Practice Patterns for Prevention of Chemotherapy-Induced Nausea and Vomiting and Antiemetic Guideline Adherence Based on Real-World Prescribing Data

BackgroundGuideline‐recommended antiemetic prophylaxis improves nausea and vomiting control in most patients undergoing chemotherapy. Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology (MASCC/ESMO) antiemetic guidelines recommend prophylaxis with a neurokinin‐1 receptor antagonist (NK₁RA), a 5‐hydroxytryptamine‐3 receptor antagonist (5‐HT₃RA), and dexamethasone for patients receiving highly emetogenic chemotherapy (HEC), including anthracycline‐cyclophosphamide (AC)‐ and carboplatin (considered moderately emetogenic chemotherapy)‐based chemotherapy. Here, we analyze the use of NK₁RA–5‐HT₃RA–dexamethasone for antiemetic prophylaxis associated with HEC and carboplatin.MethodsThe data source was the Global Oncology Monitor (Ipsos Healthcare). Geographically representative physicians from France, Germany, Italy, Spain, and the U.K. were screened for treatment involvement and number of patients treated per month. Patients’ data from January to December 2018 were collected from medical charts and extrapolated on the basis of the total number of physicians who prescribe chemotherapy. The emetic risk of chemotherapy was classified per MASCC/ESMO guidelines.ResultsData from 45,324 chemotherapy‐treated patients were collected, representing a total extrapolated prevalence of 1,394,848 chemotherapy treatments included in the analysis. NK₁RAs were used in 45%, 42%, and 19% of patients receiving cisplatin‐, AC‐, and carboplatin‐based chemotherapy, respectively; 18%, 24%, and 7% received the guideline‐recommended NK₁RA–5‐HT₃RA–dexamethasone combination; no antiemetics were prescribed for 12% of the treatments. Often, physicians’ perception of the emetic risk of chemotherapy did not follow MASCC/ESMO guideline classification.ConclusionLow adherence to antiemetic guidelines was revealed in clinical practice in five European countries, with 15% of all HEC‐/carboplatin‐based treatments receiving guideline‐recommended NK₁RA–5‐HT₃RA–dexamethasone prophylaxis and 12% of them receiving no antiemetics. New strategies for improving guideline adherence are urgently needed.Implications for PracticeDespite recent advances in antiemetic therapy, a substantial proportion of patients experience nausea and vomiting associated with chemotherapy in daily clinical practice. Antiemetic guidelines aim at prevention of chemotherapy‐induced nausea and vomiting (CINV), and guideline‐consistent antiemetic therapy can effectively prevent vomiting and, to a lesser extent, nausea in most patients with cancer. This study reports low adherence to antiemetic guidelines in the highly emetogenic chemotherapy setting in daily clinical practice across five European countries. Opportunity exists to increase adherence to antiemetic guideline recommendations. Implementation of strategies to facilitate guideline adherence can potentially improve CINV control.     

Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre,randomised, double-blind,placebo-controlled phase 3 trial

BackgroundWe evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone.Patients and methodsPatients receiving chemotherapy including cisplatin (≥70 mg/m²) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 &mgr;g/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1–3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0–120 h).ResultsThe percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0–24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24–120 h postchemotherapy) phase (65% versus 49%, P = 0.0025).ConclusionsSingle-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.     

Comparison of Granisetron,Ondansetron and Tropisetron for Control of Vomiting and Nausea Induced by Cisplatin

Abstract

Severe nausea and vomiting are common and one of the most feared side effects of cisplatin-based chemotherapy. A total of 106 patients were randomized to receive a single dose of 8 mg ondansetron or 3 mg granisetron or 5 mg tropisetron intravenously as prevention of cisplatin-induced acute nausea and vomiting. Antiemetic therapy was done within 30 minutes before initiating chemotherapy. A questionnaire evaluating nausea, vomiting and retches was administered to patients and the responses were categorized as complete, partial or failure. The response determination was repeated in the first 24 hours, and within 24-72 hours following cisplatin administration.

