Skip to main content
main-content

Chemotherapy-induced nausea and vomiting

Introduction

Anti-cancer chemotherapy is associated with a number of side effects over the long and short term. One of the major adverse effects of the treatment is chemotherapy-induced nausea and vomiting (CINV), which is associated with a significant deterioration in quality of life. Serious complications may arise from CINV, such as weakness, weight loss, dehydration, anorexia, and a decline in mental status, as well as a variety of other complications. Despite the development of more effective antiemetic agents, emesis and nausea continue to be a prominent complication of chemotherapy. Work to further understand the mechanism underlying CINV, identify patients at the greatest risk, and to find and develop effective antiemetic treatments is vitality important for patient care and continues to be an active area of investigation. This collection of recent high-quality full-text articles from Springer Nature and other prominent publishers provides some of the most exciting recent work in this area, focusing primarily on the role of pharmacological treatment of CINV.

Pathophysiology and classification

The physiology and pharmacology of nausea and vomiting induced by anticancer chemotherapy in humans

This chapter provides a review of the mechanisms of chemotherapy-induced nausea and vomiting.

Summary
  • Nausea and vomiting form part of the mechanism by which the body defends itself against toxins accidently ingested with food.
  • There are several difficulties associated with studying nausea, not least of which is the difficulty defining this self-reported sensation
  • There are essentially three working models to explain the genesis of nausea, describing the areas of the brain that are stimulated to evoke vomiting and generate the sensation of nausea.
  • In patients reporting nausea, changes occur in hormones (particularly vasopressin), the autonomic nervous system, the stomach and the brain.
  • Regarding the physiology of retching and vomiting, there are a specific pattern of mechanical events leading to expulsion. Initially there are pre-expulsion changes, largely reflecting changes in the autonomic nervous system, prior to the occurrence of a retrograde giant contraction in the small intestine, with changes in:
    • The skin – cold sweating and pallor
    • The cardiovascular system – reflecting a reduction in parasympathetic activity and increased sympathetic activity
    • The digestive tract.
  • The mechanisms by which nausea and vomiting are induced involve the following:
    • The tongue and pharynx – form part of the toxin-detecting system
    • The gastrointestinal tract and visceral afferents – abdominal vagal afferents (mechanoreceptors and mucosal afferents) and splanchnic afferents
    • The area postrema
    • The vestibular system and vestibulo-visual conflicts
    • Cortical inputs.
  • The body has several endogenous antiemetic mechanisms, mediated by pulmonary vagal afferents as well as brain mechanisms.
  • An understanding of the physiology of nausea provides a framework for investigating the prevention of chemotherapy-induced nausea, which involves an acute phase and a delayed phase, and may differ with multiple cycles of chemotherapy.
  • Control of nausea has improved, but is not as advanced as control of vomiting, with further studies needed to improve understanding of the physiology of nausea and the identification of clinically useful biomarkers.

Andrews PLR, Rudd JA. In: Management of Chemotherapy-Induced Nausea and Vomiting. Edited by Navari RM. Springer International Publishing Switzerland 2016. doi: 10.1007/978-3-319-27016-6

Chemotherapy-induced nausea and vomiting: Molecular mechanisms and clinical approaches

This chapter outlines the mechanisms of the various categories of chemotherapy-induced nausea and vomiting (CINV), examines currently available treatments, as well as providing an overview of current treatment recommendations.

Summary
  • CINV has a significant impact on quality of life and is considered by patients as a major adverse effect of treatment.
  • The mechanisms of emesis are not well defined but it may be primarily mediated through neurotransmitters (serotonin, dopamine, substance P) in the GI tract and the central nervous system.
  • The main approach to the control of emesis has been to identify the active neurotransmitters and their receptors in the central nervous system and the GI tract that mediate the afferent inputs to the vomiting center.
  • There are five categories used to classify CINV: acute, delayed, anticipatory, breakthrough and refractory.
  • The mechanisms for CINV during the first 24 hours after chemotherapy thought to differ from those of that occurring 1–5 days after chemotherapy.
  • For single-day chemotherapy, recommendations for treatment differ between the different types of CINV.
  • There have been significant advances in the prevention of CINV in patients receiving single-day chemotherapy, but prevention of CINV in multiple-day chemotherapy or high-dose chemotherapy with stem cell transplant remains a challenge.

