Olanzapine With or Without Fosaprepitant for Preventing Chemotherapy Induced Nausea and Vomiting in Patients Receiving Highly Emetogenic Chemotherapy: A Phase III Randomized, Double-Blind, Placebo-Controlled Trial (ALLIANCE A221602).

PURPOSE: A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an olanzapine-based antiemetogenic regimen was used. MATERIALS AND METHODS: A221602, a prospective double-blind, placebo-controlled clinical trial, was developed to compare 2 -olanzapine-containing antiemetic regimens, one with an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Trial patients had a malignant disease for which they received intravenous highly emetogenic chemotherapy (single day cisplatin ≥ 70 mg/m2 or doxorubicin plus cyclophosphamide on 1 day). Patients on both arms received commonly administered doses of a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Additionally, patients were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV) or a corresponding placebo. The primary objective was to compare the proportion of patients with no nausea for 5 days following chemotherapy between the 2 study arms. This trial was designed to test for the noninferiority of deleting the NK-1 receptor antagonist, with noninferiority defined as a decrease in freedom from nausea by less than 10%. RESULTS: A total of 690 patients were entered on this trial, 50% on each arm. The proportion of patients without nausea for the complete 5-day study period was 7.4% lower (upper limit of the one-sided 95% confidence interval was 13.5%) in the arm without an NK-1 receptor antagonist compared with the arm with an NK-1 receptor antagonist. CONCLUSION: This trial did not provide sufficient evidence to support that deletion of the NK-1 receptor antagonist was as good as keeping it, as a part of a 4-drug antiemetic regimen for highly emetogenic chemotherapy (ClinicalTrials.gov Identifier: NCT03578081).

2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting.

PURPOSE: This review is an update of the MASCC/ESMO 2015 recommendations for the prophylaxis of acute and delayed nausea and vomiting induced by multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting. METHODS: A systematic literature search was conducted using PubMed from June 1, 2015, through February 1, 2023. RESULTS: We identified 56 references (16 were duplications or invalid), leaving 40 manuscripts for this search. The panel classified level I evidence (three manuscripts) and level II evidence (14 manuscripts). High-dose chemotherapy and stem cell transplant were discussed in four of these manuscripts, and multiple-day chemotherapy treatment in 15. Some manuscripts covered both topics. Additionally, a search for breakthrough nausea and vomiting resulted in 12 "hits." No new relevant studies were identified. CONCLUSIONS: The recommendations for patients receiving high-dose chemotherapy with stem cell transplants and patients undergoing multiple-day cisplatin were updated. For patients receiving high-dose chemotherapy for stem cell transplant, a combination of a 5-HT3 receptor antagonist with dexamethasone and aprepitant is recommended. Olanzapine could be considered part of the antiemetic regimen. Patients receiving multiple-day cisplatin should receive a 5-HT3 receptor antagonist plus dexamethasone plus aprepitant plus olanzapine. For patients experiencing breakthrough nausea and vomiting, the available evidence suggests using a single dose of olanzapine daily for 3 days.

Work loss and activity impairment due to extended nausea and vomiting in patients with breast cancer receiving CINV prophylaxis.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV)'s impact on work loss remains poorly described. We evaluated associations between the duration of CINV episodes, CINV-related work loss (CINV-WL), and CINV-related activity impairment (CINV-AI) in patients with breast cancer receiving highly emetogenic chemotherapy. METHODS: We analyzed data from a prospective CINV prophylaxis trial of netupitant/palonestron and dexamethasone for patients receiving an anthracycline and cyclophosphamide (AC) for breast cancer (NCT0340371). Over the observed CINV duration (0-5 days), we analyzed patient-reported CINV-WL and CINV-AI for the first two chemotherapy cycles. We categorized patients as having either extended (≥ 3 days) or short (1-2 days) CINV duration and quantified its impact on work using the Work Productivity and Activity Impairment Questionnaire (WPAI). RESULTS: Overall, we captured data for 792 cycles in 402 women, including 136 (33.8%) employed patients with 35.3% reporting CINV. Of those with CINV, patients reported CINV-WL in 26 cycles and CINV-AI in 142 cycles. Of those with CINV, 55.3% of extended CINV cycles experienced CINV-WL compared to 16.7% of short CINV cycles (p < 0.001). The relative risk of CINV-WL between extended and short CINV was 3.32 (p < 0.01) for employed patients. The mean difference in CINV-AI scores (higher = worse) between extended and short duration CINV was 5.0 vs. 3.0 (p < 0.001). CONCLUSION: Extended (≥ 3 days) CINV was associated with more than triple the risk of CINV-WL and higher CINV-AI compared with short CINV.

