Vomiting Events Research Articles

Pooled analysis on characteristics of nausea and vomiting in patients receiving trastuzumab deruxtecan (T-DXd) in clinical studies.

12118 Background: The efficacy and safety profile of T-DXd has been established in patients (pts) with various tumor types, and nausea and vomiting are the most common treatment-emergent adverse events (TEAEs). T-DXd study protocols were refined over time to recommend prophylaxis (eg, neurokinin or serotonin receptor antagonists and/or steroids) before T-DXd treatment, in line with antiemetic and institutional guidelines. We conducted a pooled, post hoc analysis capturing safety information across tumor types; we report results on nausea and vomiting. While this analysis was not designed to assess antiemetic effectiveness, it reveals the incidence of nausea and vomiting in clinical trials of T-DXd 5.4 mg/kg in more detail across a large dataset. Methods: 1449 pts treated with ≥1 dose of 5.4 mg/kg T-DXd (every 3 wks) were included from 7 phase 1-3 clinical trials in metastatic HER2+ and HER2-low breast cancer, HER2+ gastric cancer, and HER2-mutant non–small cell lung cancer (DESTINY-Breast01, -Breast02, -Breast03, -Breast04, -Lung01, -Lung02, and the first-in-human phase 1 study J101 in multiple tumor types; study enrollment starting 2015-2021). Regardless of antiemetic use (including prophylaxis), the incidence, severity, time to onset, and duration of nausea and vomiting TEAEs were assessed along with event outcomes. Results: Of 1449 pts receiving T-DXd 5.4 mg/kg (median [range] number of 3-wk treatment cycles: 13 [1-60]), 74.6% (n=1081) experienced nausea, and 41.6% (n=603) reported vomiting. Most pts had grade 1/2 nausea (41.2%/27.6%) and/or vomiting (26.2%/12.8%). Grade 3 TEAEs of nausea were reported in 5.8% of pts, with grade ≥3 TEAEs of vomiting observed in 2.6% of pts. By the data cutoff for each trial, 66.9% of pts with nausea and 87.6% with vomiting had their symptoms resolve. Most pts who experienced nausea and vomiting did so during the initial 21 days (cycle 1; n=879 [81.3%] and 336 [55.7%], respectively; 35.8% of all pts received antiemetic prophylaxis at cycle 1); both TEAEs declined notably in subsequent cycles. Rates of drug discontinuation, dose reduction, and drug interruption due to nausea and vomiting were generally low (Table). Conclusions: Most nausea and vomiting events were reported during the first 3 wks of treatment and resolved. Appropriate prophylaxis of nausea and vomiting is a key management strategy and allows pts to benefit from longer treatment durations with T-DXd. Ongoing studies are exploring the implementation and impact of prophylaxis for T-DXd–related emesis. Clinical trial information: NCT03248492 , NCT03523585 , NCT03529110 , NCT03734029 , NCT03505710 , NCT04644237 , NCT02564900 . [Table: see text]

Terapi Komplementer Akupresur Menurunkan Gejala Emesis Gravidarum Pada Ibu Hamil

During pregnancy, nausea and vomiting become serious problems, especially reaching extreme levels called emesis gravidarum. Pregnant women try to overcome this problem by using medicines or complementary therapies such as acupressure. This research aims to evaluate the effectiveness of complementary acupressure therapy in reducing the symptoms of emesis gravidarum in pregnant women. A study involving 40 pregnant women, of which 20 experienced significant symptoms, used acupressure techniques at pericardium point 6 to relieve symptoms of nausea and vomiting during the early trimester of pregnancy. This research used quasi-experimental methods (pre-test and post-test) and collected data through questionnaires RINVR and observations at Posyandu Mattirotappareng 1, Tempe District, Wajo Regency, South Sulawesi Province. The results showed a significant difference in the frequency of nausea and vomiting before and after acupressure therapy. After undergoing therapy, there was a significant reduction in the average number of nausea and vomiting events per day, decreasing from 9.0 to 5.2 times. The p-value < 0.05 indicates that acupressure therapy has a significant impact in reducing the frequency of nausea and vomiting in pregnant women. Therefore, the use of acupressure therapy at pericardium point 6 as a non-pharmacological treatment option is effective in reducing symptoms in pregnant women during the early trimester of pregnancy.

Practical Applications of a Nausea and Vomiting Model in the Clinical Development of Additional Doses of Dulaglutide.

Dulaglutide 3.0 and 4.5 mg weekly doses were approved for additional glycemic control in adult patients with type 2 diabetes inadequately controlled with metformin and 0.75 or 1.5 mg weekly doses of dulaglutide. Effects such as nausea and vomiting are commonly reported with dulaglutide and other glucagon-like peptide-1 receptor agonist therapies. Based on a pharmacokinetic/pharmacodynamic model-informed approach, a stepwise dose-escalation scheme with 4-week intervals between dose increments was suggested to mitigate gastrointestinal events for dulaglutide. These gastrointestinal events are dose dependent and attenuate over time with repeated dosing. A Markov chain Monte Carlo pharmacokinetic/pharmacodynamic joint model was developed using AWARD-11 data (N = 1842) to optimize dulaglutide dose escalation to 3.0 and 4.5 mg to mitigate gastrointestinal events. Model simulations evaluated probabilities of nausea and vomiting events for various dosing scenarios in patients needing higher doses for additional glycemic control. The model indicated that patients may dose escalate from 1.5 to 3.0 mg, then 4.5 mg weekly after at least 4 weeks on each dose. No clinically meaningful differences in nausea or vomiting events were expected when patients escalated to 3.0 or 4.5 mg following initiation at 0.75 or 1.5 mg dulaglutide. Based on the findings of this model, a minimum 4-week duration at each dose before escalation was appropriate to reduce gastrointestinal events of dulaglutide, consistent with observed gastrointestinal events data from the AWARD-11 study and supporting the currently recommended dose-escalation regimen of dulaglutide doses of 3.0 and 4.5mg for additional glycemic control.