Navari RM. In: International Manual of Oncology Practice. Edited by de Mello R, Tavares Á, Mountzios G.  Springer International Publishing Switzerland 2015. doi: 10.1007/978-3-319-21683-6_37

Serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonists

First-generation 5-HT3 receptor antagonists

This chapter provides an overview of the early development and clinical studies of the serotonin (5-hydroxytryptamine-3) receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting.

Summary
  • Different chemotherapeutic treatments have different intrinsic emetogenicity, the key determinant of the probability of clinical emesis, described as high, moderate, low and minimum.
  • The 5-HT3 receptor was identified as a potential mediator of the antiemetic effect, and various strategies were employed to develop selective 5-HT3 receptor antagonists, including:
    • Screening indole analogues, leading to the development of ondansetron
    • Structure-activity relationships around cocaine resulting in development of dolasetron
    • Using serotonin as a basis, leading to the development of tropisetron
    • Structure-activity relationships around tropisetron leading to granisetron.
  • The first generation 5-HT3 receptor antagonists (ondansetron, dolasetron, tropisetron, and granisetron) all have the following properties:
    • Contain an indole ring
    • Elimination half-life of ~4–8 hours
    • Oral formulations well absorbed with approximate 60% bioavailability
    • The lowest effective dose has been determined.
    • Antiemetic efficacy superior to placebo and older antiemetics (except high-dose metoclopramide)
    • No significant differences in antiemetic efficacy between the four drugs
    • Antiemetic efficacy superior when combined with corticosteroids.
    • Adverse effects largely confined to constipation and headache, although QTc prolongation has become a regulatory concern.
  • The second generation 5-HT3 receptor antagonist, palonosetron, was identified as a compound with significantly increased affinity for the receptor, a prolonged half life (~42 hours) and no meaningful effect on QTc interval.
  • While initial formulations were intravenous, the development of oral forms provided more convenient dosing. Moreover, there are several novel delivery methods for 5-HT3 receptor antagonists available, most notable of which are transdermal granisetron and sustained-release subcutaneous granisetron.
  • The first-generation 5-HT3 receptor antagonists significantly improved emesis associated with cytotoxic chemotherapy, but nausea remains a persistent problem.

Chen R, Deng K, Raftopoulos H. In: Management of Chemotherapy-Induced Nausea and Vomiting. Edited by: Navari R. Springer International Publishing Switzerland 2016. doi: 10.1007/978-3-319-27016-6_3

Palonosetron

This chapter provides a detailed review of the place of the 5-hydroxytryptamine receptor antagonist palonosetron in the management of chemotherapy-induced nausea and vomiting.

Summary
  • Palonosetron has several pharmacologic characteristics that set it apart from first generation serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonists, including much higher affinity for the 5-HT3 receptor and a longer plasma half-life (40 hours versus 5–12 hours).
  • In terms of safety, while palonosetron has the same class-related adverse effects as first generation drugs, it is associated with significantly less mean QTc interval prolongation.
  • Clinical trials demonstrated palonosetron to be associated with higher complete response rates for CINV in the delayed and overall, but not acute, phases, compared with first-generation 5-HT3 receptor antagonists.
  • Palonosetron has demonstrated efficacy has part of triplet CINV prophylaxis regimens, in combination with aprepitant and dexamethasone, as well as in combination with olanzapine and dexamethasone.
  • Cost-effectiveness studies have shown that while palonosetron was associated with higher acquisition and treatment costs than first-generation treatments, this was offset by reduced healthcare utilization for CINV, giving lower overall than those of other treatments.
  • All guidelines recommend palonosetron as the 5-HT3 receptor antagonist of choice in moderately emetogenic chemotherapy, with guidelines for highly emetogenic chemotherapy recommending a three-drug combination, comprising a 5-HT3 receptor antagonist, dexamethasone and an NK1 receptor antagonist (or olanzapine).

Schwartzberg L. In: Management of Chemotherapy-Induced Nausea and Vomiting. Edited by: Navari R. Springer International Publishing Switzerland 2016. doi: 10.1007/978-3-319-27016-6_4

Neurokinin-1 (NK1) receptor antagonists

The role of neurokinin-1 receptor antagonists in CINV

This chapter reviews the place of the neurokinin-1 (NK1) receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting (CINV).