Avoidable Acute Care Use Associated with Nausea and Vomiting Among Patients Receiving Highly Emetogenic Chemotherapy or Oxaliplatin.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) contributes to avoidable acute care, a metric now tracked in Medicare's oncology outcome measure. CINV is preventable, yet guidelines are often not followed. We sought to quantify acute care involving CINV and other avoidable toxicities after highly emetogenic chemotherapy (HEC) to identify excess risk and assess clinician adherence to antiemesis guidelines for HEC. MATERIALS AND METHODS: We retrospectively evaluated U.S. electronic health records (2012-2018) using Medicare's OP-35 outcome measure to identify avoidable acute care involving any of 10 toxicities, including CINV, after HEC regimens relative to non-HEC. Antiemetic guideline adherence was defined as use ofneurokinin-1 (NKl) receptor antagonists Q5 (RAs) plus 5-hydroxytryptamine type 3 RA+ dexamethasone at HEC initiation. RESULTS: Among 17,609 patients receiving HEC, acute care rates associated with HEC chemotherapy included 32% cisplatin, 31% carboplatin, and 21% anthracycline/cyclosphospharnide (AC), with 76% meeting the criteria as avoidable events. Oxaliplatin rates were 29%. Avoidable acute care occurred 1.83 times (95% confidence interval, 1.76-1.91, p < .0001) as often after HEC versus non-HEC excluding oxaliplatin; CINV-related acute care occurred 2.29 times as often. Nonadherence to antiemesis guidelines occurred in 34% and 24% of cisplatin and AC courses, respectively, because of omission of a NKl RA. CONCLUSIONS: Patients treated with HEC regimens experienced high avoidable acute care use, 1.8 times the risk seen for other chemotherapy. Nonadherence to guideline-directed antiemetic prophylaxis highlights the need to ensure adherence to antiemetic guidelines, including the use of NKl RA in HEC. IMPLICATIONS FOR PRACTICE: After survival, perhaps the most important goal in oncology is limiting avoidable acute care, a goal now used by Medicare to impact cancer reimbursement. This study found that patients treated with highly emetogenic chemotherapy (HEC) regimens had high rates of avoidable acute care use, 1.8 times the risk seen for other chemotherapy. A substantial proportion of the avoidable acute care involved chemotherapy-induced nausea and vomiting. Results showed that incomplete adherence to national antiemetic guidelines for HEC regimens primarily driven by omission of upfront neurokinin-1 receptor antagonist use, suggesting that improved adherence can meaningfully resolve this gap in quality and cost of care.

Single-dose netupitant/palonosetron versus 3-day aprepitant for preventing chemotherapy-induced nausea and vomiting: a pooled analysis.

Aim: In the absence of comparative studies, guidelines consider neurokinin 1 receptor antagonists (RAs) as interchangeable. We evaluated the pooled efficacy from three cisplatin registration trials, each with arms containing netupitant/palonosetron (NEPA), a fixed neurokinin 1 RA (netupitant)/serotonin Type 3 (5-HT3) RA (palonosetron) combination, and an aprepitant (APR) regimen. Materials & methods: Efficacy data were pooled for rates of complete response (CR: no emesis/no rescue medication), complete protection (CR + no significant nausea), total control (CR + no nausea) and no significant nausea during acute (0-24 h), delayed (>24-120 h) and overall (0-120 h) phases post chemotherapy. Results: Among 621 NEPA and 576 APR patients, response rates were similar for the acute phase, and generally favored NEPA during delayed and overall phases. CR rates for NEPA versus APR were 88.4 versus 89.2%, 81.8 versus 76.9% (p < 0.05) and 78.4 versus 75.0% during the acute, delayed and overall phases, respectively. Conclusion: Oral NEPA administered on day 1 was more effective than a 3-day APR regimen in preventing delayed nausea and vomiting associated with cisplatin.