Post-marketing safety surveillance of the rotavirus vaccine in India

BackgroundROTASIIL, an oral live attenuated bovine-human reassortant pentavalent rotavirus vaccine, was approved in 2017. This post-marketing surveillance (PMS) was conducted to collect real-world data on the safety of ROTASIIL in India. MethodsObservational, active PMS was conducted in approximately 10,000 infants aged ≥ 6 weeks. ROTASIIL was administered as a 3-dose regimen, at least 4 weeks apart, beginning at ≥ 6 weeks of age concomitantly with other Expanded Programme on Immunization (EPI) vaccines. Participants were followed for one month after the last dose. The adverse events (AEs) and serious adverse events (SAEs), including intussusception (IS) reported during the follow up period were collected. FindingsA total of 9940 infants were enrolled and were considered for safety analysis. Around 9913 (99.7 %) infants received 2 doses, while 9893 (99.5 %) infants completed all three doses. Total 3693 AEs were reported in 2516 (25.3 %) participants. Most of these AEs were pyrexia (78.01 % of events) and injection-site reactions (19.14 % of events). Nearly all AEs were causally unrelated to orally administered ROTASIIL and could be caused by the concomitant injectable vaccines. Only 4 AEs (2 events of vomiting and 1 event each of discomfort and pyrexia) in 4 (<0.1 %) participants could be related to ROTASIIL. AEs were of mild or moderate severity and all resolved without any sequelae. A total of 2 SAEs (acute otitis media and skull fracture) were reported in 2 (<0.1 %) participants and were not related to ROTASIIL and recovered without sequelae. No case of IS was reported. InterpretationROTASIIL was safe and well tolerated in this study. No safety concerns were reported. FundingThe study was funded by SIIPL which is the manufacturer of the study product.

Relationship between preoperative fluid therapy and the occurrence of nausea and vomiting in post-spinal anesthetic patients

Background: Spinal anesthesia can cause a significant decrease in blood pressure and increased vagal tone, leading to bradycardia, nausea, and vomiting. To mitigate the risk of nausea and vomiting, it is important to provide appropriate fluid therapy during fasting or anesthesia. Objective: This study aims to determine the relationship between preoperative fluid therapy and the occurrence of nausea and vomiting events in post-spinal anesthetic patients at Dr. Saiful Anwar Hospital, Malang. Methods: This research employed an observational analytic design with a cross-sectional approach. A purposive sampling technique was used, and 50 respondents were selected. The research instrument included the Rhodes Index of Nausea, Vomiting, and Retching (RINVR) observation sheet and fluid calculation formulas. The statistical test employed was Spearman’s rho with a 95% confidence interval (CI) or a significant level value (?) of 0.05. Results: The results showed that 52% of respondents did not experience nausea and vomiting, 44% experienced mild nausea and vomiting, and 4% experienced moderate nausea and vomiting. The Spearman Rank statistical test yielded a p-value of &lt; 0.0001. Conclusions: In conclusion, there was a significant relationship between preoperative fluid therapy and the incidence of nausea and vomiting in post-spinal anesthesia patients. Therefore, administering adequate fluids before spinal anesthesia can reduce the risk of complications, such as nausea and vomiting, associated with spinal anesthesia.

Real-World Treatment Outcomes, Healthcare Resource Use, and Costs Associated with Antiemetics Among Cancer Patients on Cisplatin-Based Chemotherapy.

Chemotherapy-induced nausea and vomiting (CINV) is a recognized adverse outcome among patients with cancer. This retrospective study aimed to quantify the treatment outcomes, resource utilization, and costs associated with antiemetic use to prevent CINV in a broad US population who received cisplatin-based chemotherapy. Data from the STATinMED RWD Insights Database was collected from January1, 2015 to December31, 2020. Cohorts included any patients that had at least one claim for fosnetupitant + palonosetron (NEPA) or fosaprepitant + palonosetron (APPA) and evidence of initiating cisplatin-based chemotherapy. Logistic regression was used to evaluate nausea and vomiting visits within 14days after chemotherapy, and generalized linear models were used to examine all-cause and CINV-related healthcare resource utilization (HCRU) and costs. NEPA was associated with significantly lower rates of nausea and vomiting visits after chemotherapy (p = 0.0001), including 86% greater odds of nausea and vomiting events for APPA during the second week after chemotherapy (odds ratio [OR] = 1.86; p = 0.0003). The mean numbers of all-cause inpatient visits (p = 0.0195) and CINV-related inpatient and outpatient visits were lower among NEPA patients (p < 0.0001). These differences corresponded to 57% of NEPA patients and 67% of APPA patients having one or more inpatient visits (p = 0.0002). All-cause outpatient costs and CINV-related inpatient costs were also significantly lower for NEPA (p < 0.0001). The mean number of all-cause outpatient visits, all-cause inpatient costs, and CINV-related outpatient costs was not significantly different between groups (p > 0.05). In this retrospective study based on claims data, NEPA was associated with lower rates of nausea and vomiting and lower CINV-related HCRU and costs compared to APPA following cisplatin-based chemotherapy. These results complement clinical trial data and published economic models supporting the use of NEPA as a safe, effective, and cost-saving antiemetic for patients undergoing chemotherapy.

Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) unresectable and/or metastatic breast cancer (mBC): Safety follow-up of the randomized, phase 3 study DESTINY-Breast03.

1000 Background: In the DESTINY-Breast03 (NCT03529110) primary analysis (data cutoff [DCO], May 21, 2021), T-DXd showed superiority over T-DM1 in pts with HER2+ mBC, with a significant improvement of progression-free survival by blinded independent central review (HR, 0.284; 95% CI, 0.217-0.373; P &lt; 0.001), and a safety profile consistent with prior studies. This analysis provides updated safety data with longer follow-up. Methods: Pts were randomized 1:1 to T-DXd or T-DM1. Prespecified safety analysis of treatment-emergent adverse events (TEAEs) was conducted; endpoints included time to event, duration of event, and resolution. Results: At DCO (September 7, 2021), 116 (45.1%) pts vs 39 (14.9%) pts remained on treatment in the T-DXd vs T-DM1 arms; median treatment duration was 16.1 mo (range, 0.7-33.0) for T-DXd vs 6.9 mo (range, 0.7-28.5) for T-DM1. Any-grade (G), G≥3, and serious AE (SAE) rates were similar for T-DXd vs T-DM1 (99.6% vs 95.4%; 53.3% vs 49.8%; and 21.0% vs 19.2%), while exposure-adjusted incidence rates (EAIRs; per pt-year) for G≥3 and SAEs were lower for T-DXd vs T-DM1 (0.42 vs 0.70 and 0.17 vs 0.27). Median time to TEAE associated with drug discontinuation or dose reduction was longer with T-DXd vs T-DM1 (224.0 vs 147.0 d and 96.0 v 19.0 d, respectively). Most TEAEs in ≥20% of pts were hematologic or gastrointestinal. Median time to first onset of select any-G TEAEs was 70.0 vs 42.0 d for anemia, 196.0 vs 168.0 d for lymphopenia, 132.0 vs 8.0 d for thrombocytopenia, 22.0 vs 24.0 d for fatigue, 74.5 vs 92.0 d for leukopenia, and 64.0 vs 105.0 d for neutropenia, with T-DXd vs T-DM1, respectively. In both arms, most nausea and vomiting events were G1/2; while G≥3 events with T-DXd vs T-DM1 were 6.6% vs 0.4% for nausea and 1.6% vs 0.8% for vomiting, respectively. Rates of nausea, vomiting, and alopecia were highest in cycle 1 and lower in subsequent cycles for T-DXd. Rates of hematologic events were generally lower in earlier cycles vs cycle ≥8 in both arms. Rates of adjudicated, drug-related ILD/pneumonitis were 10.9% (1 G2 event since previous DCO) with T-DXd vs 1.9% with T-DM1, with no G4/5 events. Median time to first adjudicated, drug-related ILD/pneumonitis event was 5.9 vs 9.5 mo for T-DXd vs T-DM1, respectively; at DCO, most events resolved (57.1% vs 80.0%), and follow-up is ongoing. Conclusions: In this updated safety analysis, T-DXd demonstrated a tolerable safety profile consistent with prior studies. Despite longer treatment duration with T-DXd, EAIRs of G≥3 and SAEs were lower for T-DXd vs T-DM1. Rates of ILD/pneumonitis for T-DXd were similar to those in the previous DCO. Nausea, vomiting, and alopecia rates decreased over time. This longer safety update reinforces the consistent safety profile of T-DXd, supporting the clinical benefit of T-DXd over T-DM1 in patients with HER2+ mBC. Clinical trial information: NCT03529110.

Chemotherapy-Associated nausea and vomiting: A cross-sectional survey of occurrence and management patterns at jos university teaching hospital, Nigeria.

Background:The management patterns for chemotherapy-associated nausea and vomiting (CANV) in Sub-Saharan African settings have not been previously reported. The objectives of this study were to describe the prescribing pattern of antiemetics for CANV, to assess their adherence to guidelines, and to determine the occurrence of CANV.Subjects and Methods:This was a cross-sectional study, with data extracted from the records of adult patients who received chemotherapy from 2015 to 2018 at Jos University Teaching Hospital, Nigeria. The National Comprehensive Cancer Network Harmonized Guidelines™ for Sub-Saharan Africa for Antiemesis Version 3.2018 was used to determine the extent of guideline adherence.Results:Records of 165 patients were analyzed. Majority of the patients (76.4%, n = 126) received moderate-to-high emetic risk intravenous (IV) chemotherapy. Out of 129 antiemetic prescriptions for acute-phase prophylaxis, ondansetron (75.2%), corticosteroids (61.2%), and promethazine (24.8%) were the most prescribed agents. In the delayed phase, 50 patients received prophylactic antiemetics in the order of corticosteroids, ondansetron, and promethazine at 74%, 34%, and 26%, respectively. Guideline adherence was low for the acute-phase (23.6%), delayed-phase (20.6%), and overall period (17.6%). Among inpatients (n = 85), occurrences of nausea were negligible, whereas acute vomiting (9%) and delayed vomiting (15%) levels were considerable. Not receiving highly emetogenic IV chemotherapy was associated with significantly lower odds for nausea or vomiting occurrence, odds ratio 0.228 (95% confidence interval 0.054–0.967).Conclusions:Antiemetic guideline adherence was low due to antiemetic under-prescribing. A few nausea and vomiting events were recorded predominantly among patients who received highly emetogenic IV chemotherapy.

Clinical Profiles of Childhood Astrovirus-, Sapovirus-, and Norovirus-Associated Acute Gastroenteritis in Pediatric Emergency Departments in Alberta, 2014-2018.

