Chemotherapy-induced nausea and vomiting (CINV) remains a critical clinical challenge, with important deleterious effects on patients’ quality of life (QoL). Uncontrolled CINV can lead to anorexia, malnutrition, dehydration, and metabolic imbalances. Moreover, poor CINV control in previous cycles may result in anticipatory CINV. Potential consequences of uncontrolled CINV are poor treatment compliance and even discontinuation of potentially beneficial chemotherapy [
1‐
5]. Advances in antiemetic therapies have greatly reduced CINV incidence, and vomiting can be prevented in the majority of cancer patients [
6,
7]. While improvements have also occurred in the prevention of nausea, this control is markedly less than with vomiting and can be particularly prominent in delayed nausea during the course of chemotherapy [
1,
8‐
13]. Prevention of nausea has become a top priority in antiemetic clinical research, and many have considered that this should be the primary endpoint in clinical trials.
Antiemetic guidelines categorize chemotherapeutic agents based on the frequency with which patients experience acute emesis (0–24 h after chemotherapy) in the absence of antiemetic prophylaxis into four CINV risk levels: highly emetogenic chemotherapy (HEC: by non-anthracycline–cyclophosphamide (non-AC) and AC–HEC), moderately emetogenic chemotherapy (MEC; carboplatin and others), low emetogenic chemotherapy, and minimally emetogenic chemotherapy. Antiemetics with highest therapeutic index are 5-hydroxytryptamine-3 (5-HT
3) receptor antagonists (RAs), NK
1RAs, and corticosteroids, especially dexamethasone [
6,
11,
14].
The NK
1RA family of antiemetics acts by blocking substance P activity at NK
1 receptors in the brain, offering a mechanism of action distinct from and complementary to 5-HT
3RAs. NK
1RAs were rapidly incorporated into international antiemetic guidelines and are currently recommended for prevention of CINV induced by non-AC– and AC–HEC [
1,
10,
15‐
21] or carboplatin-based MEC [
21]. The two newest members of this class, netupitant (in a fixed combination with palonosetron as NEPA) and rolapitant have recently become available [
22‐
24] and are also included in antiemetic guidelines [
1,
10,
21].
Neuropharmacology of nausea
Nausea is defined as an epigastric discomfort or unpleasant awareness of being on the verge of vomiting. Vomiting is the retrograde expulsion of gastric contents through the mouth [
25].
Nausea and vomiting often are clinically associated; however, nausea can occur alone or with other symptoms such as dyspepsia. Nausea is a subjective sensation, while vomiting is an objective reflex that can be easily measured [
26].
The neuropharmacology of nausea and vomiting is also distinct and, particularly in the case of nausea, not well understood. In contrast to vomiting, nausea has been shown to require conscious awareness and cortical function [
27]. Additionally, some studies have demonstrated that nausea is accompanied by an increase in vasopressin and oxytocin levels [
28]. Elevations in plasma cortisol, β-endorphin, epinephrine, and norepinephrine concentrations and alterations in gastric myoelectric activity also occurred in subjects who developed nausea in motion sickness models [
29,
30].
The aprepitant–ondansetron–dexamethasone regimen, although significantly superior in the control of chemotherapy-induced vomiting, was not superior in the control of overall nausea when compared to ondansetron–dexamethasone [
15,
17]. This observation suggests that nausea and vomiting may occur through distinct, although shared, pharmacologic mechanisms, and that better protection against nausea likely requires targeting receptors other than 5-HT
3 and NK
1 [
31]. Muscarinic, histaminic, and adrenergic receptors, involved in the mechanism of vomiting and nausea unrelated to chemotherapy [
32], are potential candidates. Identification and characterization of brain mechanisms leading to nausea await further research.
Methodology and data gaps in nausea assessment in clinical trials
Assessment of nausea is challenging because of its subjective nature, and methods for its clinical evaluation have not evolved substantially over the past 30 years [
33]. Until recently, nausea has not been the primary efficacy endpoint in antiemetic clinical studies. Instead, nausea has been evaluated as part of the composite term “complete response” (CR) (no emesis and no rescue medication), where “no need for rescue” serves as a surrogate marker for no nausea or only mild nausea. Nausea has also been assessed as a secondary efficacy endpoint in most studies, where nausea duration and intensity are commonly reported as “no nausea” (visual analog scale (VAS) <5 mm) and/or “no significant nausea” (NSN; VAS <25 mm), measured daily and overall 0–120 h from the start of chemotherapy, and for different periods of the day. Additionally, the Functional Living Index-Emesis (FLIE) questionnaire collects patient-reported information on different aspects of nausea and vomiting that might impact patients’ daily life. Because of the subjective nature of nausea, the design of clinical studies with matching identical placebo medication in the control arm is of special importance.
