The aim of this study is to rigorously review the efficacy and safety of olanzapine in defined hematology oncology settings including (1) the setting of highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) settings (2) at 5 mg and 10 mg doses, and (3) for response rates for use in the acute, delayed, and overall settings post-MEC and HEC. Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched through April 23, 2020. The primary efficacy endpoints were the rate of complete response, in the acute (0–24 h post-chemotherapy), delayed (24–120 h post-chemotherapy), and overall (0–120 h post-chemotherapy) phases. The secondary efficacy endpoints were the rates of no nausea and no emesis, for each phase. Safety endpoints were the rate of no serious adverse events (i.e., no grade 3 or 4 toxicities), as assessed by Common Terminology Criteria for Adverse Events (CTCAE) criteria. The Mantel-Haenszel, random-effects analysis model was used to compute risk ratios and accompanying 95% confidence intervals for each endpoint. For endpoints that statistically favored one arm, absolute risk differences were computed to assess whether there is a 10% or greater difference, used as the threshold for clinical significance by MASCC/ESMO. Fragility indices were also calculated for each statistically significant endpoint, to quantitatively assess the robustness of the summary estimate. A cumulative meta-analysis was conducted for each efficacy meta-analysis with more than 5 studies, also using the Mantel-Haenszel random-effects analysis model. Three studies reported on olanzapine for the rescue of breakthrough chemotherapy-induced nausea and vomiting (CINV); 22 studies reported on olanzapine in the prophylactic setting. For studies reporting on HEC patients, olanzapine-containing regimens were statistically and clinically superior in seven of nine efficacy endpoints in the prophylaxis setting. When olanzapine is administered at a 10-mg dose, it is statistically and clinically superior to control patients in eight of nine endpoints among adults. Olanzapine may be effective in the MEC setting and when administered at 5-mg doses, but the paucity of data leads to notable uncertainty. Further RCTs are needed in the setting of MEC patients and administration of olanzapine at a lower 5-mg dose, which may be given to reduce the sedative effect of olanzapine at 10 mg.

/pdf/olanzapine-for-the-prophylaxis-and-rescue-of-chemotherapy-1vxrdlbfxn.pdf

Olanzapine for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting: a systematic review, meta-analysis, cumulative meta-analysis and fragility assessment of the literature

\n Introduction: Olanzapine administered at a 10mg dosage for prophylaxis of chemotherapy-induced nausea and vomiting may be associated with fatigue, drowsiness and reduced general activity. Therefore, a 5mg dose may be preferred, to reduce the occurrence of adverse events. The aim of this study was to conduct a network meta-analysis, and report on the efficacy of olanzapine administered at 5mg, relative to when administered at 10 mg. Methods: We used previously-published data from the systematic review by Chow et al which identified 17 adult trials which used 10mg doses, 3 which used 5mg doses, and 1 which used a mix of 5 and 10mg doses. A multivariate network meta-analysis using a restricted maximum likelihood model was used. Results: The complete response rate in the acute phase is not statistically different, between 5mg and 10mg doses of olanzapine – RR 0.97, 95% CI: 0.83 – 1.13. Additionally, in the overall phase, 5mg olanzapine is similarly as efficacious as 10mg olanzapine – RR 0.95, 95% CI: 0.56 – 1.60. Evaluation of data demonstrated that there was inadequate information to compare the toxicities of the two doses. Conclusion: Our analyses support individual published trials, and the rationale for future trials to compare 5mg to 10mg olanzapine regimens in head-to-head comparisons.

/pdf/olanzapine-5-mg-vs-10-mg-for-the-prophylaxis-of-chemotherapy-hmredi39ga.pdf

Olanzapine 5 mg vs 10 mg for the prophylaxis of chemotherapy-induced nausea and vomiting: a network meta-analysis.