Infections by previously underdiagnosed viruses astrovirus and sapovirus are poorly characterized compared with norovirus, the most common cause of acute gastroenteritis. Children <18 years old with acute gastroenteritis were recruited from pediatric emergency departments in Alberta, Canada between 2014 and 2018. We described and compared the clinical course of acute gastroenteritis in children with astrovirus, sapovirus, and norovirus. Astrovirus was detected in 56 of 2688 (2.1%) children, sapovirus was detected in 146 of 2688 (5.4%) children, and norovirus was detected in 486 of 2688 (18.1%) children. At illness onset, ~60% of astrovirus cases experienced both diarrhea and vomiting. Among sapovirus and norovirus cases, 35% experienced diarrhea at onset and 80% of 91% (sapovirus/norovirus) vomited; however, diarrhea became more prevalent than vomiting at approximately day 4 of illness. Over the full course of illness, diarrhea was 18% (95% confidence interval [CI], 8%- 29%) more prevalent among children with astrovirus than norovirus infections and had longer duration with greater maximal events; there were a median of 4.0 fewer maximal vomiting events (95% CI, 2.0-5.0). Vomiting continued for a median of 24.8 hours longer (95% CI, 9.6-31.7) among children with sapovirus versus norovirus. Differences between these viruses were otherwise minimal. Sapovirus infections attended in the emergency department are more similar to norovirus than previously reported, whereas astrovirus infections have several distinguishable characteristics.

Tolerance and Pharmacokinetics of Galliprant™ Administered Orally to Collies Homozygous for MDR1‐1Δ

The objectives of the study were to evaluate the pharmacokinetics and tolerance of grapiprant, a substrate of the human P‐gp transporter, in collies homozygous for MDR1‐1Δ when administered at the labeled dosage of 2 mg/kg once daily for 28 days. Twelve collie dogs with homozygous for MDR1‐1Δ genotype from a commercial colony were used in the study, eight in the treated group and four as placebo‐treated controls. The only treatment‐related clinical sign was self‐limiting vomiting (in 2/8 treated animals) and the only treatment‐related clinical pathological changes seen were a slight decrease in serum albumin in one dog (2.6 g/dL; reference 2.7 to 3.9 g/dL) and total protein (5.1 g/dL; reference 5.5 to 7.7 g/dL). Absorption of grapiprant was rapid with a median Tmax of 1 h, Cmax of 5.2 μg/mL, AUC0‐24 of 17.3 ± 7.1 h*μg/mL and median terminal t½ of 4.3 h after the first dose. To determine whether MDR1‐1Δ animals handle grapiprant differently from normal dogs, a population pharmacokinetic analysis was performed utilizing data from the collies and historical beagle data. Volume of the peripheral compartment of collies was estimated to be 45% that of beagles, and clearance from the central compartment was 71% less in collies than in beagles. Self‐liming vomiting events occurred at a numerically higher rate (2/8; 25%) in this group of P‐gp‐deficient dogs than seen in a clinical study (17%) composed of various dog breeds but limited numbers in this PK study make comparisons difficult. Grapiprant was otherwise well tolerated in collies homozygous for MDR1‐1Δ despite increased drug exposure compared to dogs without this mutation.

Antiemetic prophylaxis with fosaprepitant and granisetron in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation

BackgroundChemotherapy-induced nausea and vomiting (CINV) is a severe and distressing complication during allogeneic hematopoietic stem cell transplantation (alloHSCT). The antiemetic fosaprepitant has shown favorable results in pediatric and adult patients receiving chemotherapy. Data on fosaprepitant in children and adolescents undergoing alloHSCT are missing.MethodsIn this non-interventional observation study, 120 children and adolescents with a median age of 11.8 years undergoing alloHSCT after a moderately or highly emetogenic conditioning (MEC or HEC) were analyzed. They received an antiemetic prophylaxis with granisetron (2 × 40 µg/kg d−1) with or without fosaprepitant (4 mg/kg; single dose, max. 1 × 150 mg/kg BW), and were analyzed in the control (CG; n = 60) or fosaprepitant group (FG; n = 60). The efficacy and safety of the two antiemetic prophylaxis regimens were analyzed and compared with respect to the acute (0–24 h) and the delayed (> 24–120 h) CINV phase and > 120–240 h after MEC or HEC administration.ResultsDuring MEC, significantly more patients in the CG experienced vomiting during the first 0–24 h (58.6 vs. 25.0%; p = 0.0156) and during > 24–120 h (93.1% vs. 57.1%; p = 0.0020), compared with the FG. Likewise, significantly more vomiting events (269 vs. 136; p < 0.0001) were registered in the CG. During HEC, significantly more patients in the CG experienced vomiting during the first 0–24 h (32.3 vs. 9.4%; p = 0.0319) compared with the FG. Significantly more vomiting events (241 vs. 99; p < 0.0001) were registered in the CG. Laboratory and clinical adverse events were not significantly different between the two groups (p > 0.05).ConclusionsAntiemetic prophylaxis with fosaprepitant and granisetron was well tolerated, safe, and effective in pediatric patients undergoing alloHSCT. However, larger prospective trials are necessary to evaluate these findings.

