Anticipatory Nausea Research Articles

Propranolol attenuates the establishment of conditioned context aversions: differential effects compared to MK-801 in an animal model of anticipatory nausea and vomiting.

Cancer patients often experience anticipatory nausea and vomiting (ANV) due to Pavlovian conditioning. Both N-methyl-D-aspartate and beta-adrenergic receptors are known to mediate memory formation, but their role in the development of ANV remains unclear. This study used a conditioned context aversion (CCA) paradigm, an animal model for ANV, to assess whether administration of the beta-adrenergic receptor antagonist propranolol or the N-methyl-D-aspartate receptor antagonist MK-801 immediately after CCA training has an effect on the later expression of CCA in CD1 male mice. In experiment 1, three groups were injected with lithium chloride (LiCl) to induce aversion in a novel context, resulting in CCA. A control group was injected with sodium chloride (NaCl). Following conditioning, two of the LiCl-treated groups received different doses of MK-801 (0.05 or 0.2 mg/kg), while the remaining LiCl-treated and NaCl-treated groups received a second NaCl injection. In experiment 2, two groups were injected with LiCl, and one group was injected with NaCl. After conditioning, one of the LiCl-treated groups received a propranolol injection (10 mg/kg). The remaining LiCl-treated and NaCl-treated groups received NaCl injections. Water consumption was measured in all groups 72 h later within the conditioning context. Postconditioning administration of propranolol, but not MK-801, attenuated CCA, as revealed by similar levels of water consumption in animals that received LiCl and propranolol relative to NaCl-treated animals. These findings suggest that beta-adrenergic receptor activation is crucial for the development of CCA. Therefore, propranolol may represent a novel therapeutic approach for cancer patients at high risk of ANV.

Non-pharmacological treatments for anticipatory nausea and vomiting during chemotherapy: a systematic review and meta-analysis of the Clinical Practice Guidelines for Antiemesis 2023.

Anticipatory chemotherapy-induced nausea and vomiting (CINV) is a conditioned response influenced by the severity and duration of previous emetic responses to chemotherapy. We aimed to evaluate the efficacy of non-pharmacologic interventions for anticipatory CINV among patients with cancer. We conducted a systematic search in databases, including PubMed, the Cochrane Library, CINAHL, and Ichushi-Web, from January 1, 1990, to December 31, 2020. Randomized controlled trials, non-randomized designs, observational studies, or case-control studies that utilized non-pharmacological therapies were included. The primary outcomes were anticipatory CINV, with an additional investigation into adverse events and the costs of therapies. The risk-of-bias for each study was assessed using the Cochrane risk-of-bias tool, and meta-analysis was performed using Revman 5.4 software. Of the 107 studies identified, six met the inclusion criteria. Three types of non-pharmacological treatments were identified: systematic desensitization (n = 2), hypnotherapy (n = 2), and yoga therapy (n = 2). Among them, systematic desensitization significantly improved anticipatory CINV as compared to that in the control group (nausea: risk ratio [RR] = 0.60, 95% confidence interval [CI] = 0.49-0.72, p < 0.00001; vomiting: RR = 0.54, 95% CI = 0.32-0.91, p = 0.02). However, heterogeneity in outcome measures precluded meta-analysis for hypnotherapy and yoga. Additionally, most selected studies had a high or unclear risk of bias, and adverse events were not consistently reported. Our findings suggest that systematic desensitization may effectively reduce anticipatory CINV. However, further research is warranted before implementation in clinical settings.

Effect of Music Therapy on Chemotherapy Anticipatory Symptoms in Adolescents: A Mixed Methods Study

IntroductionThis study explores the feasibility and effects of music therapy on anticipatory nausea and vomiting, stress, pain and quality of life in adolescents undergoing chemotherapy. MethodsThis is a single group, quasi-experimental study using pre/post-test design. Participants received four individual sessions of music therapy (MT), led by a certified music therapist. State-Trait-Anxiety Inventory Y-1, and a 0-4 Likert scale for pain, nausea and vomiting were recorded. Heart rate variability (LF/HF) was collected during sessions. PedsQL was collected before and at the end of the trial. Semi-structured interviews were conducted with participants. ResultsA significant reduction in anxiety, nausea and vomiting, both pre-post single sessions and between different sessions, was observed. A significant increase in LF/HF and PedsQL scores was observed. Relevant themes also emerged from interviews. ConclusionResults support the feasibility of introducing music therapy with adolescents undergoing chemotherapy. Perceived stress and psychological/physical wellbeing were improved in participants.