The complete response rates for ondansetron, granisetron and tropisetron in the first 24 hours were 51.4%, 65.7% and 61.1% respectively. All three agents were highly effective against cisplatin-induced acute and late vomiting and the results were statistically significant. This study demonstrated no significant difference in effectiveness of these three antiemetics. 5-HT3 (5-hydrox-ytryptamine 3) receptor antagonists have similar efficacy in the prevention of nausea and vomiting due to cisplatin. Thus, we recommend that drug choice be based on cost-benefit and patient tolerance.     

Antiemetic effects of granisetron and dexamethasone combination therapy during cisplatin-containing chemotherapy for head and neck cancer: dexamethasone dosage verification trial

Background

Chemotherapy-induced nausea and vomiting (CINV) remains a significant problem for patients and is associated with a substantial deterioration in quality of life; appropriate use of antiemetic drugs is crucial in maintaining the quality of life in patients undergoing chemotherapy.

Methods

This randomized, crossover trial evaluated the antiemetic efficacy and safety of 8 mg per day (low-dose) and 16 mg per day (standard-dose) dexamethasone, in combination with the 5-HT₃ receptor antagonist granisetron, in 36 patients receiving cisplatin (CDDP)-containing chemotherapy for head and neck cancer. Following chemotherapy, the antinausea/vomiting inhibition rate for each dexamethasone dose was measured.

Results

During the 24-h period following administration of chemotherapy (acute phase), the antinausea/vomiting inhibition rates (no nausea and no episodes of vomiting) for 8 mg and 16 mg dexamethasone were comparably high (58.3% and 63.8%, respectively; P = 0.8092). Similar results were seen on days 2–5 following chemotherapy. Efficacy during the acute phase, based on the number of instances of vomiting and degree of nausea, was also comparably high for the two dexamethasone doses (overall efficacy rates were 94.4% and 88.8%, respectively, for 8 mg and 16 mg dexamethasone; P = 0.7637). Both doses maintained an 80% or higher response rate until day 3, and neither dose produced severe side effects.

Conclusion

The results suggest that granisetron and dexamethasone combination therapy is useful in controlling acute and delayed nausea and vomiting induced by CDDP-containing chemotherapy for head and neck cancer. Furthermore, 8 mg and 16 mg dexamethasone have equivalent antiemetic efficacy.     

奥氮平联合格拉司琼和地塞米松预防化疗所致恶心、呕吐的Ⅰ期爬坡试验

目的 探讨奥氮平联合格拉司琼和地塞米松预防化疗所致恶心、呕吐的最大耐受剂量。方法 奥氮平设6个剂量水平,分别为2.5、5、7.5、10、15和20mg,联合格拉司琼和地塞米松进行治疗,每个剂量组至少3例受试者。初始剂量为奥氮平2.5mg,每晚1次,试验前1天至试验第14天（d-1～d14）;如无方案规定的剂量限制性毒性（LTD）则进入下一剂量组,直至观察到最大耐受剂量（MTD）,若20mg组未出现MTD不再增加剂量。结果 18例肿瘤患者纳入试验,依次进行了前5个剂量组的研究;在进行15mg剂量组的3例患者中出现1例3级口干,后追加2例患者出现1例3级嗜睡,试验终止于此剂量组。2级及以上的不良反应主要为嗜睡、头晕、静坐不能、口干、便秘、疲劳和骨髓抑制。结论 奥氮平长期使用（口服15天）的耐受性好,安全性高,推荐剂量为10mg,每晚1次,d-1～d14。     

Phase II Trial of Neoadjuvant Carboplatin and Nab-Paclitaxel in Patients with Triple-Negative Breast Cancer