Efficacy, safety and feasibility of fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in pediatric patients receiving moderately and highly emetogenic chemotherapy \u2013 results of a non-interventional observation study

BackgroundChemotherapy-induced nausea and vomiting (CINV) belong among the most burdensome side effects in hemato-oncology. Mostly, a combination of ondansetron and dexamethasone is used as antiemetic prophylaxis in pediatric patients undergoing emetogenic chemotherapy. However, dexamethasone is prohibited in different pediatric chemotherapy protocols. Currently, data on the use of ondansetron with the new antiemetic agent fosaprepitant without dexamethasone is not available for pediatric patients.MethodsIn this non-interventional observation study, 79 pediatric patients with a median age of 8.0 years (range 0.5–17.9 years) who received a CINV prophylaxis regimen with either fosaprepitant (4 mg/kg; maximum 150 mg) and ondansetron (as 24-h continuous infusion) (n = 40; fosaprepitant group/FG) or ondansetron only (n = 39; control group/CG) during moderately or highly emetogenic chemotherapy were analyzed. The groups were analyzed and compared for frequency of vomiting, administered doses of on-demand antiemetic dimenhydrinate and adverse events during the acute (0-24 h after chemotherapy administration) and delayed (> 24 h–120 h) CINV phases.ResultsA total of 112 and 116 chemotherapy blocks were analyzed in the fosaprepitant and the control group, respectively. The emetogenic potential of the administered chemotherapy did not significantly differ (p = 0.8812) between the two cohorts. In the acute CINV phase, the percentage of patients experiencing vomiting (n = 26 patients) and the vomiting events were significantly higher (p = 0.0005 and p < 0.0001, respectively) in the CG (n = 26 patients (66.7%); 88 events) compared with the FG (n = 10 patients (25.0%); 37 events). In the delayed CINV phase, the percentage of patients experiencing vomiting and the vomiting events were also significantly higher (p = 0.0017 and p < 0.0001, respectively) in the CG (n = 31 patients (79.5%); 164 events) compared with the FG (n = 17 patients (42.5%); 103 events). Additionally, significantly more dimenhydrinate doses were administered in the CG compared with the FG patients (n = 322/n = 198; p < 0.0001). The occurrence of adverse events did not significantly differ between the two groups (p > 0.05).ConclusionFosaprepitant (4.0 mg/kg) in addition to ondansetron, without application of dexamethasone, was well tolerated, safe, effective and superior to ondansetron only as CINV prophylaxis in pediatric patients during moderately and highly emetogenic chemotherapy.

Prophylaxis of Chemotherapy-Induced Nausea and Vomiting with Fosaprepitant and Granisetron in Pediatric Patients after Allogeneic HSCT

1. BackgroundChemotherapy-induced nausea and vomiting (CINV) is a feared and burdensome complication after emetogenic chemotherapy (EC), especially in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Antiemetic prophylaxis (AEP) is thus a substantial factor in the transplantation management. Guidelines recommend a comprehensive AEP with NK1R-antagonists (neurokinin-1 receptor), 5-HT3R-antagonists (5-hydroxytryptamine-3 receptor), and corticosteroids. The water-soluble aprepitant derivative fosaprepitant (NK1R-antagonist) was shown to be highly effective in adult patients with moderately to highly EC when combined with granisetron (5-HT3R-antagonist). There is very little experience with fosaprepitant in pediatric patients.2. Patients and MethodsIn this single-center retrospective study, 80 pediatric patients during allogeneic HSCT who received AEP either with intravenous fosaprepitant and granisetron (fosaprepitant group; FG) or a standard prophylaxis regimen with granisetron two times per day(historical control group; CG) were analyzed for safety and efficacy of the prophylaxis regimen. Efficacy of the two AEP regimen was evaluated comparing the vomiting frequency, percentages of patients vomiting and the need for rescue medication (dimenhydrinate) during the acute (<24h) and the delayed (24-120h) CINV phase in both groups. Safety was evaluated comparing drug-related clinical and laboratory-chemical side-effects (exanthema, gastrointestinal symptoms, sweating, liver and kidney parameters, and electrolytes). Exclusion criteria were vomiting or receiving antiemetic medication within 48 hours before the start of antiemetic prophylaxis.3. ResultsA total of 80 pediatric patients with a median age of 9 years (range 2-17 years) who underwent allogeneic HSCT between 2015 and 2018 were consecutively enrolled and analyzed. Patients were transplanted for the treatment of acute leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), ALL-relapse, AML-relapse; total: 36.5% of the patients), myelodysplastic syndromes (4.8% of the patients) solid tumors and lymphoma (neuroblastoma, brain tumor, non-Hodgkin's lymphoma, Hodgkin's lymphoma; 44.9% of the patients), and non-malignant hematopoietic diseases (thalassemia major, sickle cell anemia; 13.8% of the patients). The patients received allogeneic grafts from matched unrelated donors (48.4%), matched family donors (16.2%) and mismatched family donors (35.5%). Distribution of the patient characteristics was not significantly different in both study groups (p>0.05).The patients of the FG (n=40; HSCT between 2017 and 2018) received a single dose of fosaprepitant (3.5-4 mg per kg bodyweight (mg/kg); maximum 150 mg; intravenous (IV) infusion) directly before starting the myeloablative conditioning and as PRN (pro re nata) medication every five days after HSCT (same dosage; IV infusion), as well as granisetron (2x20 µg/kg per day; starting on the first day of the conditioning; max. 3 mg; IV infusion <30 min.). The patients of the historical CG (n=40; patients transplanted between 2013 and 2014) received granisetron only at the same dosages. Discontinuation of the antiemetic medication was not necessary for any of the patients (CG and FG). Clinical side-effects and laboratory-chemical changes were not significantly different in both study groups (p>0.05). When compared to the patients of the CG, significantly less patients of the FG experienced vomiting in both, the acute (p<0.001) and the delayed CINV phase (p<0.0001); accordingly, significantly less vomiting events (p<0.0001) were observed during both CINV phases in the FG. Furthermore, the FG received significantly fewer doses of dimenhydrinate in comparison to the CG (p<0.001).4. ConclusionsThe prophylaxis regimen with fosaprepitant in combination with granisetron was safe and more effective in comparison to the standard prophylaxis regimen with granisetron only in pediatric patients undergoing allogeneic HSCT with a myeloablative conditioning. However, larger prospective trials are needed to evaluate these findings.5. KeywordsChemotherapy-induced nausea and vomiting; antiemetic prophylaxis; fosaprepitant; pediatric patients6. AcknowledgmentsThis study was supported by the Stefan-Morsch-Stiftung, Birkenfeld, Germany. DisclosuresSchlegel:Miltenyi Biotec: Patents & Royalties, Research Funding. Seitz:Miltenyi Biotec: Patents & Royalties, Research Funding. Lang:Miltenyi Biotec: Patents & Royalties, Research Funding. Handgretinger:Miltenyi Biotec: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding.