Effects of immersive virtual reality for alleviating anxiety, nausea and vomiting among patients with paediatric cancer receiving their first chemotherapy: protocol for a randomised controlled trial

IntroductionAnxiety, nausea and vomiting are common side effects suffered by paediatric patients receiving chemotherapy. Emerging evidence supports the efficacy of immersive virtual reality (IVR) on improving anxiety and distress symptoms...

Improving Waiting Time for Chemotherapy with Ahead-of-Time Drug Preparation.

Waiting time for chemotherapy infusion is a fundamental factor to measure quality of care. It has been shown that a prolonged waiting time is related to a higher incidence of anticipatory nausea and poor patient adherence to scheduled appointments and recommended oncology treatment programs. Some chemotherapy regimens can be prepared hours ahead-of-time, due to long stability. We aimed to study the effect of an informatic-led workflow redesign intervention, facilitating workflow changes in the Oncology Pharmacy, on patient waiting time. This intervention included changes on EHR processes and the chemotherapy CPOE. Their main effect was allowing ahead-of-time preparation of selected chemotherapy regimes. We conducted a cross sectional study, comparing waiting times pre and post intervention periods. A total of 4600 programmed chemotherapy episodes were included. We found a 26.5 % decrease in the mean wait time in the post intervention period (p > 0.02). We were able to show a decrease in waiting time and a measurable impact of the intervention. This evaluation produced valuable and actionable data for Oncology units and adds a valuable, Latin American experience to the literature.

Prevalence of anticipatory nausea and vomiting in breast cancer patients undergoing highly emetogenic chemotherapy.

Anticipatory nausea and vomiting are unpleasant symptoms observed before undergoing chemotherapy sessions. Less is known about the occurrence of symptoms since the advent of the new neurokinin-1 antagonist. This prospective cohort study was performed at a single Brazilian Institution. This study included breast cancer patients who received doxorubicin and cyclophosphamide chemotherapy and an appropriate antiemetic regimen (dexamethasone 10 mg, palonosetron 0.56 mg, and netupitant 300 mg in the D1 followed by dexamethasone 10 mg 12/12 h in D2 and D4). Patients used a diary to record nausea, vomiting, and use of rescue medication in the first two cycles of treatment. The prevalence of anticipatory nausea and vomiting was assessed before chemotherapy on day 1 of C2. From August 4, 2020, to August 12, 2021, 60 patients were screened, and 52 patients were enrolled. The mean age was 50.8 (28-69) years, most had stage III (53.8%), and most received chemotherapy with curative intent (94%). During the first cycle, the frequency of overall nausea and vomiting was 67.31%, and that of severe nausea and vomiting (defined as grade>4 on a 10-point visual scale or use of rescue medication) was 55.77%. Ten patients had anticipatory nausea and vomiting (19.23%). The occurrence of nausea and vomiting during C1 was the only statistically significant predictor of anticipatory nausea and vomiting (OR=16, 95%CI 2.4-670.9, p=0.0003). The prevalence of anticipatory nausea is still high in the era of neurokinin-1 antagonists, and failure of antiemetic control in C1 remains the main risk factor. All efforts should be made to control chemotherapy-induced nausea or nausea and vomiting on C1 to avoid anticipatory nausea.