Ann Palliat Med 2020 | http://dx.doi.org/10.21037/apm-20-1018 The area postrema and nucleus tractus solitarius are an important source of afferent input to the central pattern generator (CPG) and also are a main site of neurokinin-1 (NK1), serotonin [5-hydroxytryptamine (5-HT)], muscarinic (M1), dopamine (D2), and histamine (H1) receptors. Olanzapine inhibits several neurotransmitter receptors, which most of those neurotransmitter receptors involve with vomiting reflex. Although, olanzapine mainly inhibits 5-HT2 receptor. However, the pathophysiology of chemotherapy-induced nausea and vomiting (CINV) demonstrated that there are not only 5-HT3 and NK-1 receptors in vagal afferent nerves directly involved with the CPG, but also central 5-HT2, dopamine, serotonin, histamine, GABA and cannabinoid receptors are partly stimuli an emetogenic reflex causing nausea/vomiting either acute or delay type (1). Multiple international guidelines have recommended olanzapine in combination with dexamethasone, 5-HT antagonists with or without NK1 receptors antagonists for prevention of CINV from high to moderate emetogenic chemotherapy regimen (2,3). The interesting question is whether the role of NK1 receptor antagonists in four-drug regimen regarding to its efficacy and cost effectiveness. A randomized phase III trial evaluated the effectiveness of olanzapine 10 mg versus aprepitant while all patients received palonosetron and dexamethasone. The complete response rate in all periods and the proportion of patients without nausea in the acute period was not different between both treatment arms (4). NCCN panel recommends an olanzapine-containing threedrug regimen with palanosetron and dexamethasone, since; there was no large clinical trial available for the other 5-HT3 antagonists (2). However, several phase II trials also supported the superiority efficacy in terms of nausea control by olanzapine 10 mg in combination with ondansetron plus dexamethasone when compared to the standard dose of aprepitant in combination (5,6). Our study also demonstrated the efficacy of olanzapine 10 mg in the three-drug regimen with ondansetron and dexamethasone in terms of the nausea control and the complete response rate in acute phase (7). Additionally, a systematic review of NK-1 receptor antagonist, 5-HT3 antagonist and dexamethasone revealed 72% complete response rate in the acute phase which was similar to 75% complete response rate in the acute phase from olanzapine, ondansetron and dexamethasone in our study (7,8). There are not only disparities in access to active cancer treatment but also to supportive care such as prevention of CINV are well established between lowand highincome countries. There were racial disparities in use of NK1 receptor antagonists for CINV prevention among breast cancer patients in the United States (9). The authors concluded that the affordability to the NK1 receptor antagonists may partly be explained these disparities. A multinational study in Southeast Asia including Thailand demonstrated the cost effectiveness of olanzapine in addition to dexamethasone and first generation 5-HT3 antagonist. In Singapore, switching aprepitant to olanzapine in three-drug regimen increased 0.0005 QALY with cost saving of USD 60.91 (10). Letter to the Editor

/pdf/olanzapine-is-it-enough-for-cinv-prevention-2rgorns550.pdf

Olanzapine: is it enough for CINV prevention?

Objective: This study aimed to determine the effectiveness and safety of 5 mg olanzapine (OLZ) in preventing vomiting and nausea caused by carboplatin chemotherapy. Methods: All patients with malignant tumors (n = 113) who underwent Carboplatin (AUC ≥ 5) treatment were randomly categorized into two groups: the standard group (n = 57) and the OLZ regimen (n = 56). The major endpoints of the trial were the TC (total control) between two groups during the OP (Overall phase, 0-120 hours), DP (delayed phase, 25-120 hours), and AP (acute phase, 0-24 hours). The secondary endpoints were the CR (complete response) and TP (total protection) during AP, OP, and DP. The time of first vomiting was compared between the two groups using Kaplan-Meier curves. The impact of CINV on the quality of life was assessed by the Functional Living Index-Emesis (FLIE). OLZ-related side effects were also recorded. Results: (1) The primary endpoint TC rates were more favorable in the OLZ regimen group than in the standard group during the AP 87.50% (49/56) vs. 63.15% (36/57) P = 0.003, OP 62.50% (35/56) vs. 31.57% (18/57) P = 0.001, and DP 64.28% (36/56) vs. 33.33% (19/57) P = 0.001. (2) The secondary endpoints TP were 82.14% (46/56) vs. 63.15% (36/57), P = 0.024, 83.92% (47/56) vs. 63.15% (36/57). P = 0.012 during the DP and OP. There was no statistical significance during AP between the two groups. The CR rates were not statistically different between the two groups during the three periods, P &gt; 0.05; (3) The first vomiting time in the OLZ group was delayed compared with the standard group (P = 0.248). The effect on life quality (score ≥ 108) assessed by FLIE was 62.50% vs. 43.48% between the two groups, P &lt; 0.05. The primary side effects of OLZ are fatigue (85%) and somnolence (75%). The primary side effects of the standard group are fatigue (77%) and loss of appetite (85%). Conclusion: The 5 mg OLZ-based triple antiemetic regimen is effective and safe in preventing vomiting and nausea induced by Carboplatin. 