Association of weight change with telotristat ethyl in the treatment of carcinoid syndrome.

e15692 Background: In the Phase 3 TELESTAR study, the oral tryptophan hydroxylase inhibitor telotristat ethyl (TE) significantly reduced bowel movement (BM) frequency compared with placebo (pbo) over a 12-week Double-blind Treatment (DBT) period in patients with carcinoid syndrome (CS). Weight loss has previously been associated with uncontrolled CS and may result in reduced survival, so it is important to examine weight changes in patients with neuroendocrine tumors (NETs). Methods: We conducted an analysis, prespecified in the statistical analysis plan, of the incidence of weight change of ≥3% at Week 12 in TELESTAR. Patients with metastatic NETs, CS, and ≥4 BMs per day were randomly assigned to receive pbo, TE 250 mg 3x/day (tid), or TE 500 mg tid for 12 weeks, in addition to somatostatin analog therapy. Results: There were 45 patients in each group. Mean baseline age was 63.5 years, with 5.8 BMs/day and mean body mass index 24.87 kg/m2. Weight gain ≥3% at Week 12 was observed in 2/39 (5.1%), 7/41 (17.1%), and 13/40 (32.5%) patients on pbo, TE 250 tid, and TE 500 mg tid, respectively. The Cochrane–Armitage test for trend in weight gain incidence across groups yielded p = 0.0017. Among the 20 patients with a ≥3% weight gain on TE, 10 patients experienced a reduction of at least 30% in BM frequency at Week 12 (maximum reduction 75%). Weight loss ≥3% at Week 12 was observed in 5 (12.8%), 4 (9.8%), and 6 (15.0%) patients on pbo, TE 250 tid, and TE 500 mg tid. Adverse events of vomiting, decreased appetite, cachexia, and performance status decreased were reported during the DBT period among those with weight loss but not those with weight gain. Conclusions: The incidence of weight gain was dose-related on TE and was greater than that on pbo. It was possibly related to a reduction in diarrhea severity, and it may be a relevant aspect of TE efficacy among patients with functioning metastatic NETs. Clinical trial information: NCT01677910.

Effects of dexmedetomidine versus morphine on surgical stress response and analgesia in postoperative open cardiac surgery

Background The aim of this study was to compare between dexmedetomidine and morphine for use as sedative/analgesics and to evaluate their effects on surgical stress response during the first 24 h following open cardiac surgery in the Cardiac Intensive Care Unit (CICU). Patients and methods The present double-blind study was carried out on 30 adult patients 60 years of age or older admitted to the Cardiothoracic Surgery Department of the Alexandria Main University Hospital of ASA physical status grade II and III, scheduled for elective coronary artery bypass grafting surgery under general anesthesia. Immediately after sternal closure at the end of surgery, patients were classified randomly using the closed-envelope technique into two equal groups, started immediately on a continuous intravenous infusion (without a loading dose) of either dexmedetomidine or morphine and continued for 24 h postoperatively. Dexmedetomidine group (group D): dexmedetomidine was prepared at a concentration of 0.1 μg/kg/ml and was infused at a dose of 0.1-0.7 μg/kg/h (equivalent to an infusion rate of 1-7 ml/h). Morphine group (group M): morphine was prepared at a concentration of 10 μg/kg/ml and was infused at a dose of 10-70 μg/kg/h (equivalent to an infusion rate of 1-7 ml/h). Patients were followed up in the CICU for the first 24 h following open cardiac surgery on the basis of hemodynamic changes, plasma interleukin (IL)-6 and cortisol levels, time to successful tracheal extubation, postoperative pain, incidence of delirium, and postoperative nausea and vomiting. Results The mean heart rate values were significantly lower in group D compared with group M during most of the postoperative period. The mean values of systolic blood pressure, diastolic blood pressure, and mean arterial pressure, on comparing the two groups, had showed no statistically significant difference during the entire postoperative period. The mean values of IL-6, cortisol, and glucose were increased significantly in group M relative to group D at 6 and 24 h postoperatively. Time to successful tracheal extubation was significantly shorter in patients of group D than in patients of group M. Visual analogue scale for pain score and Motor Activity Assessment Scale for sedation score showed no significant difference when both groups were compared during the entire postoperative period. The total number of patients with delirium was significantly fewer in group D than group M. The incidences of nausea and vomiting events were insignificantly lower in group D than group M. Conclusion The administration of dexmedetomidine exerted a potent negative chronotropic effect with decreased heart rate. Both dexmedetomidine and morphine equivalently decreased the blood pressure (systolic blood pressure, diastolic blood pressure, and mean arterial pressure) in a range of 15-20% in relation to the preoperative readings. Dexmedetomidine significantly attenuated the surgical stress response and the neuroendocrine response in comparison with morphine through the suppression of the postoperative increase of IL-6 and cortisol, respectively. Dexmedetomidine had promoted earlier recovery and tracheal extubation than morphine, with no accompanying respiratory depression. Both dexmedetomidine and morphine were efficient sedative/analgesics for postoperative cardiac surgery. Dexmedetomidine significantly reduced the incidence and duration of delirium after cardiac surgery.

