Authors: Akito Hata, Yoshimasa Shiraishi, Naoki Inui, Morihito Okada, Masahiro Morise, Kohei Akiyoshi, Masayuki Takeda, Yasutaka Watanabe, Shunichi Sugawara, Naofumi Shinagawa, Kaoru Kubota, Toshiaki Saeki & Tomohide Tamura Abstract Introduction We describe the results of an exploratory analysis performed on the first head-to-head study (JapicCTI-194611) comparing two different intravenous (IV) neurokinin 1 (NK 1 ) receptor antagonists, fosnetupitant and fosaprepitant, in combination with palonosetron (PALO) and dexamethasone (DEX) for the prevention of highly emetogenic chemotherapy (HEC)-induced nausea and vomiting (CINV).

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

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

A model that incorporates eight readily available risk factors accurately predicts a patient’s likelihood for experiencing grade 2 or above chemotherapy-induced nausea and vomiting on a cycle-by-cycle basis, researchers report.

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

Treatment-related adverse events (TRAEs) of grade 3 occurred in 40% of the 25 participants evaluable for safety, with the most common being vomiting (16%), nausea (12%), and dizziness (12%).

This paper reviews the role of the neurokinin-1 (NK 1 ) 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

The rates of grade 3 or 4 diarrhea, vomiting, and nausea in the oral group were 5%, 4%, and 3%, respectively, compared with rates below 1% in the intravenous group.