Low dose olanzapine in the prevention and treatment of carboplatin induced nausea and vomiting: a prospective clinical randomized controlled trial.

Durch den Einsatz moderner Antiemetika wie 5-HT3-Rezeptorantagonisten und Neurokinin-1-Rezeptorantagonisten in Kombination mit Steroiden können Übelkeit und Erbrechen selbst bei Patienten unter hoch emetogener Tumortherapie in 70–90 % der Fälle effektiv verhindert werden. Optimale Ansprechraten lassen sich jedoch nur dann realisieren, wenn die antiemetische Prophylaxe entsprechend der Empfehlungen aktueller Leitlinien umgesetzt wird. Wichtigster Risikofaktor für das Entstehen der Zytostatika-induzierten Nausea und Emesis ist das emetogene Potenzial der applizierten Therapie. Man unterscheidet zwei bzw. vier Risikoklassen, in die orale bzw. intravenös verabreichte Substanzen im Hinblick auf den Anteil an Patienten, die ohne entsprechende Prophylaxe unter Erbrechen leiden würden, eingeteilt werden. Diese Klassifizierung in hoch/moderat oder gering/minimal bei oralen Substanzen bzw. in hoch, moderat, gering oder minimal emetogene intraventöse Substanzen ist die Grundlage für die Wahl der Prophylaxestrategie. Bei anhaltendem Erbrechen trotz optimaler Prophylaxe muss differenzialdiagnostisch nach einer anderen Ursache gesucht werden. Rescue-Medikamente stellen eine weitere Therapiestrategie dar. 

Leitlinien in der antiemetischen Prophylaxe und Therapie – Medikamentöse Tumortherapie

11504Background: Management of chemotherapy-induced nausea and vomiting (CINV) remains challenging. OLN might provide several benefits over APR which is current standard of care – particularly in t...

Olanzapine (OLN) versus aprepitant (APR) in patients receiving high-emetogenic chemotherapy: Final results of randomized phase II trial.

The aim of the study was to create a patient-derived xenograft (PDX) model of human colorectal cancer and to determine its histologic and molecular characteristics, such as the status of KRAS, NRAS, and BRAF genes and the presence of microsatellite instability.Materials and methods. First generation xenograft models in vivo were created using tumors from patients with colorectal cancer (n = 4) and immunodeficient Balb/c Nude mice (n = 20); second, third, and fourth generation models were created in the same mouse line (n = 3 for each generation). A caliper was used to measure subcutaneous xenografts; their size was calculated by the ellipsoid formula. Cryopreservation involved immersing the samples in a freezing medium (80% RPMI 1640, 10% fetal bovine serum, 10% dimethyl sulfoxide (DMSO)) and storing them at –80 °C. The histologic analysis was performed according to the standard technique (preparation of paraffin blocks and staining of microsections with hematoxylin and eosin). Mutations in the KRAS, NRAS, and BRAF genes were determined by direct Sanger sequencing; microsatellite instability was determined by the fragment analysis at five loci: Bat-25, Bat-26, NR21, NR24, and NR27.Results. Stable, transplantable xenografts of colorectal cancer were obtained from two out of four patients. The average waiting time from the implantation to the growth of the first generation xenograft was 28 days. The latency phase after cryopreservation was comparable to that at the creation of the first generation PDX model. The model reproduced the histotype, grade and mutational status of the KRAS, NRAS, and BRAF genes, as well as microsatellite instability of the donor tumor.Conclusion. The developed model of human colorectal cancer was characterized in terms of growth dynamics, cryopreservation tolerance, and histologic and molecular genetic parameters.

/pdf/development-and-characterization-of-patient-derived-35moxk5m.pdf

Development and characterization of patient-derived xenograft models of colorectal cancer for testing new pharmacological substances

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Olanzapine (OLN) versus aprepitant (APR) in patients receiving high-emetogenic chemotherapy: Final results of randomized phase II trial.

Development and characterization of patient-derived xenograft models of colorectal cancer for testing new pharmacological substances