A Randomized Trial of the Effectiveness of Topical “ABH Gel” (Ativan®, Benadryl®, Haldol®) vs. Placebo in Cancer Patients With Nausea

ContextThe topical gel known as “ABH gel,” comprising lorazepam (Ativan®), diphenhydramine (Benadryl®), and haloperidol (Haldol®), is frequently used to treat nausea because of its perceived efficacy, relatively low cost, and ease of use in the home setting. There are limited scientific data on this medication, however. Recent pilot studies showed no absorption of the active ingredients of the gel, prompting further prospective studies into the cause of the perceived efficacy in the clinical setting. ObjectivesTo determine any difference in the effectiveness of ABH gel compared with placebo in cancer patients with nausea. MethodsA randomized, double-blind, placebo-controlled, crossover, noninferiority clinical trial was developed to test the hypothesis that there is no difference in the effectiveness of ABH gel compared with placebo in cancer patients with nausea. The primary outcome was the difference in nausea score (on a 0–10 scale) at baseline and at 60 minutes in each treatment group. The difference in the ABH gel-treated group compared with placebo was evaluated for noninferiority. Secondary outcomes included the number of vomiting episodes and side effects over time. ResultsThe mean change in nausea score from baseline to 60 minutes after treatment in the ABH gel group was 1.7 ± 2.05 and 0.9 ± 2.45 for the placebo group (P = 0.42). The placebo group was found to be noninferior to the ABH gel group in reducing the nausea score. ABH gel also did not decrease vomiting events better than placebo (P = 0.34). Only one patient reported any side effects from the treatments in either arm of the study. ConclusionABH gel in its current formulation should not be used in cancer patients experiencing nausea.

Chemotherapy combined with target drugs in the treatment of advanced colorectal cancer: a meta-analysis based on Chinese patients.

Colorectal carcinoma is one of most diagnosed solid malignant carcinoma. The chemotherapy combined with target drugs in the treatment of advanced colorectal cancer in not conclusive. The clinical studies reporting the activity and adverse events between chemotherapy alone versus chemotherapy combined with anti-epidermal growth factor receptor drugs were screened in the databases of Medline, the Cochrane Library, Wanfang and CNKI and included in this meta-analysis. The risk ratio (RR) and its 95% confidence interval (CI) for treatment response and adverse events were pooled by random or fixed effect model. A total of 10 clinical studies reporting chemotherapy combined with the target in the treatment of advanced colorectal cancer were included in this study. The pooled RR was 3.26 (95% CI: 1.74-6.11, P < 0.05), 1.49 (95% CI: 1.23-1.80) and 1.65 (95% CI: 1.37-1.98) for complete response (CR), partial response and objective response rate, respectively. For nausea and vomiting events, the RR was 1.62 (95% CI: 1.33-1.97, P < 0.05) indicating higher incidence of nausea and vomiting was observed in the combined group compared with chemotherapy alone. However, the diarrhea (RR = 1.10, 95% CI: 0.86-1.42, P > 0.05), liver function damage (RR = 1.03, 95% CI: 0.74-1.42), myelosuppression (RR = 1.04, 95% CI: 0.83-1.31) and neurotoxicity (RR = 1.12, 95% CI: 0.93-1.35) were not different between the two groups. For Chinese patients with advanced colorectal cancer, chemotherapy combined with target drug can improve the response rate, but also increase the risk of nausea and vomiting.

A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia

BackgroundWe compared the time to discontinuation due to lack of tolerability over 24 weeks in patients suffering from schizophrenia treated with pomaglumetad methionil (LY2140023 monohydrate, the prodrug of metabotropic glutamate 2/3 receptor agonist, LY404039) or standard of care (SOC: olanzapine, risperidone, or aripiprazole).MethodsStudy HBBR was a multicenter, randomized, open-label study comparing the long-term safety and tolerability of LY2140023 with SOC for schizophrenia. Patients had moderate symptomatology with prominent negative symptoms and evidence of functional impairment. Those who met entry criteria were randomized to open-label treatment with either LY2140023 (target dose: 40 mg twice daily [BID]; n = 130) or SOC (n = 131).ResultsThere was no statistically significant difference between LY2140023 and SOC for time to discontinuation due to lack of tolerability (primary objective; P = .184). The Kaplan-Meier estimates revealed comparable time to event profiles. Only 27% of LY2140023 and 45% of SOC patients completed the 24-week open-label, active treatment phase. Twenty-seven patients (20.8%) in the LY2140023 group and 15 patients (11.5%) in the SOC group discontinued due to lack of efficacy (P = .044). Twenty-three patients (17.7%) in the LY2140023 group and 19 patients (14.5%) in the SOC group discontinued due to adverse events (physician and subject decision combined, P = .505). The incidence of serious adverse events was comparable between groups. LY2140023-treated patients reported significantly more treatment-emergent adverse events of vomiting, agitation, and dyspepsia, while SOC-treated patients reported significantly more akathisia and weight gain. The incidence of treatment-emergent parkinsonism (P = .011) and akathisia (P = .029) was significantly greater in SOC group. Improvement in PANSS total score over the initial 6 to 8 weeks of treatment was similar between groups, but improvement was significantly greater in the SOC group at 24-week endpoint (P = .004). LY2140023 and SOC groups had comparable negative symptom improvement at 24-week endpoint (P = .444).ConclusionThese data provide further evidence that the potential antipsychotic LY2140023 monohydrate, with a glutamatergic mechanism of action, may have a unique tolerability profile characterized by a low association with some adverse events such as extrapyramidal symptoms and weight gain that may characterize currently available dopaminergic antipsychotics.Trials registrationA Long-term, Phase 2, Multicenter, Randomized, Open-label, Comparative Safety Study of LY2140023 Versus Atypical Antipsychotic Standard of Care in Patients with DSM-IV-TR SchizophreniaClinicalTrials.gov identifier: NCT00845026.