Lay abstract Oral netupitant/palonosetron (NEPA) is an innovative product that combines two drugs (netupitant and palonosetron) in a single capsule to prevent nausea and vomiting associated with certain types of chemotherapy. In this paper we pooled together the results of three studies comparing the efficacy of NEPA to two drugs from the same classes administered separately (aprepitant regimen) in patients with various solid tumors receiving cisplatin, a type of chemotherapy with a high likelihood of causing nausea and vomiting. In summary, NEPA was more effective than the aprepitant regimen in preventing nausea and vomiting in the later days (days 3­5) following chemotherapy.

Cost-effectiveness analysis of olanzapine-containing antiemetic therapy for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in highly emetogenic chemotherapy (HEC) patients.

PURPOSE: Olanzapine-containing regimens have been reported to be effective in preventing CINV following highly emetogenic chemotherapy (HEC), but it is unsure whether it is cost-effective. There has been no cost-effectiveness analysis conducted for olanzapine using costs from the USA. The aim of this study is to determine whether olanzapine-containing antiemetic regimens are cost-effective in patients receiving HEC. METHODS: A decision tree model was constructed to evaluate the cost and health outcomes associated with olanzapine-containing antiemetic regimens and otherwise-identical regimens. One-way sensitivity analyses were conducted to individually investigate the effect of (i) lower complete response (CR) rates of olanzapine, closer to non-olanzapine-containing regimens; (ii) higher FLIE scores for patients who achieved no/incomplete response, closer to FLIE scores of patients achieving a complete response; (iii) differing costs of olanzapine to reflect different costs per hospitals, globally, due to different insurance systems and drug costs; and (iv) varying costs for uncontrolled CINV, to account for varying durations of chemotherapy and accompanying uncontrolled CINV. RESULTS: Olanzapine regimens have an expected cost of $325.24, compared with $551.23 for non-olanzapine regimens. Meanwhile, olanzapine regimens have an expected utility/index of 0.89, relative to 0.87 for non-olanzapine regimens. Olanzapine-containing regimens dominate non-olanzapine-containing regimens even if CR of olanzapine-containing regimens fall to 0.63. Only when CR is between 0.60 and 0.62 is olanzapine both more effective and more costly. CONCLUSION: Olanzapine-containing regimens are both cheaper and more effective in the prophylaxis of CINV in HEC patients, compared with non-olanzapine-containing regimens. Future CINV trial resources should be allocated to understand newer antiemetics and compare them to olanzapine-containing regimens as the control arm. Further analysis should use nationally representative data to examine medication costs by payer type.

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.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

What the HEC? Clinician Adherence to Evidence-Based Antiemetic Prophylaxis for Highly Emetogenic Chemotherapy.

BACKGROUND: Clinician adherence to antiemetic guidelines for preventing chemotherapy-induced nausea and vomiting (CINV) caused by highly emetogenic chemotherapy (HEC) remains poorly characterized. The primary aim of this study was to evaluate individual clinician adherence to HEC antiemetic guidelines. PATIENTS AND METHODS: A retrospective analysis of patients receiving HEC was conducted using the IBM Watson Explorys Electronic Health Record Database (2012-2018). HEC antiemetic guideline adherence was defined as prescription of triple prophylaxis (neurokinin-1 receptor antagonist [NK1 RA], serotonin type-3 receptor antagonist, dexamethasone) at initiation of cisplatin or anthracycline + cyclophosphamide (AC). Clinicians who prescribed ≥5 HEC courses were included and individual guideline adherence was assessed, noting the number of prescribing clinicians with >90% adherence. RESULTS: A total of 217 clinicians were identified who prescribed 2,543 cisplatin and 1,490 AC courses. Patients (N=4,033) were primarily women (63.3%) and chemotherapy-naïve (92%) with a mean age of 58.6 years. Breast (36%) and thoracic (19%) cancers were the most common tumor types. Guideline adherence rates of >90% were achieved by 35% and 58% of clinicians using cisplatin or AC, respectively. Omission of an NK1 RA was the most common practice of nonadherence. Variation in prophylaxis guideline adherence was considerable for cisplatin (mean, 71%; SD, 29%; coefficient of variation [CV], 0.40) and AC (mean, 84%; SD, 26%; CV, 0.31). CONCLUSIONS: Findings showed substantial gaps in clinician adherence to HEC CINV guidelines, including a high variability across clinicians. Clinicians should review their individual clinical practices and ensure adherence to evidence-based CINV guidelines to optimize patient care.

