TY - JOUR
T1 - Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE)
T2 - a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
AU - Hashimoto, Hironobu
AU - Abe, Masakazu
AU - Tokuyama, Osamu
AU - Mizutani, Hideaki
AU - Uchitomi, Yosuke
AU - Yamaguchi, Takuhiro
AU - Hoshina, Yukari
AU - Sakata, Yasuhiko
AU - Takahashi, Takako Yanai
AU - Nakashima, Kazuhisa
AU - Nakao, Masahiko
AU - Takei, Daisuke
AU - Zenda, Sadamoto
AU - Mizukami, Koki
AU - Iwasa, Satoru
AU - Sakurai, Michiru
AU - Yamamoto, Noboru
AU - Ohe, Yuichiro
N1 - Funding Information:
This was an investigator-initiated study, supported by the Japan Supportive, Palliative and Psychosocial Oncology Group, and funded by the Japan Agency for Medical Research and Development. We thank the patients and the study teams for their participation in this study. We are also grateful to the members of the National Cancer Center Hospital Data Management Section for their support in data management (Kaoru Koike, Mikio Mori), and oversight of the study management (Haruhiko Fukuda). The study was supported in part by the Japan Supportive, Palliative and Psychosocial Oncology Group and funded by the Japan Agency for Medical Research and Development, grant number JP18ck0106214.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/2
Y1 - 2020/2
N2 - Background: Olanzapine 10 mg added to standard antiemetic therapy including aprepitant, palonosetron, and dexamethasone has been recommended for the prevention of chemotherapy-induced nausea and vomiting. Guidelines suggest that a dose reduction to 5 mg should be considered to prevent sedation. In several phase 2 studies, olanzapine 5 mg has shown equivalent activity to olanzapine 10 mg and a favourable safety profile in relation to somnolence. We evaluated the efficacy of olanzapine 5 mg combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting caused by cisplatin-based chemotherapy. Methods: This was a randomised, double-blind, placebo-controlled, phase 3 study to evaluate the efficacy of olanzapine 5 mg with triplet-combination antiemetic therapy done in 26 hospitals in Japan. Key inclusion criteria were patients with a malignant tumour (excluding those with a haemopoietic malignancy) who were scheduled to be treated with cisplatin (≥50 mg/m2) for the first time, age between 20 and 75 years, and with Eastern Cooperative Oncology Group performance status of 0–2. Eligible patients were randomly assigned (1:1) to receive either oral olanzapine 5 mg or placebo once daily on days 1–4 combined with aprepitant, palonosetron, and dexamethasone (dosage based on the standard antiemetic therapy against highly emetogenic chemotherapy). Patients were randomly assigned to interventions by use of a web entry system and the minimisation method with a random component, with sex, dose of cisplatin, and age as factors of allocation adjustment. Patients, medical staff, investigators, and individuals handling data were all masked to treatment assignment. The primary endpoint was the proportion of patients who achieved a complete response, defined as absence of vomiting and no use of rescue medications in the delayed phase (24–120 h). All randomly assigned patients who satisfied eligibility criteria received a dose of cisplatin 50 mg/m2 or more, and at least one study treatment, were included in efficacy analysis. All patients who received any treatment in this study were assessed for safety. This study is registered at UMIN Clinical Trials Registry, number UMIN000024676. Findings: Between Feb 9, 2017, and July 13, 2018, 710 patients were enrolled; 356 were randomly assigned to receive olanzapine and 354 were assigned to receive placebo. All eligible patients were observed 120 h after cisplatin initiation. One patient in the olanzapine group and three in the placebo group did not receive treatment and were excluded from all analyses. One patient in the olanzapine group discontinued treatment on day 1 and was excluded from the efficacy analysis. In the delayed phase, the proportion of patients who achieved a complete response was 280 (79% [95% CI 75–83] of 354 patients in the olanzapine group and 231 (66% [61–71] of 351 patients in the placebo group (p<0·0001). One patient had grade 3 constipation and one patient had grade 3 somnolence related to treatment in the olanzapine group. Interpretation: Olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy for patients undergoing cisplatin-based chemotherapy. Funding: Japan Agency for Medical Research and Development.
AB - Background: Olanzapine 10 mg added to standard antiemetic therapy including aprepitant, palonosetron, and dexamethasone has been recommended for the prevention of chemotherapy-induced nausea and vomiting. Guidelines suggest that a dose reduction to 5 mg should be considered to prevent sedation. In several phase 2 studies, olanzapine 5 mg has shown equivalent activity to olanzapine 10 mg and a favourable safety profile in relation to somnolence. We evaluated the efficacy of olanzapine 5 mg combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting caused by cisplatin-based chemotherapy. Methods: This was a randomised, double-blind, placebo-controlled, phase 3 study to evaluate the efficacy of olanzapine 5 mg with triplet-combination antiemetic therapy done in 26 hospitals in Japan. Key inclusion criteria were patients with a malignant tumour (excluding those with a haemopoietic malignancy) who were scheduled to be treated with cisplatin (≥50 mg/m2) for the first time, age between 20 and 75 years, and with Eastern Cooperative Oncology Group performance status of 0–2. Eligible patients were randomly assigned (1:1) to receive either oral olanzapine 5 mg or placebo once daily on days 1–4 combined with aprepitant, palonosetron, and dexamethasone (dosage based on the standard antiemetic therapy against highly emetogenic chemotherapy). Patients were randomly assigned to interventions by use of a web entry system and the minimisation method with a random component, with sex, dose of cisplatin, and age as factors of allocation adjustment. Patients, medical staff, investigators, and individuals handling data were all masked to treatment assignment. The primary endpoint was the proportion of patients who achieved a complete response, defined as absence of vomiting and no use of rescue medications in the delayed phase (24–120 h). All randomly assigned patients who satisfied eligibility criteria received a dose of cisplatin 50 mg/m2 or more, and at least one study treatment, were included in efficacy analysis. All patients who received any treatment in this study were assessed for safety. This study is registered at UMIN Clinical Trials Registry, number UMIN000024676. Findings: Between Feb 9, 2017, and July 13, 2018, 710 patients were enrolled; 356 were randomly assigned to receive olanzapine and 354 were assigned to receive placebo. All eligible patients were observed 120 h after cisplatin initiation. One patient in the olanzapine group and three in the placebo group did not receive treatment and were excluded from all analyses. One patient in the olanzapine group discontinued treatment on day 1 and was excluded from the efficacy analysis. In the delayed phase, the proportion of patients who achieved a complete response was 280 (79% [95% CI 75–83] of 354 patients in the olanzapine group and 231 (66% [61–71] of 351 patients in the placebo group (p<0·0001). One patient had grade 3 constipation and one patient had grade 3 somnolence related to treatment in the olanzapine group. Interpretation: Olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy for patients undergoing cisplatin-based chemotherapy. Funding: Japan Agency for Medical Research and Development.
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U2 - 10.1016/S1470-2045(19)30678-3
DO - 10.1016/S1470-2045(19)30678-3
M3 - Article
C2 - 31838011
AN - SCOPUS:85078469165
VL - 21
SP - 242
EP - 249
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 2
ER -