乌鸦传媒

Adding cannabis extract to standard antiemetics tripled the rate of complete response for treatment-refractory chemotherapy-induced nausea and vomiting (CINV), a randomized trial showed.

The complete response rate increased from 8% with antiemetics plus placebo to 24% with the tetrahydrocannabinol/cannabidiol (THC-CBD) extract. Adjunctive use of THC-CBD offered similar improvement over placebo with respect to absence of significant nausea, use of rescue medication, daily vomiting, and improvement in emesis-related quality of life (QoL).

The improved control of CINV came at a cost of additional bothersome adverse events (AEs), including sedation, dizziness, and transient anxiety, reported Peter Grimison, PhD, MPH, MBBS, of Chris O'Brien Lifehouse in Sydney, and co-authors in the (JCO).

"The absolute improvement and relative improvement in complete response rates in our study exceeded the absolute improvement of 10% considered sufficient to warrant changing recommendations in , and -- within the limits of cross-trial comparisons with heterogeneous trial designs -- was at least comparable with modern studies of aprepitant and olanzapine, and older studies of cannabinoids" the authors stated.

"Our data support the claim that oral THC-CBD is an effective and safe option for the prevention of refractory CINV," they added. "Availability, access, affordability, cultural attitudes, societal barriers, and legal barriers may limit implementation."

For patients with treatment-refractory CINV, "oral THC-CBD is a safe option, although potential side effects should be kept in mind," noted JCO Associate Editor Camilla Zimmermann, MD, PhD, MPH, of the University of Toronto. "Implementation may be limited due to restricted access and availability."

Despite development of effective antiemetic regimens, CINV remains a major complication of anticancer therapy and is associated with worse QoL, increased use of healthcare resources, and reduced adherence to chemotherapy, Grimison and co-authors noted in their introduction. At least a third of patients treated with moderately or highly emetogenic chemotherapy have significant nausea or vomiting despite receiving guideline-recommended prophylaxis.

CINV is mediated by a network of pathways linked to receptors for serotonin, dopamine, substance P, and the . Improved understanding of the role of the cannabinoid receptor in CINV, as well as empiric observations of cannabis' effects, led to early clinical studies of THC and synthetic cannabinoids, the authors continued. The studies showed improvement in CINV but at a cost of troublesome dose-dependent side effects. Usage of cannabinoids to manage CINV has been limited by results of trials with suboptimal designs and the development of more effective antiemetic drugs and regimens.

Distinct from THC, CBD has anxiolytic properties that might counteract neuropsychiatric effects of THC, Grimison and colleagues noted. A small, of a buccal spray of THC-CBD showed improvement in complete response from 22% to 71%. The findings provided impetus for a larger randomized clinical trial.

Investigators in the multicenter trial recruited 147 patients with treatment-refractory CINV despite prophylaxis that included corticosteroid/5-hydroxytryptamine antagonist, neurokinin-1 antagonist, and olanzapine. Patients were randomized to continue background antiemetic therapy plus placebo or oral THC-CBD (2.5 mg of each), taken three times a day, beginning day -1 and continuing through day 5.

Patients crossed over to the opposite antiemetic prophylaxis during the second cycle of chemotherapy and then chose the regimen they preferred for the third cycle. The authors reported only the results from the initial randomized treatment during the first cycle.

The primary outcome was the proportion of patients who had complete response (no vomiting or retching and no use of rescue medications) during hours 0-120 after the first cycle of chemotherapy.

The results showed a statistically significant threefold increase in complete response rate with THC-CBD (P=0.01). The addition of oral THC-CBD extract also demonstrated superiority for key secondary outcomes, including:

• No use of rescue medication: 28% vs 9%, P=0.01
• No significant nausea (score <2): 20% vs 7%, P=0.03
• No vomiting or retching: 70% vs 58%, P=0.14
• Number of vomits per day: 0.2 vs 0.5, P=0.01
• Mean nausea score: 2.8 vs 4.3, P<0.001
• Maximum nausea measure score (mean): 3.8 vs 5.7, P<0.001
• QoL-nausea score (higher=better): 67 vs 48, P<0.001

Self-reported AEs of special interest occurred more often in the THC-CBD group during the first cycle of chemotherapy, including any severity (74% vs 38%) and moderate-severe (25% vs 8%). The most commonly reported moderate-severe AEs were sedation (18% vs 7%) and dizziness (10% vs 0%). Anxiety, disorientation, hallucination, and palpitation occurred infrequently in both groups. Clinician-rated AEs of grade 3 or 4 were reported with similar frequency among those assigned THC-CBD and placebo (19% vs 12%).

The authors acknowledged several limitations: early closure of enrollment because of slow accrual, the preplanned primary analysis initially included combined results from the crossover phase and the patient-selected treatment phase, only 10% of patients received guideline-backed olanzapine, and lack of long-term results.

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