Lipopolysaccharide (LPS) attenuates the primary conditioning of lithium chloride (LiCl)-induced context aversion but not the secondary conditioning of context aversion or taste avoidance

A first-order association can be formed between toxin-induced nausea and a context, as well as nausea and a taste cue. However, comparatively little is understood about second-order associations. The present study examined if the bacterial endotoxin, LPS, could impair the first- and second-order conditioning of context aversion (anticipatory nausea paradigm) and subsequent conditioned taste avoidance (two-bottle task). Adult male Long Evans rats were treated with LiCl (127 mg/kg, intraperitoneal [i.p.]) or vehicle control (NaCl) and then exposed to a distinct context for 4 first-order conditioning trials. LPS (200 μg/kg, i.p.) or NaCl were administered 24 h after each trial. Seventy-two h after the final first-order conditioning trial, rats underwent 2 second-order conditioning trials where they were treated with 2% saccharin (i.p.) and then exposed to the same context. Twenty-four h after the final second-order conditioning trial, rats were tested in a two-bottle task (2 trials), where they were given a choice between water and a palatable 0.2% saccharin solution. LiCl-treated rats demonstrated a context aversion by the 3rd conditioning trial in the anticipatory nausea paradigm. Rats previously exposed to LiCl also displayed a conditioned taste avoidance of saccharin within the two-bottle task. LPS attenuated first-order context aversion but did not alter either second-order context aversion or conditioned taste avoidance in the two-bottle task. This study demonstrated that a secondary association formed within an aversive context could result in a conditioned taste avoidance. Further, LPS may be able to attenuate primary conditioning, but not secondary conditioning.

Effects of Oral Cryotherapy on Anticipatory, and Acute Nausea and Vomiting in Patients With Breast Cancer Undergoing Adjuvant Chemotherapy: A Randomized Controlled Clinical Trial

PurposeTo determine the effects of oral cryotherapy (OC) on the anticipatory, and acute nausea and vomiting of patients with breast cancer who are receiving adjuvant chemotherapy. Patients and MethodsSeventy eligible patients with breast cancer were assigned to 2 groups by stratified randomization. This parallel grouped, randomized, clinical trial used the ice application protocol. OC application for an intervention group (IG, n = 35) was performed in 3 stages: i) instructions on by the investigator at the hospital; ii) the implementation accompanied by the investigator at the hospital; iii) the individual application of at home by patients. The IG had been doing the application for 12 weeks. The patients in the control group (CG, n = 35) received standard care. Additionally, Rhodes Index of Nausea Vomiting, and Retching, and EORTC QLQ-C30 Life Quality Index were conducted on the first (T1 = cycle 1 day 0), second (T2 = cycle 2 day 21), third (T3 = cycle 3 day 42), and fourth (T4 = cycle 4 day 63) cycles of adjuvant chemotherapy. ResultsThe anticipatory nausea scores in the T2 and T4, IG were significantly lower than the CG (P < .05). In the T3, all symptom sub-dimensions except symptom occurrence (t = -0,48; P = .63) of the IG were significantly lower than those of the CG (P < .05). In the T1, T2, T3, and T4, acute nausea, acute vomiting, acute retching, and anticipatory retching scores, were significantly lower than the CG (P < .05). ConclusionOC alone was effective and safe for the treatment of nausea and vomiting. The results of this study showed the clinical applicability of OC in the management of nausea and vomiting.

Surge of Midazolam Use in the Midst of Lorazepam Shortage.

Lorazepam is a widely prescribed benzodiazepine that is used to manage anxiety, insomnia, and status epilepticus and is used for pre-anesthetic care as well as several off-label indications including aggression, alcohol withdrawal, panic disorder, chemotherapy-associated anticipatory nausea, and catatonia. Recent increases in demand, manufacturing changes, and quality control issues have resulted in a shortage of injectable and oral lorazepam, prompting clinicians to use alternatives. One such alternative is midazolam, a drug that has been used primarily in the intensive care unit and anesthesia settings. This article examines the significant pharmacologic differences between lorazepam and midazolam. In addition, this article provides dosage guidelines based on the current scientific knowledge and recommendations for conversion equivalencies. The clinical preference for lorazepam can be attributed to its simpler metabolism with no active metabolites, better suitability for patients with less severe hepatic and renal impairment, less risk of adverse reactions, fewer drug-drug interactions, and greater desirability for special populations. In periods of shortages, midazolam has been shown to be effective for a number of off-label uses. To manage conditions that have not been extensively studied, clinicians may opt to use conversion equivalencies, with the caveat that guidelines may vary greatly between institutions and online sources; therefore, it would be best to start low and titrate slowly. Our goal is to aid clinicians in safely and effectively prescribing midazolam during the shortage of injectable lorazepam so that patients are provided the same effects and benefits.