BackgroundIn this phase II clinical trial, we evaluated the efficacy of the nonanthracycline combination of carboplatin and nab‐paclitaxel in early stage triple‐negative breast cancer (TNBC).Patients and MethodsPatients with newly diagnosed stage II–III TNBC (n = 69) were treated with neoadjuvant carboplatin (area under the curve 6) every 28 days for four cycles plus nab‐paclitaxel (100 mg/m²) weekly for 16 weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor‐infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS).ResultsSixty‐seven patients were evaluable for safety and response. Fifty‐three (79%) patients experienced grade 3/4 adverse events, including grade 3 anemia (43%), neutropenia (39%), leukopenia (15%), thrombocytopenia (12%), fatigue (7%), peripheral neuropathy (7%), neutropenia (16%), and leukopenia (1%). Twenty‐four patients (35%) had at least one dose delay, and 50 patients (72%) required dose reduction. Sixty‐three (94%) patients completed scheduled treatment. The responses were as follows: 32 of 67 patients (48%) had pCR (RCB 0), 10 of 67 (15%) had RCB I, 19 of 67 (28%) had RCB II, 5 of 67 (7%) had RCB III, and 1 of 67 (2%) progressed and had no surgery. Univariate analysis showed that immune‐hot GSIS and DNA repair defect (DRD) were associated with higher pCR with odds ratios of 4.62 (p = .005) and 4.76 (p = .03), respectively, and with RCB 0/I versus RCB II/III with odds ratio 4.80 (p = .01). Immune‐hot GSIS was highly correlated with DRD status (p = .03), TIL level (p < .001), and TNBC molecular subtype (p < .001). After adjusting for age, race, stage, and grade, GSIS remained associated with higher pCR and RCB class 0/I versus II/III with odds ratios 7.19 (95% confidence interval [CI], 2.01–25.68; p = .002) and 8.95 (95% CI, 2.09–38.23; p = .003), respectively.ConclusionThe combination of carboplatin and nab‐paclitaxel for early stage high‐risk TNBC showed manageable toxicity and encouraging antitumor activity. Immune‐hot GSIS is associated with higher pCR rate and RCB class 0/1. This study provides an additional rationale for using nonanthracycline platinum‐based therapy for future neoadjuvant trials in early stage TNBCs. Clinical trial identification number: {"type":"clinical-trial","attrs":{"text":"NCT01525966","term_id":"NCT01525966"}}NCT01525966Implications for PracticePlatinum is an important neoadjuvant chemotherapy agent for treatment of early stage triple‐negative breast cancer (TNBC). In this study, carboplatin and nab‐paclitaxel were well tolerated and highly effective in TNBC, resulting in pathological complete response of 48%. In univariate and multivariate analyses adjusting for age, race, tumor stage and grade, “immune‐hot” GeparSixto immune signature (GSIS) and DNA repair defect (DRD) were associated with higher pathological complete response (pCR) and residual cancer burden class 0/1. The association of immune‐hot GSIS with higher pCR holds promise for de‐escalating neoadjuvant chemotherapy for patients with early stage TNBC. Although GSIS is not routinely used in clinic, further development of this immune signature into a clinically applicable assay is indicated.     

Infusion of palonosetron plus dexamethasone for the prevention of chemotherapy-induced nausea and vomiting

Serotonin (5-HT3) receptor antagonists are the foundation of standard antiemetic care for cancer patients receiving emetogenic chemotherapy. To enhance the efficacy of these supportive care agents, dexamethasone is routinely admixed with the 5-HT3 receptor antagonist, which is administered by intravenous infusion before chemotherapy begins. This phase II study evaluated the safety and efficacy of intravenous palonosetron admixed with dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy. Cancer patients received palonosetron 0.25 mg plus dexamethasone 8 mg admixed in 50 mL of infusion solution before receiving at least one qualifying chemotherapeutic agent (cyclophosphamide < or = 1,500 mg/m2, doxorubicin > or = 20 mg/m2, carboplatin, or oxaliplatin). Patients used diaries to record nausea and emesis experienced and rescue medications used. Of 32 participants, 27 (84%) had a complete response (no emesis and no rescue medication) during the acute (0-24 hours) interval posttherapy, 19 (59%) had a complete response during the delayed (> 24-120 hours) posttherapeutic interval, and 19 (59%) had a complete response during the overall (0-120 hours) posttreatment interval. A total of 23 patients (72%) had no emetic episodes, 16 (50%) had no nausea, and 21 (66%) used no rescue medication throughout the overall 5-day interval. The combination was well tolerated. Palonosetron plus dexamethasone given as a pretreatment infusion is effective and safe in preventing acute and delayed CINV in patients receiving moderately emetogenic chemotherapy.     