Summary
  • Nausea and vomiting remain a clinically significant problem for patients receiving highly and moderately emetogenic chemotherapy.
  • With triple therapy, (comprising the NK1 receptor antagonist aprepitant, a serotonin [5-hydroxytryptamine-3; 5-HT3] receptor antagonist and corticosteroids) 70% of patients receiving cisplatin-based highly emetogenic chemotherapy have been shown to achieve an overall antiemetic complete response.
  • The NK1 receptor antagonists are aprepitant and fosaprepitant (a prodrug of aprepitant), casopitant, netupitant and rolapitant.
  • While the 5-HT3-mediated effect of emetogenic chemotherapy occurs within a few hours of administration, the NK1-mediated effect starts at approximately 15 hours after administration and continues past the acute phase into the delayed phase.
  • In clinical trials a fixed combination of netupitant and oral palonosetron (NEPA) has been shown to be associated with better control of nausea than palonosetron alone, even when used in subsequent cycles of chemotherapy.
  • The addition of aprepitant to palonosetron and dexamethasone was found to be safe and effective in patients receiving high-dose chemotherapy and undergoing stem cell transplant.
  • Use of NK1 receptor antagonists is endorsed in combination with 5-HT3 receptor antagonists and dexamethasone, as triple therapy prophylaxis, recommended for preventing CINV associated with highly emetogenic chemotherapy and moderately emetogenic anthracycline/cyclophosphamide-based chemotherapy.

Rapoport BL. In: Management of chemotherapy-induced nausea and vomiting. Edited by Navari R. Adis, Cham, 2016. doi: 10.1007/978-3-319-27016-6_5

Is the addition of a neurokinin-1 receptor antagonist beneficial in moderately emetogenic chemotherapy? A systematic review and meta-analysis

This systematic review evaluates the efficacy of adding a neurokinin-1 (NK1) receptor antagonist to a serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonist and a steroid for the prevention of nausea and vomiting in patients receiving moderately emetogenic chemotherapy.

Summary
  • International guidelines recommend that an NK1 receptor antagonist be given along with a 5-HT3 receptor antagonist and a steroid for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy, but not for those receiving moderately emetogenic treatment.
  • The current category of moderately emetogenic risk encompasses a broad range of emesis risk, from 30% to 90%.
  • Researchers identified a total of 626 published articles or abstracts related to the use of NK1 receptor antagonists in patients with cancer, with 13 journal articles and 3 abstracts (a total of 3484 patients) fitting the inclusion criteria.
  • Complete response (CR) results in all phases for patients receiving moderately emetogenic chemotherapy (without carboplatin or oxaliplatin) were available for two studies (n=715), with a pooled odds ratio (OR) for overall CR with the addition of an NK1- receptor antagonist of 1.46 (95% confidence interval [CI] 1.06–2.02), with a calculated risk difference (RD) for overall CR of 8%, favouring NK1 receptor antagonist regimens.
  • Nine studies (n=1790) provided results on CR for patients receiving carboplatin-based chemotherapy, with an OR for an overall CR of 1.96 (95% CI 1.57–2.45), and an absolute RD of 15%, favouring the NK1 receptor antagonist regimen.
  • Four studies (n=1344) reported results from oxaliplatin-based chemotherapy, with a OR for a CR of 1.34 (95% CI 0.88–2.04) and an absolute RD for overall CR of 4%, favouring NK1 receptor antagonist regimens.
  • The beneficial effect of the addition of an NK1 receptor antagonist was most pronounced for patients receiving carboplatin-based chemotherapy and was comparable to that seen in patients receiving cisplatin-based highly emetogenic chemotherapy.

Jordan K et al. Support Care Cancer 2018. doi: 10.1007/s00520-017-3857-7

Prevention of chemotherapy-induced nausea: the role of neurokinin-1 (NK1) receptor antagonists

This paper reviews the role of the neurokinin-1 (NK1) receptor antagonists in the prevention of chemotherapy-induced nausea.