A deep learning-based interpretable decision tool for predicting high risk of chemotherapy-induced nausea and vomiting in cancer patients prescribed highly emetogenic chemotherapy.

This study aims to develop a risk prediction model for chemotherapy-induced nausea and vomiting (CINV) in cancer patients receiving highly emetogenic chemotherapy (HEC) and identify the variables that have the most significant impact on prediction. Data from Tianjin Medical University General Hospital were collected and subjected to stepwise data preprocessing. Deep learning algorithms, including deep forest, and typical machine learning algorithms such as support vector machine (SVM), categorical boosting (CatBoost), random forest, decision tree, and neural network were used to develop the prediction model. After training the model and conducting hyperparameter optimization (HPO) through cross-validation in the training set, the performance was evaluated using the test set. Shapley additive explanations (SHAP), partial dependence plot (PDP), and Local Interpretable Model-Agnostic Explanations (LIME) techniques were employed to explain the optimal model. Model performance was assessed using AUC, F1 score, accuracy, specificity, sensitivity, and Brier score. The deep forest model exhibited good discrimination, outperforming typical machine learning models, with an AUC of 0.850 (95%CI, 0.780-0.919), an F1 score of 0.757, an accuracy of 0.852, a specificity of 0.863, a sensitivity of 0.784, and a Brier score of 0.082. The top five important features in the model were creatinine clearance (Ccr), age, gender, anticipatory nausea and vomiting, and antiemetic regimen. Among these, Ccr had the most significant predictive value. The risk of CINV decreased with increased Ccr and age, while it was higher in the presence of anticipatory nausea and vomiting, female gender, and non-standard antiemetic regimen. The deep forest model demonstrated good discrimination in predicting the risk of CINV in cancer patients prescribed HEC. Kidney function, as represented by Ccr, played a crucial role in the model's prediction. The clinical application of this predictive tool can help assess individual risks and improve patient care by proactively optimizing the use of antiemetics in cancer patients receiving HEC.

Genetic and environmental influences on one-trial conditioned context aversion in mice.

Anticipatory nausea (AN) is caused by an association between contextual cues and the experience of nausea (the side effects of chemotherapy or radiation treatment) and it develops predominantly in female patients undergoing chemotherapy. Preclinical studies in rodents show that the administration of an illness-inducing agent in the presence of novel contextual cues can cause conditioned context aversion (CCA) and this has been proposed to model AN. The literature also suggests that brief pre-exposure to a novel context prior to shock delivery is critical in the development of contextual fear conditioning in rodents (a phenomenon known as Immediate Shock Deficit), but this has not been assessed in CCA. The aim of present study was to develop a CCA paradigm to assess this in outbred (CD1) and inbred (C57BL/6J) mice and evaluate potential sex differences. The results revealed that a single conditioning trial in which a distinctive context was paired with LiCl-induced illness was sufficient to elicit a conditioned response in both female and male CD1 outbred mice, but not in C57BL/6J inbred mice. In addition, CCA was facilitated when animals had prior experience with the context. Finally, outbred female mice showed longer and more robust retention of CCA than male mice, which parallels clinical findings. The results indicate the importance of using CD1 outbred mice as an animal model of AN as well as examining sex differences in the CCA paradigm. Similar findings in humans encourage the future use of this novel CCA preclinical mouse model.

Immune activation attenuates memory acquisition and consolidation of conditioned disgust (anticipatory nausea) in rats