Optimal timing of granisetron administration for the prevention of carboplatin-induced acute emesis

This prospective pilot study was undertaken to determine whether delayed administration of one of the serotonin-receptor antagonists (granisetron) reduced carboplatin--induced emesis. The subjects were patients who were scheduled to undergo at least three courses of carboplatin based chemotherapy, in whom acute emesis occurred at the first course. Granisetron was administered therapeutically for the first course. Conventional prophylactic granisetron was given 30 min before carboplatin administration for the second course. For the third course, granisetron was administered 5 hr after completion of carboplatin administration. The degrees of appetite loss, nausea and frequency of vomiting on the Day 1 were compared between the three courses. Thirteen patients were evaluated. Acute emesis occurred 8 +/- hr after completion of carboplatin administration in the first courses of these patients. The degree of nausea and frequency of vomiting were reduced by administrating the granisetron five hours after carboplatin when compared with therapeutic granisetron administration or administration 30 min before carboplatin. The degree of appetite loss was significantly lowered by administering the granisetron 5 hr after carboplatin administration. Administration of granisetron 5 hr after carboplatin may thus lessen carboplatin-induced emesis more than conventional granisetron administration. A large-scale comparative study is warranted.     

Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors

BackgroundAvapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18‐mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence‐based guidance on management of avapritinib‐associated adverse events (AEs), including cognitive effects and intracranial bleeding.Materials and MethodsWe performed a post hoc analysis of data from a two‐part, single‐arm dose escalation/expansion phase I study (NAVIGATOR; {"type":"clinical-trial","attrs":{"text":"NCT02508532","term_id":"NCT02508532"}}NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30–600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression‐free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose).ResultsOf 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18‐mutation; 66.8% started avapritinib at 300 mg. The most common treatment‐related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment‐related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all‐cause cognitive effects rate (grade 1–2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3–3.1 weeks) than without (4.9–7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without.ConclusionTolerability‐guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs.Implications for PracticeEarly recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment‐related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients'' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events.     

Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal,Non-Small Cell Lung,and Pancreatic Cancer

Lessons Learned

• Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy.
• Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d.
• Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined.

BackgroundAntitumor effects of MEK inhibitors are limited in KRAS‐mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3‐kinase–AKT pathway. Therefore, this phase I trial was initiated with the pan‐HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild‐type tumors.MethodsAfatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy.ResultsTwenty‐six patients were enrolled with colorectal cancer (n = 19), non‐small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose‐limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response.ConclusionAfatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited.     

Phase Ib/II Study of Biweekly TAS-102 in Combination with Bevacizumab for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies (BiTS Study)

Lessons Learned

• A biweekly TAS‐102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS‐102 plus BEV combination.
• Biweekly TAS‐102 plus BEV combination could reduce unnecessary dose reduction of TAS‐102, maintain higher doses, and possibly be effective even in cases without chemotherapy‐induced neutropenia (CIN).
• The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS‐102 plus BEV.

BackgroundTAS‐102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS‐102 (70 mg/m²/day on days 1–5 and 8–12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS‐102 plus BEV combination.MethodsPatients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS‐102 (twice daily on days 1–5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression‐free survival rate at 16 weeks (16‐w PFS rate).ResultsFrom October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS‐102 (70 mg/m²/day). Of the 44 eligible patients, the 16‐w PFS rate was 40.9% (95% confidence interval, 26.3%–56.8%), and the null hypothesis was rejected (p < .0001). Median progression‐free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%).ConclusionBiweekly TAS‐102 plus BEV showed promising antitumor activity with safety.     

Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least Three Prior Lines of Therapy

BackgroundMost gastrointestinal stromal tumors (GIST) driven by KIT or platelet‐derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two‐part, single‐arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST.Materials and MethodsEligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy.ResultsAs of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment‐related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response‐evaluable patients with GIST harboring KIT or non‐D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10–25). Median duration of response was 10.2 months (95% CI, 7.2–10.2), and median progression‐free survival was 3.7 months (95% CI, 2.8–4.6).ConclusionAvapritinib has manageable toxicity with meaningful clinical activity as fourth‐line or later treatment in some patients with GIST with KIT or PDGFRA mutations.Implications for PracticeIn the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet‐derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist.     