Summary
  • Assessment of nausea is challenging due to its subjective nature. As a result many studies have evaluated nausea as either part of a complete response or as a secondary endpoint to emesis.
  • Overall, studies have not shown any consistent superiority of the addition of aprepitant/fosaprepitant to a serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonist and dexamethasone for the control of nausea after highly or moderately emetogenic chemotherapy.
  • Aprepitant/fosaprepitant has been shown to be as effective as prochlorperazine in delayed nausea control, while olanzapine was superior to aprepitant/fosaprepitant both in the delayed phase and overall.
  • During the delayed phase, no significant differences were observed in rates of nausea or in maximum nausea severity or nausea duration in patients receiving aprepitant/palonosetron/dexamethasone before chemotherapy who were randomized to receive aprepitant or dexamethasone on days 2–3. Similar results were shown for the delayed phase in a study comparing aprepitant on days 2–3 with metoclopramide on days 2–4.
  • Regarding the use of rolapitant, discrepancies between studies mean that no clear conclusions can be drawn regarding its use in nausea associated with highly emetogenic chemotherapy.
  • NEPA is a fixed-combination antiemetic comprising netupitant and palonosetron, which has found to be associated with significantly better nausea control compared with oral palonosetron.
  • Additional factors to consider when selecting an NK1 receptor antagonist for the control of chemotherapy-induced nausea include:
    • Safety
    • Schedule and convenience of administration, and implications of such for patient compliance
    • The choice of 5-HT3 receptor antagonist
    • International guideline recommendations.
  • Studies are needed to define the overall potential for chemotherapy-induced nausea in individual patients, including factors related to the patient and the disease, as well as to the specific anticancer treatments.

Bošnjak SM et al. Support Care Cancer 2017. doi: 10.1007/s00520-017-3585-z

Aprepitant and fosaprepitant: A 10-year review of efficacy and safety

This review discusses the safety and efficacy data for aprepitant and fosaprepitant from key clinical trials on the prevention of chemotherapy-induced nausea and vomiting (CINV).

Summary
  • Early clinical trials revealed that, compared with dual therapy, triple therapy with aprepitant, a serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonist and dexamethasone provided improved control of acute and delayed CINV.
  • The safety and efficacy of aprepitant were subsequently evaluated in several milestone clinical trials in patients receiving highly emetogenic chemotherapy. Research into multiple-day dosing revealed:
    • Aprepitant and fosaprepitant were more effective than ondansetron for control of delayed-phase emesis and need for rescue medication
    • Aprepitant plus dexamethasone was effective for control of delayed emesis with highly emetogenic chemotherapy
    • Aprepitant treatment was associated with significantly improved complete response rate over the total treatment period and during acute and delayed phases.
  • Although originally recommended to be given for 3 days to control CINV, single doses (oral or intravenous) of aprepitant have been shown to be effective in preventing both acute and delayed CINV.
  • Studies have also shown aprepitant to protect against CINV over multiple cycles of cisplatin-based chemotherapy, with control of CINV sustained over six cycles.
  • Studies have shown aprepitant to be generally well tolerated. A systematic review of 17 trials of neurokinin-1 (NK1) receptor antagonists added to antiemetic regimens for the prevention of CINV showed statistically significant, but clinically trivial differences, in fatigue, hiccups and lower constipation than controls.
  • Importantly, aprepitant does not appear to alter the pharmacokinetics of high-dose melphalan when used as conditioning therapy prior to stem cell transplantation in patients with multiple myeloma.
  • Clinical trials have demonstrated that most drug-drug interactions with aprepitant have few/no clinical consequences, with no differences in severe adverse events noted between treatment arms with or without aprepitant.
  • All clinical practice guidelines recommend aprepitant be added to combination 5-HT3 receptor antagonist and dexamethasone for patients receiving highly emetogenic chemotherapy; adherence to antiemetic clinical practice guidelines resulted in a significantly reduced incidence of CINV.

Aapro M et al. Oncologist 2015; 20: 450–458. doi: 10.1634/theoncologist.2014-0229

Netupitant/palonosetron combination

The role of neurokinin-1 receptor antagonists in CINV

This chapter reviews the place of the neurokinin-1 (NK1) receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting (CINV).