Anticipatory nausea is a classically conditioned response to cues (e.g. contexts) that have been previously paired with a nauseating stimulus, such as chemotherapy in humans. In rodents, anticipatory nausea can be modeled by pairing a novel context with lithium chloride (LiCl), which leads to conditioned disgust behaviours (such as gaping) when exposed to the context alone. Growing evidence suggests that selective immune activation attenuates various forms of learning and memory. The present study investigated the effects of the endotoxin lipopolysaccharide (LPS) on LiCl-induced anticipatory nausea across critical stages of associative memory including acquisition, consolidation, and extinction. Adult male Long Evans rats were subject to intraperitoneal (i.p.) LiCl (127 mg/kg) or vehicle control (NaCl) paired with a 30 min conditioning trial in a distinct context for a total of 4 trials. To study acquisition, rats were administered either LPS or NaCl (200 μg/kg, i.p.) 90 mins before the conditioning trials. To study consolidation, different rats were administered either LPS or NaCl (200 μg/kg, i.p.) immediately after the conditioning trials. These trials were followed by 4 drug-free extinction trials within the same context. LPS significantly reduced conditioned gaping behaviours by the 4th conditioning trial and on the 1st drug-free extinction trial when administered 90 mins before or immediately after the conditioning trials. LPS had no significant effect on extinction. The present study provides strong evidence for the attenuating effects of LPS exposure on the acquisition and consolidation of LiCl-induced anticipatory nausea.

Abstract C048: Benzodiazepines modify the pancreatic ductal adenocarcinoma tumor microenvironment

Abstract Benzodiazepines (BZDs) are a class of drugs commonly prescribed to pancreatic ductal adenocarcinoma (PDAC) patients to treat anxiety, anticipatory nausea prior to chemotherapy, and insomnia. We discovered that approximately 1 in 4 pancreatic cancer patients are prescribed BZDs and that significant differences in survival outcomes are associated with the type of BZD prescribed. Lorazepam is associated with poorer recurrence-free survival (HR 3.83 (1.53,9.57)) while alprazolam is associated with improved recurrence-free survival (HR 0.38 (0.16,0.92)). We hypothesize that these differences in survival result from off-target activation of the proton-sensing GPCR, GPR68, by n-unsubstituted BZDs, such as lorazepam. GPR68 is preferentially expressed in PDAC cancer-associated fibroblasts (CAFs). We found that n-unsubstituted BZDs commonly prescribed to PDAC patients potentiate activation of GPR68 in the presence of acidity, subsequently promoting secretion of IL-6 by CAFs in a GPR68-dependent manner. Conversely, we found that n-substituted BZDs, such as alprazolam, decrease IL-6 secretion by CAFs in a GPR68-independent manner. Using a syngeneic KPC transplant model, we found that tumors from mice treated with lorazepam had increased expression of inflammatory signaling pathways and ECM-related genes by RNA sequencing. Histologically, lorazepam-treated tumors had increased levels of collagen, alpha-smooth muscle actin staining, and high levels of ischemic necrosis in the centers of the tumors. Overall, these findings indicate that benzodiazepines can modify the PDAC tumor microenvironment, which may subsequently impact chemotherapeutic efficacy and patient survival. Citation Format: Abigail C. Cornwell, Abdulrahman A. Alahmari, Arwen A. Tisdale, Kathryn Maraszek, Swati Venkat, Michael E. Feigin. Benzodiazepines modify the pancreatic ductal adenocarcinoma tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C048.

Central correlates of placebo effects in nausea differ between men and women.

IntroductionDespite growing evidence validating placebo effects in nausea, little is known about the underlying cortical mechanisms in women and men. Therefore, the present study examined sex differences and electroencephalography (EEG) characteristics of the placebo effect on nausea.MethodsOn 2 consecutive days, 90 healthy subjects (45 females) were exposed to a nauseating visual stimulus. Nausea was continuously rated on an 11‐point numeric rating scale, and 32 EEG channels were recorded. On day 2, subjects were randomly allocated to either placebo treatment or no treatment: the placebo group received sham acupuncture, whereas the control group did not receive any intervention.ResultsIn contrast to the control group, both sexes in the placebo group showed reduced signs for anticipatory nausea in the EEG, indexed by increased frontal lobe and anterior cingulate activity. Among women, the improvement in perceived nausea in the placebo group was accompanied by decreased activation in the parietal, frontal, and temporal lobes. In contrast, the placebo‐related improvement of perceived nausea in men was accompanied by increased activation in the limbic and sublobar (insular) lobes.ConclusionActivation of the parietal lobe in women during the placebo intervention may reflect altered afferent activity from gastric mechanoreceptors during nausea‐induced tachyarrhythmia, whereas in men, altered interoceptive signals in the insular cortex might play a role. Thus, the results suggest different cerebral mechanisms underlying the placebo effects in men and women, which could have implications for the treatment of nausea.

