Time to reconsider olanzapine dose for CINV prevention?

Olanzapine 5 mg, used in combination with standard triplet antiemetic therapy, is effective in controlling chemotherapy-induced nausea and vomiting (CINV) and associated with a low rate of grade 3 somnolence, according to results of a phase III trial conducted in Japan.

The J-FORCE trial evaluated olanzapine 5 mg vs placebo, both given in combination with aprepitant, palonosetron and dexamethasone, in cancer patients receiving cisplatin. With olanzapine 5 mg demonstrating superior complete response (CR) rate and a <1 percent rate of grade 3 somnolence, an editorialist who also reviewed evidence from other studies suggested that it is time to reconsider the dose of olanzapine used in CINV prevention. [Lancet Oncol 2019, doi: 10.1016/S1470-2045(19)30678-3; Lancet Oncol 2019, doi: 10.1016/S1470-2045(19)30791-0]

Current guidelines of the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) recommend olanzapine 10 mg in combination with a standard triplet antiemetic regimen in patients receiving highly emetogenic chemotherapy (HEC) agents, including cisplatin, while suggesting that olanzapine 5 mg should be considered in patients aged >75 years and those with excessive sedation while on the 10 mg dose. [J Clin Oncol 2017;35:3240-3261; NCCN Clinical Practice Guidelines in Oncology Version 1, Antiemesis, 2018]

However, guidelines of the European Society for Medical Oncology (ESMO) and Multinational Association of Supportive Care in Cancer warn against excessive sedation following treatment with olanzapine 10 mg. [Ann Oncol 2010;21(Suppl 5):v232-v243]

In the J-FORCE trial, 710 cancer patients aged 20–75 years (median age, 65–66 years; 67 percent male) scheduled to receive first-line cisplatin (≥50 mg/m²) treatment were recruited from 26 hospitals in Japan. The patients were randomized (1:1) to receive olanzapine 5 mg or placebo, administered after dinner on days 1–4, in combination the aforementioned triplet regimen.

The primary endpoint of CR (absence of vomiting and no use of rescue antiemetic medications) in the delayed phase (24–120 hours after cisplatin initiation) was achieved by 79 percent of patients in the olanzapine 5 mg group vs 66 percent of those in the placebo group (p<0.0001).

CR rates were also significantly higher with olanzapine 5 mg vs placebo in the acute phase (0–24 hours after cisplatin initiation) (95 percent vs 89 percent; p=0.0021) and the overall phase (0–120 hours after cisplatin initiation) (78 percent vs 64 percent; p<0.0001).

Grade 3 treatment-related somnolence and constipation were each reported in one patient (<1 percent) in the olanzapine 5 mg group and in no patients in the placebo group. Grade 1/2 somnolence was reported in 43 percent vs 33 percent of the patients.

In a previous phase II study by the same group of researchers, olanzapine 5 mg demonstrated a higher delayed-phase CR rate (85.7 percent vs 77.6 percent; p<0.001) and a lower incidence of somnolence (45.5 percent vs 53.3 percent) vs its 10 mg dose in 153 patients receiving HEC with cisplatin. Both doses of olanzapine were used with aprepitant, palonosetron and dexamethasone. [Int J Clin Oncol 2018;23:382-388]

The J-FORCE investigators thus concluded that olanzapine 5 mg in combination with aprepitant, palonosetron and dexamethasone could be a new standard antiemetic regimen for patients receiving cisplatin-based chemotherapy.

“The question of [olanzapine] dose … is sufficiently answered by this trial, alongside other small studies and phase II trials,” wrote Alex Molassiotis from the School of Nursing, Hong Kong Polytechnic University, in an editorial. “Perhaps a 10 mg dose can be reserved for patients who continue to experience CINV despite the use of olanzapine 5 mg.” [Lancet Oncol 2019, doi: 10.1016/S1470-2045(19)30791-0]