Summary
  • Nausea and vomiting remain a clinically significant problem for patients receiving highly and moderately emetogenic chemotherapy.
  • With triple therapy, (comprising the NK1 receptor antagonist aprepitant, a serotonin [5-hydroxytryptamine-3; 5-HT3] receptor antagonist and corticosteroids) 70% of patients receiving cisplatin-based highly emetogenic chemotherapy have been shown to achieve an overall antiemetic complete response.
  • The NK1 receptor antagonists are aprepitant and fosaprepitant (a prodrug of aprepitant), casopitant, netupitant and rolapitant.
  • While the 5-HT3-mediated effect of emetogenic chemotherapy occurs within a few hours of administration, the NK1-mediated effect starts at approximately 15 hours after administration and continues past the acute phase into the delayed phase.
  • In clinical trials a fixed combination of netupitant and oral palonosetron (NEPA) has been shown to be associated with better control of nausea than palonosetron alone, even when used in subsequent cycles of chemotherapy.
  • The addition of aprepitant to palonosetron and dexamethasone was found to be safe and effective in patients receiving high-dose chemotherapy and undergoing stem cell transplant.
  • Use of NK1 receptor antagonists is endorsed in combination with 5-HT3 receptor antagonists and dexamethasone, as triple therapy prophylaxis, recommended for preventing CINV associated with highly emetogenic chemotherapy and moderately emetogenic anthracycline/cyclophosphamide-based chemotherapy.

Rapoport BL. In: Management of chemotherapy-induced nausea and vomiting. Edited by Navari R. Adis, Cham, 2016. doi: 10.1007/978-3-319-27016-6_5

Is the addition of a neurokinin-1 receptor antagonist beneficial in moderately emetogenic chemotherapy? A systematic review and meta-analysis

This systematic review evaluates the efficacy of adding a neurokinin-1 (NK1) receptor antagonist to a serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonist and a steroid for the prevention of nausea and vomiting in patients receiving moderately emetogenic chemotherapy.

Summary
  • International guidelines recommend that an NK1 receptor antagonist be given along with a 5-HT3 receptor antagonist and a steroid for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy, but not for those receiving moderately emetogenic treatment.
  • The current category of moderately emetogenic risk encompasses a broad range of emesis risk, from 30% to 90%.
  • Researchers identified a total of 626 published articles or abstracts related to the use of NK1 receptor antagonists in patients with cancer, with 13 journal articles and 3 abstracts (a total of 3484 patients) fitting the inclusion criteria.
  • Complete response (CR) results in all phases for patients receiving moderately emetogenic chemotherapy (without carboplatin or oxaliplatin) were available for two studies (n=715), with a pooled odds ratio (OR) for overall CR with the addition of an NK1- receptor antagonist of 1.46 (95% confidence interval [CI] 1.06–2.02), with a calculated risk difference (RD) for overall CR of 8%, favouring NK1 receptor antagonist regimens.
  • Nine studies (n=1790) provided results on CR for patients receiving carboplatin-based chemotherapy, with an OR for an overall CR of 1.96 (95% CI 1.57–2.45), and an absolute RD of 15%, favouring the NK1 receptor antagonist regimen.
  • Four studies (n=1344) reported results from oxaliplatin-based chemotherapy, with a OR for a CR of 1.34 (95% CI 0.88–2.04) and an absolute RD for overall CR of 4%, favouring NK1 receptor antagonist regimens.
  • The beneficial effect of the addition of an NK1 receptor antagonist was most pronounced for patients receiving carboplatin-based chemotherapy and was comparable to that seen in patients receiving cisplatin-based highly emetogenic chemotherapy.

Jordan K et al. Support Care Cancer 2018. doi: 10.1007/s00520-017-3857-7

Prevention of chemotherapy-induced nausea: the role of neurokinin-1 (NK1) receptor antagonists

This paper reviews the role of the neurokinin-1 (NK1) receptor antagonists in the prevention of chemotherapy-induced nausea.