Nausea and Vomiting in Advanced Cancer.

OPINION STATEMENT: Nausea and vomiting is a common clinical issue in the advanced cancer patient. The etiology may be related to treatment (chemotherapy, radiation, surgery) or non-treatment clinical issues related to the advanced cancer. A very detailed initial assessment of nausea/vomiting is indicated including frequency, duration, intensity, associated activities, and the presence of anorexia or cachexia and is necessary in order to determine a specific etiology which may allow a potentially specific successful intervention. Various international antiemetic guidelines have been developed for the successful prevention of chemotherapy- and radiotherapy-induced nausea and emesis but the treatment of post-chemotherapy nausea/vomiting and of radiation-induced nausea/vomiting has been less successful. Chronic nausea/vomiting in the advanced cancer patient unrelated to treatment remains a significant clinical problem with few successful treatments and interventions. NCCN and ASCO palliative care guidelines provide various treatment suggestions but these are based on empiric evidence with very few clinical trials available to provide demonstrated effective treatments. Recent randomized clinical trials have demonstrated that olanzapine may be an effective agent for the prevention and treatment of chemotherapy-induced nausea and emesis as well as treatment of chronic nausea and vomiting unrelated to treatment.

Unscheduled hydrations: redefining complete response in chemotherapy-induced nausea and vomiting studies.

Breakthrough chemotherapy-induced nausea and vomiting (CINV) is nausea and/or vomiting occurring within 5 days of chemotherapy administration despite using guideline-directed prophylactic antiemetic agents. It is highly prevalent (30-40%), usually requiring immediate treatment or "rescue" medication. If breakthrough CINV occurs, antiemetic guidelines recommend using an antiemetic agent from a different class not used in prophylaxis, along with intravenous hydration and/or dexamethasone. Data supporting these guideline recommendations are limited. Importantly, costs associated with breakthrough CINV can be substantial (i.e., unscheduled hydrations). Two retrospective analyses evaluating guideline-adherent CINV prophylaxis suggest that the initial antiemetic selection may decrease breakthrough CINV. Here we review optimal CINV prophylactic strategies and introduce unscheduled hydration as a potential important surrogate for breakthrough CINV aligning with cost-effective cancer care.

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting.

BACKGROUND: We examined the efficacy of olanzapine for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy. METHODS: In a randomized, double-blind, phase 3 trial, we compared olanzapine with placebo, in combination with dexamethasone, aprepitant or fosaprepitant, and a 5-hydroxytryptamine type 3-receptor antagonist, in patients with no previous chemotherapy who were receiving cisplatin (≥70 mg per square meter of body-surface area) or cyclophosphamide-doxorubicin. The doses of the three concomitant drugs administered before and after chemotherapy were similar in the two groups. The two groups received either 10 mg of olanzapine orally or matching placebo daily on days 1 through 4. Nausea prevention was the primary end point; a complete response (no emesis and no use of rescue medication) was a secondary end point. RESULTS: In the analysis, we included 380 patients who could be evaluated (192 assigned to olanzapine, and 188 to placebo). The proportion of patients with no chemotherapy-induced nausea was significantly greater with olanzapine than with placebo in the first 24 hours after chemotherapy (74% vs. 45%, P=0.002), the period from 25 to 120 hours after chemotherapy (42% vs. 25%, P=0.002), and the overall 120-hour period (37% vs. 22%, P=0.002). The complete-response rate was also significantly increased with olanzapine during the three periods: 86% versus 65% (P<0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001), respectively. Although there were no grade 5 toxic effects, some patients receiving olanzapine had increased sedation (severe in 5%) on day 2. CONCLUSIONS: Olanzapine, as compared with placebo, significantly improved nausea prevention, as well as the complete-response rate, among previously untreated patients who were receiving highly emetogenic chemotherapy. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02116530.).