Correctly reporting the onset of nausea (as acute, delayed, or overall) is also of great relevance. Of special concern is the management of delayed nausea, which has a higher incidence [
34‐
37] and greater severity than acute nausea, and is less responsive to treatment [
36,
38]. The subjective nature of nausea and communication barriers between healthcare professionals and patients may result in nausea underreporting by patients and in underestimation of its incidence, especially during the delayed phase, by healthcare professionals [
37,
39,
40]. Subjective toxicities are more likely to be underreported by physicians in oncology clinical trials [
41]. For nausea, an underreporting of 40.7% has been described in this large pooled database (
N = 1090) of three randomized trials [
41].
Future directions
Nausea control has become the top priority of current antiemetic research, to reach the final goal of “no nausea/no vomiting” after anticancer treatment. Progress in understanding the pathophysiology of nausea, and the design of clinical trials with nausea as primary efficacy endpoint should help determine the most effective antiemetic combination for nausea prevention.
The accurate measurement of nausea, both in clinical trials and in daily practice, remains a priority. While VAS and categorical scales (as documented in the MASCC antiemesis tool (MAT) [
25]) may provide reproducible and useful measurements, results are often documented inconsistently, and NSN or no nausea are not reported at times. We would advise that the VAS actual scores be reported and analyzed, rather than be categorized. These additional measures should improve the consistency of the data and could assist in statistical review. Reporting exact VAS scores for nausea and for individual items on the nausea domain of the FLIE questionnaire in all patients (including those for whom treatment has failed) would also aid in understanding the effect of antiemetics on patients’ QoL as suggested by Andrews [
76]. Furthermore, strategies to improve patient-healthcare professional communication and use of tools that incorporate patient-reported outcomes to evaluate toxicity in cancer clinical trials may help prevent underreporting of nausea [
41].
The benefit of adding olanzapine to a triplet aprepitant/fosaprepitant–5-HT
3RA–dexamethasone regimen for the control of nausea has been evaluated in a phase III study in 380 patients receiving cisplatin- or AC-based HEC [
77]. Nausea prophylaxis was the primary endpoint. The proportion of patients with no nausea (0, scale 0–10, VAS) was significantly greater in the olanzapine group during the acute (74 vs. 45%;
p = 0.002), delayed (42 vs. 25%;
p = 0.002), and overall (37 vs. 22%;
p = 0.002) periods. Olanzapine (10 mg daily for 4 days) was associated with transient but significantly increased sedation [
77]. No grade 3–4 olanzapine-related AEs have been reported in CINV clinical trials [
32,
59,
77]. The addition of olanzapine to aprepitant-/fosaprepitant-containing antiemetic regimens can improve CINV control without substantial added costs [
78]. In addition, the effectiveness of olanzapine was comparable to aprepitant for the prevention of CINV [
57] and provides a more cost-effective alternative to aprepitant-based regimens.
Further efforts should be made to better define the overall potential for CIN in a given patient, including anticancer drug-, patient-, and disease-related factors [
79,
80]. Moreover, the efficacy of guideline-recommended antiemetics in real-life situations (outside of controlled conditions of clinical trials, in patients receiving medications or interventions known to induce nausea, for example, opioids) should be analyzed. Currently, a need to improve guideline adherence by clinicians and compliance with antiemetic regimens by patients exists. Simplification of antiemetic regimens with agents that are administered orally once per chemotherapy cycle, such as rolapitant (as single-agent NK
1RA) or NEPA (as a fixed combination of an NK
1RA and a 5-HT
3RA) may contribute to this improvement. While the addition of olanzapine to the triple combination has proven to improve CINV prophylaxis [
77], compliance with this complex four-drug antiemetic regimen and its feasibility outside of clinical trials needs to be evaluated.