Prevalence of antecipatory nausea and vomiting in cancer patients exposed to highly emetogenic chemotherapy.

e24112 Background: Anticipatory nausea (AN) and vomiting are unpleasant symptoms observed in anticipation of chemotherapy regimens. It is best described as a learned response through classical conditioning when one or more distinctive features of the chemotherapy clinic (conditioned stimuli) associated with the administration of emetogenic chemotherapy (unconditioned stimuli) trigger the emetogenic reflex. Little is known about AN's occurrence after the advent of the new neurokinin-1 antagonist. This prospective study evaluated AN's prevalence in ambulatory breast cancer patients receiving high effective antiemetic prophylaxis and evaluated potential predictors of AN. Methods: This prospective observational study was performed at a single Brazilian Institution. Key inclusion criteria were patients aged 18 years or older with breast cancer scheduled to receive anthracycline chemotherapy with an appropriate antiemetic regimen, including a neurokinin-1 receptor antagonist, a serotonin-3 receptor antagonist, and a corticosteroid. Eligible patients used a diary to record nausea, vomiting, and use of rescue medication in the first 2-cycle of treatment through 120 after infusion. AN was assessed before chemotherapy on day 1 of cycle two. We excluded patients with nausea and vomiting presented 24h before cycle one and patients who did not receive standard antiemetic prophylaxis. Results: Between August 04, 2020, and August 12, 2021, 60 patients were screened, and 52 patients were enrolled. The mean age was 50,8 (28 – 69), the majority had stage III (53,8%) and received chemotherapy with curative intent (94%). During cycle 1, the frequency of overall nausea and vomiting was 67.31%, and severe nausea and vomiting (defined as grade &gt; 4 at a 10-point visual scale or use of rescue medication) was 55.77%. Ten patients had AN (19.23%). The occurrence of nausea and vomiting during cycle one was the only statistically significant predictor of AN (OR = 16, 95% CI 2.4, 670.9, p-value = 0.0003). Conclusions: The prevalence of AN is still high in the era of neurokinin-1 antagonists, and failure of antiemetic control on cycle one remains the main risk factor. All efforts should be made to control chemotherapy-induced nausea or nausea and vomiting on cycle one to avoid AN. Clinical trial information: NCT04785495.

Male and female rats exhibit comparable gaping behavior but activate brain regions differently during expression of conditioned nausea.

Twenty-five to fifty percent of patients undergoing chemotherapy will develop anticipatory nausea and vomiting (ANV), in which symptoms occur in anticipation of treatment. ANV is triggered by environmental cues and shows little response to traditional antiemetic therapy, suggesting that unique neural pathways mediate this response. Understanding the underlying neural mechanisms of this disorder is critical to the development of novel therapeutic interventions. The purpose of the present study was to identify brain areas activated during ANV and characterize sex differences in both the behavior and the brain areas activated during ANV. We used a rat model of ANV by pairing a novel context with the emetic drug lithium chloride (LiCl) to produce conditioned nausea behaviors in the LiCl-paired environment. We quantitated gaping, an analog of human vomiting, after acute or repeated LiCl in a unique environment. To identify brain regions associated with gaping, we measured c-fos activation by immunochemical staining after these same treatments. We found that acute LiCl activated multiple brain regions including the supraoptic nucleus of the hypothalamus, central nucleus of the amygdala, nucleus of the solitary tract and area postrema, none of which were activated during ANV. ANV activated c-fos expression in the frontal cortex, insula and paraventricular nucleus of the hypothalamus of males but not females. These data suggest that therapies such as ondansetron which target the area postrema are not effective in ANV because it is not activated during the ANV response. Further studies aimed at characterizing the neural circuits and cell types that are activated in the conditioned nausea response will help identify novel therapeutic targets for the treatment of this condition, improving both quality of life and outcomes for patients undergoing chemotherapy.