Summary
  • Assessment of nausea is challenging due to its subjective nature. As a result many studies have evaluated nausea as either part of a complete response or as a secondary endpoint to emesis.
  • Overall, studies have not shown any consistent superiority of the addition of aprepitant/fosaprepitant to a serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonist and dexamethasone for the control of nausea after highly or moderately emetogenic chemotherapy.
  • Aprepitant/fosaprepitant has been shown to be as effective as prochlorperazine in delayed nausea control, while olanzapine was superior to aprepitant/fosaprepitant both in the delayed phase and overall.
  • During the delayed phase, no significant differences were observed in rates of nausea or in maximum nausea severity or nausea duration in patients receiving aprepitant/palonosetron/dexamethasone before chemotherapy who were randomized to receive aprepitant or dexamethasone on days 2–3. Similar results were shown for the delayed phase in a study comparing aprepitant on days 2–3 with metoclopramide on days 2–4.
  • Regarding the use of rolapitant, discrepancies between studies mean that no clear conclusions can be drawn regarding its use in nausea associated with highly emetogenic chemotherapy.
  • NEPA is a fixed-combination antiemetic comprising netupitant and palonosetron, which has found to be associated with significantly better nausea control compared with oral palonosetron.
  • Additional factors to consider when selecting an NK1 receptor antagonist for the control of chemotherapy-induced nausea include:
    • Safety
    • Schedule and convenience of administration, and implications of such for patient compliance
    • The choice of 5-HT3 receptor antagonist
    • International guideline recommendations.
  • Studies are needed to define the overall potential for chemotherapy-induced nausea in individual patients, including factors related to the patient and the disease, as well as to the specific anticancer treatments.

Bošnjak SM et al. Support Care Cancer 2017. doi: 10.1007/s00520-017-3585-z

Aprepitant and fosaprepitant: A 10-year review of efficacy and safety

This review discusses the safety and efficacy data for aprepitant and fosaprepitant from key clinical trials on the prevention of chemotherapy-induced nausea and vomiting (CINV).

Summary
  • Early clinical trials revealed that, compared with dual therapy, triple therapy with aprepitant, a serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonist and dexamethasone provided improved control of acute and delayed CINV.
  • The safety and efficacy of aprepitant were subsequently evaluated in several milestone clinical trials in patients receiving highly emetogenic chemotherapy. Research into multiple-day dosing revealed:
    • Aprepitant and fosaprepitant were more effective than ondansetron for control of delayed-phase emesis and need for rescue medication
    • Aprepitant plus dexamethasone was effective for control of delayed emesis with highly emetogenic chemotherapy
    • Aprepitant treatment was associated with significantly improved complete response rate over the total treatment period and during acute and delayed phases.
  • Although originally recommended to be given for 3 days to control CINV, single doses (oral or intravenous) of aprepitant have been shown to be effective in preventing both acute and delayed CINV.
  • Studies have also shown aprepitant to protect against CINV over multiple cycles of cisplatin-based chemotherapy, with control of CINV sustained over six cycles.
  • Studies have shown aprepitant to be generally well tolerated. A systematic review of 17 trials of neurokinin-1 (NK1) receptor antagonists added to antiemetic regimens for the prevention of CINV showed statistically significant, but clinically trivial differences, in fatigue, hiccups and lower constipation than controls.
  • Importantly, aprepitant does not appear to alter the pharmacokinetics of high-dose melphalan when used as conditioning therapy prior to stem cell transplantation in patients with multiple myeloma.
  • Clinical trials have demonstrated that most drug-drug interactions with aprepitant have few/no clinical consequences, with no differences in severe adverse events noted between treatment arms with or without aprepitant.
  • All clinical practice guidelines recommend aprepitant be added to combination 5-HT3 receptor antagonist and dexamethasone for patients receiving highly emetogenic chemotherapy; adherence to antiemetic clinical practice guidelines resulted in a significantly reduced incidence of CINV.

Aapro M et al. Oncologist 2015; 20: 450–458. doi: 10.1634/theoncologist.2014-0229

Olanzapine

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

This meta-analysis was conducted to investigate the efficacy of olanzapine compared with other antiemetics in both the prevention of chemotherapy-induced nausea and vomiting (CINV) and for breakthrough CINV.