HTX-019: polysorbate 80- and synthetic surfactant-free neurokinin 1 receptor antagonist for chemotherapy-induced nausea and vomiting prophylaxis.

Chemotherapy-induced nausea and vomiting (CINV) may occur during the acute (0-24 h) or delayed (25-120 h) phase following chemotherapy administration. The addition of a neurokinin 1 receptor antagonist to antiemetic regimens containing a 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone has resulted in improved CINV prophylaxis. Due to numerous adverse events and hypersensitivity reactions associated with fosaprepitant, a commonly used neurokinin 1 receptor antagonist, there remains an unmet need for better-tolerated formulations. HTX-019, the US FDA-approved polysorbate 80- and synthetic surfactant-free aprepitant injectable emulsion, is bioequivalent to and better tolerated (fewer treatment-emergent adverse events) than fosaprepitant. HTX-019 represents a valuable alternative to fosaprepitant for CINV prophylaxis.

Managing Nausea and Vomiting in Patients With Cancer: What Works.

The approach to the treatment of nausea and vomiting in a cancer patient should begin with a complete assessment, including the frequency, duration, and intensity of the nausea/vomiting; associated activities; and whether anorexia or cachexia is present. It is important to determine whether the nausea and vomiting is related to treatment (chemotherapy, radiation) or is independent of cancer treatment. Nausea/vomiting unrelated to chemotherapy and/or radiation may have an etiology for which there is a specific and potentially successful intervention. Various national and international antiemetic guidelines have been developed for the prevention of chemotherapy- and radiotherapy-induced nausea and emesis. The antiemetics recommended in these guidelines (5-hydroxytryptamine type 3 receptor antagonists, neurokinin-1 receptor antagonists, dexamethasone) have significantly reduced emesis but not nausea. Recent randomized clinical trials have demonstrated that olanzapine may be an effective agent for the prevention and treatment of chemotherapy-induced nausea as well as emesis.

Should palonosetron be a preferred 5-HT3 receptor antagonist for chemotherapy-induced nausea and vomiting? An updated systematic review and meta-analysis.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) continues to be a common side effect of systemic anticancer therapy, decreasing quality of life and increasing resource utilization. The aim of this meta-analysis was to investigate the comparative efficacy and safety of palonosetron relative to other 5-HT3RAs. METHODS: A literature search was carried out in Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Full-text references were then screened and included in this meta-analysis if they were an RCT and had adequate data regarding one of the five primary endpoints-complete response (CR), complete control (CC), no emesis, no nausea, or no rescue medications. RESULTS: A total of 24 RCTs were included in this review. Palonosetron was statistically superior to other 5-HT3RAs for 10 of the 19 assessed endpoints. Only one endpoint-emesis in the overall phase-had noticeable more favorable data for palonosetron to the point that it approached the 10% risk difference (RD) threshold as specified by the MASCC/ESMO antiemetic panel; another two endpoints (CR in the overall phase and nausea in the delayed phase) approached the 10% threshold. CONCLUSIONS: Palonosetron seems to be more efficacious and safe than other 5-HT3RAs-statistically superior in 10 of 19 endpoints. It is, however, only clinically significant in one endpoint and approached clinically significant difference in another two endpoints. Within the limits of this meta-analysis, our results indicate that palonosetron may not be as superior in efficacy and safety as reported in a previous meta-analysis, and supports the recent MASCC/ESMO, ASCO, and NCCN guidelines in not generally indicating palonosetron as the 5-HT3RA of choice.

2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting.