Computational Prediction of State Anxiety in Asian Patients With Cancer Susceptible to Chemotherapy-Induced Nausea and Vomiting

State anxiety, a risk factor for chemotherapy-induced nausea and vomiting (CINV), is a subjective symptom and difficult to quantify. Clinicians need appropriate anxiety measures to assess patients' risks of CINV. This study aimed to determine the anxiety characteristics that can predict CINV based on computational analysis of an objective assessment tool. A single-center, prospective, observational study was carried out between January 2007 and July 2010. Patients with breast, head and neck, and gastrointestinal cancers were recruited and treated with a variety of chemotherapy protocols and appropriate antiemetics. Chemotherapy-induced nausea and vomiting characteristics and antiemetic use were recorded using a standardized diary, whereas patients' anxiety characteristics were evaluated using the Beck Anxiety Inventory. Principal component (PC) analysis was performed to analyze the anxiety characteristics. A subset known as principal variables, which had the highest PC weightings, was identified for patients with and without complete response, complete protection, and complete control. Chemotherapy-induced nausea and vomiting events and anxiety characteristics of 710 patients were collated; 51%, 30%, and 20% were on anthracycline-, oxaliplatin-, and cisplatin-based therapies, respectively. Most patients suffered from delayed CINV, with decreasing proportions achieving complete response (58%), complete protection (42%), and complete control (27%). Seven symptoms (fear of dying, fear of the worst, unable to relax, hot/cold sweats, nervousness, faintness, numbness) were identified as potential CINV predictors. This study demonstrates the usefulness of PC analysis, an unsupervised machine learning technique, to identify 7 anxiety characteristics that are useful as clinical CINV predictors. Clinicians should be aware of these characteristics when assessing CINV in patients on emetogenic chemotherapies.

Abstract P4-02-05: A Phase II Trial of Fulvestrant and RAD001 (Everolimus) in Patients with Metastatic Estrogen Receptor Positive Breast Cancer after Aromatase Inhibitor Failure; a Study in Progress

Abstract Background: Fulvestrant is a potent estrogen receptor (ER) antagonist that has superior antitumor activity in preclinical models. Unfortunately, clinical data showed a more modest antitumor effect for fulvestrant and it is currently reserved for use after aromatase inhibitor (AI) failure in metastatic disease. Reasons for the disappointing clinical results of fulvestrant may be related to suboptimal dosing and possibly to growth factor signaling that may render breast cancer resistant to ER inhibition by fulvestrant. The PI3K/AKT/mTOR pathway is frequently aberrant in breast cancer and preclinical data suggest that it may mediate fulvestrant resistance. We rationalized that using RAD001, an orally active mTOR inhibitor, with fulvestrant may overcome resistance and prolong time to progression. Methods: We conducted a phase II trial of fulvestrant and RAD001 in postmenopausal women with metastatic ER positive breast cancer if they had progressed/relapsed after AI use within 6 months of enrollment. Fulvestrant is administered as a loading dose (500 mg IM d1, 250 mg day 14, 250 mg day 28 and monthly thereafter). RAD001 was initially given at 5 mg orally once daily in the first month to the first 5 patients in order to assess safety and tolerability, and then increased to 10 daily thereafter and for subsequent patients. Patients are required to have measurable or evaluable disease and have adequate performance status and organ function. Primary endpoint is time to progression (TTP) and secondary endpoints include safety, response rate, and tissue biomarker assessment. 40 evaluable patients are required to meet a median TTP of 7.0 months compared to 3.7 months for fulvestrant alone as reported in the EFECT trial. Patients are followed monthly for clinical and lab evaluation and imaging studies for tumor assessment are obtained every 2 months. Results: Median age at entry is 49 years (Range 40-71). To date, 11 patients have enrolled. 8 patients are off study; 7 because of disease progression, and 1 because of a serious adverse event-grade 3 renal failure. Most common adverse events to date are mucositis in 7 patients, rash in 5 and nausea in 3. Most common lab abnormalities are elevated cholesterol in 6 patients, hypokalemia in 5, elevated ALT/AST in 5, and hyperglycemia in 4. Most of the toxicities are grade 1. There were 4 serious adverse events reported; acute renal failure, acute cholecystitis, and two grade 3 vomiting events in the same subject. No grade 4 toxicities occurred. Overall, treatment is well tolerated. Current analysis reveals a median TTP of 389 days (13 months). Bayesian interim monitoring of TTP indicates &amp;gt;90% posterior probability of mean TTP greater than the null value of 3.7 months. Credible intervals and stopping bounds also indicate continuation of patient accrual. Conclusions: Combined RAD001 with fulvestrant in this trial shows promising antitumor activity in metastatic breast cancer and has manageable toxicity. The trial remains open for accrual and updated efficacy and toxicity data will be presented. Clinical trials that target endocrine therapy resistance are critical and can help patients avoid the early use of more toxic treatments. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-05.