Summary
  • A total of 13 eligible randomised controlled trials were identified
    • Ten in the preventative setting, with a total of 546 patients randomised to olanzapine and 536 to other serotonin (5-hydroxytryptamine-3; 5-HT3) or neurokinin-1 (NK1) receptor antagonists
    • Three in the breakthrough setting, with a total of 120 patients randomised to olanzapine and 188 to other rescue antiemetics.
  • The primary endpoints of the included studies were the percentage of patients achieving either no emesis or no nausea in the acute, delayed and overall phases.
  • For the endpoint of no emesis in the acute phase, olanzapine was superior to other treatments, with a risk ratio (RR) of 1.10 (95% confidence interval [CI] 1.03–1.17), although the risk difference calculation did not meet the >10% threshold considered sufficient to warrant guideline changes.
  • Olanzapine was superior to other standard regimens for both no emesis and no nausea in the delayed phase, with RRs of 1.31 (95% CI 1.14-1.52) and 1.50 (95% CI 1.15–1.97), respectively. The risk differences for both endpoints exceeded the >10% threshold described above (21% and 24%, respectively).
  • In the overall phase, olanzapine was superior to other regimens for no emesis (RR 1.41; 95% CI 1.18–1.68) and no nausea (RR 1.53; 95% CI 1.18–1.97), the risk differences for both endpoints exceeded the >10% threshold described above (both 24%).
  • For breakthrough treatment, the RRs also demonstrated statistical superiority of olanzapine over other rescue therapies for no emesis, which was the only endpoint available for meta-analysis, with a RR of 2.09 (95% CI 1.63–2.68), a risk difference of 36%.
  • Subanalyses compared two doses of olanzapine: 5mg versus 10mg. Results showed the 5mg dose to be equally efficacious  but with potential safety benefits.
  • Overall, results indicate that olanzapine is more efficacious than other standard antiemetics in the preventative and breakthrough CINV settings.

Chiu L et al. Support Care Cancer 2016; 24: 2381–2392. doi: 10.1007/s00520-016-3075-8

The physiology and pharmacology of nausea and vomiting induced by anticancer chemotherapy in humans

This chapter provides an overview of clinical trials of olanzapine in the prevention of chemotherapy-induced nausea and vomiting (CINV). 

Summary
  • While effective treatments exist for the prevention of emesis in patients receiving chemotherapy, nausea is not as well controlled. Nausea can be difficult to measure, as it is a subjective sensation, the mechanisms of which have not been completely elucidated.
  • The mechanisms by which olanzapine, an atypical antipsychotic drug, appears to work to reduce CINV are not completely understood, but the drug does block the neurotransmitters dopamine and serotonin, known mediators of CINV.
  • Initially, a role of olanzapine as an antinausea treatment came from several case reports, which prompted a phase I study in which olanzapine was added to granisetron and dexamethasone in cancer patients receiving chemotherapy, followed by phase II studies using maximally tolerated doses from the phase I study. 
  • Results of several phase III trials revealed that:
    • Olanzapine was more frequently associated with a complete response (CR) of delayed CINV and improved quality of life in patients receiving moderately and highly emetogenic chemotherapy
    • Olanzapine and aprepitant (combined with palonosetron and dexamethasone) were comparable in the control of chemotherapy-induced emesis, whereas nausea was better controlled with olanzapine
    • Olanzapine was more effective for control of nausea than placebo in patients undergoing moderately or highly emetogenic chemotherapy and receiving a serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonist, dexamethasone and a neurokinin-1 (NK1) receptor antagonist.
  • Olanzapine was significantly better than metoclopramide for breakthrough emesis and nausea in a study of breakthrough CINV in chemotherapy-naïve patients receiving highly emetogenic chemotherapy and guideline-directed prophylactic antiemetics.
  • Olanzapine has been shown to be effective in controlling both acute and delayed CINV in patients receiving single-day chemotherapy. Olanzapine may also have utility in multiple-day or high-dose chemotherapy.

Navari RM. In: Management of chemotherapy-induced nausea and vomiting. Edited by Navari R. Adis, Cham, 2016. doi: 10.1007/978-3-319-27016-6_2

Cannabinoids

A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: A focus on pharmacokinetic variability and pharmacodynamics

This review provides an overview of oral cannabinoids, such as dronabinol and nabilone, for the treatment of patients with cancer and chemotherapy-induced nausea and vomiting (CINV).

Summary
  • Efficacy of delta(Δ)9-tetrahydrocannabinol (THC) for the treatment of chemotherapy-induced nausea and vomiting was demonstrated in a placebo-controlled study in 1975.
  • Subsequently many clinical studies have evaluated the antiemetic efficacy of oral synthetic pharmaceutical grade THC treatments, dronabinol and nabilone, demonstrating similar or improved efficacy compared with conventional antiemetics.
  • An important issue associated with oral THC is the high pharmacokinetic variability seen in healthy individuals.
  • The antiemetic efficacy of medical marijuana, the use of which is controversial, is also hindered by variable pharmacokinetics, as well as by variable pharmacodynamics, both of which differ by method of administration.
  • A newer oral dronabinol solution has been shown to have less pharmacokinetic variability, which may reduce the need for individualised dosing. Also, patients may derive therapeutic benefit faster with this formulation than with dronabinol capsules.
  • Oral cannabinoids are associated with a higher incidence of adverse effects than conventional antiemetics, such as a “high” feeling, euphoria, disorientation and depression.