Oral granisetron alone and in combination with dexamethasone: A double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin-induced emesis

PATIENTS AND METHODS:: Three anti-emetic treatment regimens were compared in 357 patientsreceiving cisplatin therapy (mean dose 81 mg/m²) in this double-blindrandomized study. Regimens studied were i) granisetron 1 mgbd orally for 7 days (granisetron alone); ii) gran 1 mg bd orallyfor 7 days plus prophylactic dexamethasone (12 mg i.v.) on thefirst day only (gran/dex); iii) metoclopramide (3 mg/kg i.v.loading dose; 4 mg/kg i.v. infusion) plus dex (12 mg i.v.) onthe first day followed by met 10 mg orally tds for a further6 days (met/dex). RESULTS:: At 24 hours, gran/dex was significantly superior to met/dexin terms of total anti-emetic control, defined as no nausea,no vomiting, no rescue anti-emetic therapy, not withdrawn (54.7%gran/dex vs. 37.2/ met/dex; (P < 0.01). There was also asignificant delay in time to onset of nausea (P < 0.01) andvomiting (P < 0.01) following gran/dex compared with met/dex.Oral granisetron alone was as effective as met/dex in controlof acute emesis in all parameters examined. There were no significantdifferences between the three groups in the control of delayednausea and vomiting. The most common adverse experiences in both granisetron groupswere headache and constipation, both characteristic of 5-HT₃antagonists. Agitation, somnolence, diarrhoea and decreasedappetite were reported more frequently by the met/dex group. CONCLUSIONS:: Oral granisetron as a single agent is as effective as high dosesof i.v. met/dex in preventing cisplatin-induced emesis. Oralgranisetron in combination with a corticosteroid provides superioranti-emetic control to the met/dex regimen in patients undergoinghighly emetogenic chemotherapy. granisetron, oral, metoclopramide, dexamethasone, anti-emetic, cisplatin     

A Phase Ib Study of NUC-1031 in Combination with Cisplatin for the First-Line Treatment of Patients with Advanced Biliary Tract Cancer (ABC-08)

BackgroundCisplatin/gemcitabine is standard first‐line treatment for patients with advanced biliary tract cancer (ABC). NUC‐1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites.MethodsPatients with untreated ABC, Eastern Cooperative Oncology Group performance status 0–1 received NUC‐1031 (625 or 725 mg/m²) and cisplatin (25 mg/m²) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression‐free survival (PFS), and overall survival (OS).ResultsTwenty‐one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC‐1031 625 mg/m² (n = 8 and expansion n = 7; median six cycles) or 725 mg/m² (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment‐emergent grade 3–4 adverse events occurring in more than one patient with 625 mg/m² NUC‐1031 were increased gamma‐glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m², increased GGT, 67%, and fatigue, 33%. NUC‐1031 725 mg/m² was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3–10.1), and median OS was 9.6 months (95% CI, 6.7–13.1). The median estimates of area under the plasma concentration–time curve from time 0 to last measurable time and maximum concentration were highest for NUC‐1031 (218–324 μg•h/mL and 309–889 μg/mL, respectively) and lowest for di‐fluoro‐deoxycytidine (0.47–1.56 μg•h/mL and 0.284–0.522 μg/mL, respectively).ConclusionThis is the first study reporting on the combination of NUC‐1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m² NUC‐1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: {"type":"clinical-trial","attrs":{"text":"NCT02351765","term_id":"NCT02351765"}}NCT02351765; EudraCT ID: 2015‐000100‐26).Implications for PracticeThe prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first‐line treatment for patients with ABC. NUC‐1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC‐08) demonstrated a favorable safety profile of NUC‐1031 in combination with cisplatin for the first‐line treatment of patients with ABC, and 725 mg/m² NUC‐1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling.     

Metoclopramide,Dexamethasone, or Palonosetron for Prevention of Delayed Chemotherapy‐Induced Nausea and Vomiting After Moderately Emetogenic Chemotherapy (MEDEA): A Randomized,Phase III,Noninferiority Trial

