34):4040-4050. doi:10.1200/JCO.23.01836