Badowski ME. Cancer Chemother Pharmacol. doi: 10.1007/s00280-017-3387-5

Concise review of the management of iatrogenic emesis using cannabinoids: Emphasis on nabilone for chemotherapy-induced nausea and vomiting

This paper reviews the clinical evidence for the cannabinoids, with a focus on nabilone, for the prevention of chemotherapy-induced nausea and vomiting (CINV).

Summary
  • While there are many available options for the prevention of CINV, evidence-guided prophylaxis remains suboptimal.
  • Given the lack of absolute effectiveness of any single treatment in the prevention of CINV, cannabinoids are emerging again as a ‘new’ treatment option.
  • The psychoactive properties of marijuana and its potential for misuse have limited research into these drugs, but recent regulatory changes, as well as changing public perception, have brought these drugs into the spotlight, particularly given their effective analgesic and antiemetic properties.
  • Neither dronabinol or nabilone, oral synthetic pharmaceutical grade delta(Δ)9-tetrahydrocannabinol (THC) drugs, feature in current antiemetic guidelines for chemotherapy.
  • Clinical trials of nabilone have demonstrated:
    • An antiemetic effect greater than placebo against CINV
    • A statistical advantage over prochlorperazine in reduction of emesis, severity of nausea and improvement of appetite in patients undergoing chemotherapy.
  • In terms of safety, clinical trials demonstrated nabilone to be associated with a higher incidence of adverse events than placebo, although most were mild or moderate and were not treatment limiting.
  • Cannabinoid receptor agonists may be a useful option for the management of emesis, with these “new old” drugs worthy of consideration as important alternatives in the management of CINV.

Pergolizzi Jr JV et al. Cancer Chemother Pharmacol 2017; 79: 467–477. doi: 10.1007/s00280-017-3257-1

Management of CINV in pediatric patients

Management of chemotherapy-induced nausea and vomiting in pediatric patients

This review provides a summary of the safety and efficacy of currently available antiemetic drugs for the prevention of chemotherapy-induced nausea and vomiting (CINV) in children.

Summary
  • CINV has a significant impact on quality of life and is considered by patients to be a major adverse effect of treatment.
  • Uncontrolled CINV may cause serious complications in paediatric patients and preventative measures should be used.
  • Available antiemetic treatmetns include:
    • Dopamine receptor antagonists, but clinical use limited by extrapyramidal reactions, disorientation and sedation
    • Serotonin (5-hydroxytryptamine-3; 5-HT3) receptor antagonists – granisetron, ondansetron and tropisetron (first generation drugs recommended for the paediatric population) and palonosetron (second generation drug).
    • Dopamine-serotonin receptor antagonists (metoclopramide), but clinical use is limited by the risk of extrapyramidal disorders
    • Neurokinin-1 (NK1) receptor antagonists – aprepitant/fosaprepitant, netupitant, rolapitant
    • Dexamethasone
    • Olanzapine.
  • Recommended treatment for the prevention of acute CINV for children receiving:
    • Highly emetogenic chemotherapy – prophylaxis with a 5-HT3 receptor antagonist, plus dexamethasone plus aprepitant
    • Moderately emetogenic chemotherapy – prophylaxis with a 5-HT3 receptor antagonist plus dexamethasone
    • Low emetogenic chemotherapy – prophylaxis with a 5-HT3 receptor antagonist.
  • Prevention of delayed CINV has not yet been sufficiently studied in children to allow any recommendations to be made.
  • For the treatment of breakthrough CINV, olanzapine should be considered, in addition to the guideline-directed prophylactic treatment, with metoclopramide considered in children aged >1 year who are unable to receive olanzapine.
  • For refractory CINV and highly emetogenic chemotherapy, changing from ondansetron or granisetron to palonosetron is an option; consideration should also be given to adding aprepitant if not already used. If palonosetron and/or aprepitant are already used, the addition of olanzapine should be considered.

Navari RM. Management of chemotherapy-induced nausea and vomiting in pediatric patients. Pediatr Drugs 2017; 19: 213–222. doi: 10.1007/s40272-017-0228-2