PURPOSE: This review summarizes the recommendations for the prophylaxis of acute and delayed nausea and vomiting induced by multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting as agreed at the MASCC/ESMO Antiemetic Guidelines update meeting in Copenhagen in June 2015. METHODS: A systematic literature search using PubMed from January 01, 2009 through January 06, 2015 with a restriction to papers in English was conducted. RESULTS: There were three phase III randomized trials in patients undergoing high-dose chemotherapy and stem cell transplant and eight single arm non-randomized clinical studies (single in patients undergoing transplantation and one in patients receiving multiple-day chemotherapy treatment). We used a total of two randomized clinical trials in this guideline update. For patients receiving treatment for breakthrough chemotherapy-induced nausea and vomiting, a phase III randomized trial investigating the use of olanzapine versus metoclopramide in patients receiving highly emetogenic chemotherapy and a second single arm study looking at the effectiveness of olanzapine were identified. CONCLUSIONS: It was concluded that for patients receiving high-dose chemotherapy with stem cell transplant, a combination of a 5-HT3 receptor antagonist with dexamethasone and aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4) is recommended before chemotherapy. For patients undergoing multiple-day chemotherapy-induced nausea and vomiting, a 5-HT3 receptor antagonist, dexamethasone, and aprepitant, are recommended before chemotherapy for the prophylaxis of acute emesis and delayed emesis. For patients experiencing breakthrough nausea and vomiting, the available evidence suggests the use of 10 mg oral olanzapine, daily for 3 days. Mild to moderate sedation in this patient population (especially elderly patients) is a potential problem with this agent.

2016 Updated MASCC/ESMO Consensus Recommendations: Prevention of Nausea and Vomiting Following High Emetic Risk Chemotherapy.

PURPOSE: This review summarizes the recommendations for the prophylaxis of nausea and vomiting in adults receiving highly emetogenic chemotherapy (HEC) which includes cisplatin, mechlorethamine, streptozocin, cyclophosphamide >1500 mg/m2, carmustine, dacarbazine, and the combination of an anthracycline and cyclophosphamide (AC) administered to women with breast cancer, as agreed at the MASCC/ESMO Antiemetic Guidelines Update meeting in Copenhagen in June 2015. METHODS: A systematic review of the literature using PubMed and the Cochrane Database from 2009 to June 2015 was performed. RESULTS: The NK1-receptor antagonists netupitant (300 mg given in combination with palonosetron 0.5 mg as NEPA) and rolapitant have both completed phase II and III programs and were approved by FDA (both) and EMA (NEPA) in 2014-2015. Addition of one of these agents (or of (fos)aprepitant) to a combination of a serotonin (5-HT)3-receptor antagonist and dexamethasone improved the number of patients with a complete response (no emesis and no rescue medication) days 1-5 after AC HEC with 8-9 % and after non-AC HEC by 8-20 %. Olanzapine has improved control of delayed nausea as compared to aprepitant in a randomized open designed study. In the prophylaxis of delayed nausea and vomiting, metoclopramide is an option instead of aprepitant in patients receiving cisplatin-based chemotherapy and dexamethasone is an option instead of aprepitant in patients receiving AC chemotherapy. CONCLUSIONS: Two new NK1-receptor antagonists (netupitant and rolapitant) have been included in the updated recommendations as additional options to aprepitant or fosaprepitant. Addition of one of these NK1-receptor antagonists to a combination of a 5-HT3-receptor antagonist and dexamethasone is recommended in both non-AC HEC and AC HEC. Olanzapine is included as an option in HEC in particular if nausea is the main symptom.

5-HT3 receptors as important mediators of nausea and vomiting due to chemotherapy.

