Author: By Shreeya Nanda, Senior medwireNews Reporter
medwireNews: A Japanese phase III trial suggests that chemotherapy-induced nausea and vomiting could be alleviated by the addition of olanzapine 5 mg to the standard three-drug antiemetic regimen in cancer patients receiving cisplatin-based chemotherapy.
The researchers explain that a combination of olanzapine 10 mg plus aprepitant, palonosetron, and dexamethasone is recommended by various guidelines based on positive trial data, but concerns have been expressed regarding the side effects associated with this dose, in particular sleepiness.
They therefore investigated the 5 mg dose of olanzapine in the double-blind J-FORCE trial that recruited 705 patients aged 20–75 years who were scheduled to receive first-line cisplatin-based chemotherapy for a solid tumour at one of 26 Japanese hospitals.
The primary endpoint of a complete response – defined as no vomiting and no use of rescue medications – during the delayed period (ie, 24–120 hours) after chemotherapy was achieved by 79% of the 354 participants who were randomly assigned to receive olanzapine 5 mg/day on days 1–4 alongside the standard doses of aprepitant, palonosetron and dexamethasone used for highly emetogenic chemotherapy.
This was significantly higher than the 66% rate observed for the 351 patients who were given placebo plus the three-drug regimen and gave a between-group difference of 13 percentage points favouring olanzapine, which exceeds the minimum difference of 10% considered as the cutoff for clinical relevance by most efficacy assessments, say the study authors.
They additionally report in The Lancet Oncology that olanzapine was associated with significantly higher rates of complete response than placebo in the acute phase (0–24 hours; 95 vs 89%) and overall period (0–120 hours; 78 vs 64%), and also with significantly greater rates of total control, defined as no patient-reported nausea during a complete response, in the delayed (60 vs 50%) and overall (59 vs 48%) periods.
A significantly higher proportion of olanzapine- versus placebo-treated patients graded the severity of their daytime sleepiness as “very much” on day 1, after which the rates were comparable between the treatment arms.
Masakazu Abe, from Shizuoka Cancer Center in Nagaizumi, Japan, and co-workers comment that the absence of additional sleepiness with olanzapine, contrary to what was observed in previous studies, may be due to not only the lower olanzapine dose, but also its administration after the evening meal, which means that “the concentration of olanzapine in the blood reaches its peak while patients are sleeping.”
In light of these data, the J-FORCE investigators conclude that “olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy in patients undergoing cisplatin-based chemotherapy.”
The author of an accompanying commentary describes the trial as “very well designed and executed”, but points out certain limitations, such as using placebo instead of olanzapine 10 mg as the comparator and the lack of “more patient-sensitive outcomes”, which can enable “a more comprehensive evaluation of clinical trial outcomes.”
Moreover, “all the participants were Japanese and recruited from a single health-care system”, which could limit the applicability of the results to a more diverse population, writes Alex Molassiotis, from The Hong Kong Polytechnic University.
However, he does not believe that these limitations “call the results into question”.
The commentator continues: “We have mounting evidence that olanzapine is a useful addition to antiemetic regimens. The question of dose, which is the pertinent issue, is sufficiently answered by this trial, alongside other smaller studies and phase 2 trials.”
Hashimoto H, Abe M, Tokuyama O, et al. Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol; Advance online publication 11 December 2019. doi: 10.1016/S1470-2045(19)30678-3
Molassiotis A. Time to re-think the olanzapine dose. Lancet Oncol; Advance online publication 11 December 2019. doi: 10.1016/S1470-2045(19)30791-0
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