Effects of auricular acupressure on chemotherapy-induced nausea and vomiting in breast cancer patients: a preliminary randomized controlled trial

BackgroundAuricular acupressure (AA) has been viewed as a promising approach to managing chemotherapy-induced nausea and vomiting (CINV) but relevant research evidence has been inconclusive. This study aimed to examine the effects of AA on CINV in breast cancer (BC) patients undergoing chemotherapy.MethodsA preliminary randomized controlled trial was conducted in 114 BC patients. Participants were randomly allocated to a true AA group (n = 38), a sham AA group (n = 38), and a standard care group (n = 38). All the participants were provided with standard antiemetic treatment and care, while the true AA group and the sham AA group received an additional 5-day true AA and a 5-day sham AA, respectively. Acute and delayed CINV were assessed by using the MASCC Antiemesis Tool (MAT), anticipatory nausea and vomiting were measured by the Index of Nausea, Vomiting, and Retching (INVR), and patients’ quality of life (QoL) was evaluated by the Functional Assessment of Cancer Therapy-Breast (FACT-B).ResultsBoth the true and sham AA groups reported improved CINV outcomes than the standard care group, with the true AA demonstrating larger effects than the sham comparison. The true and sham AA groups had higher complete response (CR) rates of CINV when compared with the standard care group, with the difference in the CR of acute CINV achieving statistical significance (p = 0.03). Both the true and sham AA groups demonstrated lower incidence and severity of acute CINV compared with the standard care group with the among-group difference reaching statistical significance for the occurrence (p = 0.04) and severity (p = 0.001) of acute nausea. No significant differences in anticipatory CINV and QoL were found among the groups.ConclusionThe use of AA plus standard antiemetic treatment and care was superior to the use of standard antiemetic treatment and care alone in managing CINV among BC patients receiving chemotherapy. The antiemetic effects of AA were identified to be more profound in improving acute CINV, particularly acute nausea. The antiemetic effects of AA were deemed to be a mixture of specific treatment effects and placebo effects, and the placebo effects were very large and even reached clinical significance.Trial registrationClinicalTrials.gov; NCT02403037; Registered March 31, 2015.

Emetogenicity of Antibody-Drug Conjugates (ADCs) in Solid Tumors with a Focus on Trastuzumab Deruxtecan: Insights from an Italian Expert Panel.

Simple SummaryFour antibody-drug conjugates (ADCs) are approved for the treatment of solid tumors, improving the therapeutic index. Despite their high selectivity, nausea and vomiting are the most frequently observed side effects. A deeper understanding of the potential risk for nausea and vomiting is crucial, as they can affect patients’ quality of life and treatment adherence. Prophylaxis with the potential combination of antiemetic therapy with complementary non-pharmacological approaches are even more important, considering that ADC therapies are generally given continuously until disease progression or the occurrence of toxicities.In the past decade, nine antibody-drug conjugates (ADCs) have been approved for the treatment of various tumors, four of which specifically for solid malignancies. ADCs deliver the cytotoxic payload to the cancer site, thereby improving chemotherapy efficacy while reducing systemic drug exposure and toxicity. With their high selectivity, ADCs are associated with a manageable side-effect profile, with nausea and vomiting being among the most frequent toxicities, although this may vary according to the respective ADC and the associated payload. Information about the emetic risk of the new ADC compounds is limited. Three virtual focus groups of Italian oncologists were held to raise awareness on the importance of an antiemetic prophylaxis regimen to prevent and mitigate ADC-associated emesis and its sequelae. After reviewing published evidence and guidelines, the three expert panels shared their experience on the early use of ADCs gained through the participation in specific clinical trials and their clinical practice. The following issues were discussed: antiemetic therapy during trastuzumab deruxtecan treatment, with a protocol adopted at the San Raffaele Hospital (Milan, Italy); the use of steroids; the management of anticipatory nausea during trastuzumab deruxtecan therapy; nutritional counselling; and effective doctor–patient communication. The experts acknowledged that recommendations should be drug-specific, and formulated opinion-based advice intended to guide physicians in their daily practice until further evidence emerges.