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, dexamethasone, and a neurokinin-1 (NK-1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. The first generation 5-HT3 receptor antagonists have been very effective in the control of chemotherapy induced emesis in the first 24 h postchemotherapy (acute emesis), but have not been as effective against delayed emesis (24-120 h postchemotherapy). Palonosetron, a second generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity, and a different mechanism of action than the first generation 5-HT3 receptor antagonists appears to be the most effective agent in its class. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a FDA approved antipsychotic that blocks multiple neurotransmitters: dopamine at D1, D2, D3, D4 brain receptors, serotonin at 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors, has emerged in recent trials as an effective preventative agent for chemotherapy-induced emesis and nausea, as well as a very effective agent for the treatment of breakthrough emesis and nausea. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Efficacy of olanzapine for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting (CINV): a systematic review and meta-analysis.

PURPOSE: Olanzapine is a potent antipsychotic medication that inhibits a wide variety of receptors. It has been used in trials for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting (CINV). This study systematically investigates the efficacy of olanzapine in relation to other antiemetics in the prophylaxis and rescue of CINV. METHODS: A literature search of Ovid MEDLINE, EMBASE, and CENTRAL was conducted to identify randomized controlled trials (RCTs) comparing olanzapine to other standard antiemetics for either prevention or rescue. The primary endpoints were the percentage of patients achieving no emesis or no nausea, in the acute, delayed, and overall phases. RESULTS: Ten RCTs in the preventative setting and three RCTs in the breakthrough setting were identified. Subgroup analysis demonstrated a similar degree of benefit from a 5- and 10-mg dose of olanzapine for the no emesis endpoint in the overall phase. In the prophylaxis setting, olanzapine was statistically superior in five of six endpoints and clinically superior in four of six endpoints. In the breakthrough setting, olanzapine was statistically and clinically superior in the only endpoint analyzed: no emesis. CONCLUSION: Olanzapine is more efficacious than other standard antiemetics for the rescue of CINV and its inclusion improves control in the prevention setting. Given the possible reduction in side effects, the use of a 5-mg dose of olanzapine should be considered. Future RCTs should compare the 5-mg versus the 10-mg dosages further and report on the efficacy and percentage of patients developing side effects. Further analyses should be done without the influence of corticosteroids.

Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial.

BACKGROUND: Chemotherapy-induced nausea and vomiting is a common side-effect of many antineoplastic regimens and can occur for several days after treatment. We aimed to assess the neurokinin-1 receptor antagonist rolapitant, in combination with a serotonin (5-HT3) receptor antagonist and dexamethasone, for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide. METHODS: We conducted a global, randomised, double-blind, active-controlled, phase 3 study at 170 cancer centres in 23 countries. We included patients with cancer aged 18 years or older, who had not received moderately or highly emetogenic chemotherapy before, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly allocate patients to receive either oral rolapitant (one 180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) 1-2 h before administration of moderately emetogenic chemotherapy. Patients were stratified by sex. All patients also received granisetron (2 mg orally) and dexamethasone (20 mg orally) on day 1 (except for patients receiving taxanes as part of moderately emetogenic chemotherapy, who received dexamethasone according to the package insert) and granisetron (2 mg orally) on days 2-3. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients received the same study drug they were assigned in cycle 1, unless they chose to leave the study or were removed at the treating clinician's discretion. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a study site compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (defined as no emesis or use of rescue medication) in the delayed phase (>24-120 h after initiation of chemotherapy) in cycle 1. This study is registered with ClinicalTrials.gov, number NCT01500226. The study has been completed. FINDINGS: Between March 5, 2012, and Sept 6, 2013, 1369 patients were randomised to receive either rolapitant (n=684) or active control (n=685). 666 patients in each group received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients receiving rolapitant had complete responses in the delayed phase than did those receiving active control (475 [71%] vs 410 [62%]; odds ratio 1·6, 95% CI 1·2-2·0; p=0·0002). The incidence of adverse events was similar in the rolapitant and control groups, with the most frequently reported treatment-related treatment-emergent adverse events being fatigue, constipation, and headache. For cycle 1, the most common grade 3-4 adverse event in the rolapitant versus active control groups was neutropenia (32 [5%] vs 23 [3%] patients). No serious adverse event was treatment-related, and no treatment-related treatment-emergent adverse event resulted in death. INTERPRETATION: Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the 5-day (0-120 h) at-risk period after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide. FUNDING: TESARO, Inc.