Abstract PO-100: Lorazepam promotes desmoplasia and ischemic necrosis in murine pancreatic ductal adenocarcinoma

Abstract The goal of this research is to identify the effect of the GPR68-activator benzodiazepine (BZD) lorazepam on the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment (TME). BZDs are commonly prescribed to PDA patients to treat anxiety and anticipatory nausea prior to chemotherapy. Certain types of BZDs are known to promote off-target activation of GPR68 under acidic conditions. We hypothesize that GPR68-activating BZDs will stimulate pro-fibrotic and pro-inflammatory signaling pathways by cancer-associated fibroblasts (CAFs), producing a more desmoplastic TME that will subsequently constrict the tumor vasculature, decreasing chemotherapeutic efficacy, and ultimately decreasing patient survival. Using a subcutaneous KPC allograft mouse model, we found that lorazepam modified the TME by significantly increasing α-SMA (smooth muscle actin) protein expression, collagen deposition, and ischemic necrosis. Preliminary, we found that treating tumor-bearing KPC mice with lorazepam similarly promoted ischemic necrosis. RNA sequencing of the lorazepam-treated allograft tumors indicated that CAF and ECM-related genes such as PDPN, LOX, SERPINB2, and ITGA11 were significantly upregulated. Pathway analysis revealed that lorazepam treatment promoted pathways related to inflammation, EMT, hypoxia, as well as known GPR68 downstream signaling pathways such as TNF-alpha signaling via NF-kB and IL6/JAK/STAT3 signaling. qRT-PCR of immortalized CAFs treated with lorazepam indicated that IL6 expression is increased by lorazepam in a GPR68-dependent manner at acidic pH, supporting that the promotion of IL6 expression we observed in vivo was likely GPR68 and CAF-dependent. To validate the clinical significance of our work, covariate adjusted analyses of pancreatic cancer patients who received chemotherapy at Roswell Park from 2004-2020 was performed. Patients taking GPR68 activator benzodiazepines versus non-activator benzodiazepines had poorer progression-free survival (HR 6.85(2.12,22.06)), suggesting that GPR68 activation by benzodiazepines may negatively impact survival. Overall, these findings suggest that lorazepam significantly modifies the PDA TME by promoting desmoplasia and ischemic necrosis, due in part to activation of GPR68. Future experimental work will determine if lorazepam negatively impacts survival and chemotherapeutic efficacy. Significance: This research may guide the development of new clinical recommendations for prescribing benzodiazepines to PDA patients, which will likely be applicable to other cancer types. Citation Format: Abigail C. Cornwell, Abdulrahman A. Alahmari, Arwen A. Tisdale, Kathryn Maraszek, Swati Venkat, Michael E. Feigin. Lorazepam promotes desmoplasia and ischemic necrosis in murine pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-100.

Effects of immersive virtual reality for preventing and managing anxiety, nausea and vomiting among paediatric cancer patients receiving their first chemotherapy: A study protocol for an exploratory trial.

BackgroundAnxiety, nausea and vomiting are common side effects suffered by paediatric patients receiving chemotherapy. Emerging evidence supports the efficacy of immersive virtual reality (IVR) on improving anxiety and distress symptoms including nausea and vomiting among this vulnerable group. This trial aims to assess the feasibility and acceptability of IVR for preventing and managing anxiety, nausea and vomiting among paediatric cancer patients receiving their first chemotherapy.Method and analysisAn exploratory trial supplemented by qualitative methods will be conducted. We will recruit 20 paediatric patients who are aged between 6 and 12 years, chemotherapy naïve, scheduled to receive their first intravenous chemotherapy and able to understand Chinese. Participants will be randomly allocated to intervention or control groups. The intervention group will receive the IVR intervention for three sessions as follows: 4 hours before chemotherapy, 5 minutes before and during their first course chemotherapy and 5 minutes before and during their second course chemotherapy. The control group will receive standard care only. Main outcome measures included (1) key parameters for the design of a definitive trial (i.e. screening, eligibility, consent and withdrawal rates); (2) anxiety, anticipatory and acute chemotherapy-induced nausea and vomiting for collection of preliminary data; (3) feasibility and acceptability of the intervention. Semi-structured interviews will be conducted with patients, parents and oncology nurses. Generalized estimating equations model will be used to compare each of the outcome measures across the time points between the two groups. Qualitative data will be analysed by conventional content analysis.Expected resultsThe results of this exploratory trial will inform the design and conduct of future definitive trial.Trial registration number ChiCTR1900021694; Pre-results.