BackgroundFor the prevention of chemotherapy‐induced nausea and vomiting (CINV) during the delayed phase (24–120 hours) after moderately emetogenic chemotherapy (MEC), the use of 3‐day dexamethasone (DEX) is often recommended. This study compared the efficacy and safety of two DEX‐sparing regimens with 3‐day DEX, focusing on delayed nausea.Patients and MethodsThis open‐label, randomized, phase III study was designed to demonstrate noninferiority of two DEX‐sparing regimens: ondansetron + DEX on day 1 + metoclopramide on days 2–3 (MCP arm), and palonosetron + DEX on day 1 (PAL arm) versus ondansetron on day 1 + DEX on days 1–3 (DEX arm) in chemotherapy‐naïve patients receiving MEC. Primary efficacy endpoint was total control (TC; no emetic episodes, no use of rescue medication, no nausea) in the delayed phase. Noninferiority was defined as a lower 95% CI greater than the noninferiority margin set at −20%. Secondary endpoints included no vomiting, no rescue medication, no (significant) nausea, impact of CINV on quality of life, and antiemetics‐associated side effects.ResultsTreatment arms were comparable for 189 patients analyzed: predominantly male (55.7%), median age 65.0 years, colorectal cancer (85.7%), and oxaliplatin‐based chemotherapy (81.5%). MCP demonstrated noninferiority to DEX for delayed TC (MCP 56.1% vs. DEX 50.0%; 95% CI, −11.3%, 23.5%). PAL also demonstrated noninferiority to DEX (PAL 55.6% vs. DEX 50.0%; 95% CI, −12.0%, 23.2%). There were no statistically significant differences for all secondary endpoints between treatment arms.ConclusionThis study showed that DEX‐sparing regimens are noninferior to multiple‐day DEX in terms of delayed TC rate in patients undergoing MEC. ClinicalTrials.gov identifier. {"type":"clinical-trial","attrs":{"text":"NCT02135510","term_id":"NCT02135510"}}NCT02135510.Implications for PracticeChemotherapy‐induced nausea and vomiting (CINV) in the delayed phase (24–120 hours after chemotherapy) remains one of the most troublesome adverse effects associated with cancer treatment. In particular, delayed nausea is often poorly controlled. The role of dexamethasone (DEX) in the prevention of delayed nausea after moderately emetogenic chemotherapy (MEC) is controversial. This study is the first to include nausea assessment as a part of the primary study outcome to better gauge the effectiveness of CINV control and patients’ experience. Results show that a DEX‐sparing strategy does not result in any significant loss of overall antiemetic control: DEX‐sparing strategies incorporating palonosetron or multiple‐day metoclopramide are safe and at least as effective as standard treatment with a 3‐day DEX regimen with ondansetron in controlling delayed CINV—and nausea in particular—following MEC.     

Avoidable Acute Care Use Associated with Nausea and Vomiting Among Patients Receiving Highly Emetogenic Chemotherapy or Oxaliplatin

PurposeChemotherapy‐induced nausea and vomiting (CINV) contributes to avoidable acute care, a metric now tracked in Medicare''s oncology outcome measure. CINV is preventable, yet guidelines are often not followed. We sought to quantify acute care involving CINV and other avoidable toxicities after highly emetogenic chemotherapy (HEC) to identify excess risk and assess clinician adherence to antiemesis guidelines for HEC.Materials and MethodsWe retrospectively evaluated U.S. electronic health records (2012‐2018) using Medicare''s OP‐35 outcome measure to identify avoidable acute care involving any of 10 toxicities, including CINV, after HEC regimens relative to non‐HEC. Antiemetic guideline adherence was defined as use ofneurokinin‐1 (NKl) receptor antagonists Q5 (RAs) plus 5‐hydroxytryptamine type 3 RA+ dexamethasone at HEC initiation.ResultsAmong 17,609 patients receiving HEC, acute care rates associated with HEC chemotherapy included 32% cisplatin, 31% carboplatin, and 21% anthracycline/cyclosphospharnide (AC), with 76% meeting the criteria as avoidable events. Oxaliplatin rates were 29%. Avoidable acute care occurred 1.83 times (95% confidence interval, 1.76‐1.91, p < .0001) as often after HEC versus non‐HEC excluding oxaliplatin; CINV‐related acute care occurred 2.29 times as often. Nonadherence to antiemesis guidelines occurred in 34% and 24% of cisplatin and AC courses, respectively, because of omission of a NKl RA.ConclusionsPatients treated with HEC regimens experienced high avoidable acute care use, 1.8 times the risk seen for other chemotherapy. Nonadherence to guideline‐directed antiemetic prophylaxis highlights the need to ensure adherence to antiemetic guidelines, including the use of NKl RA in HEC.Implications for PracticeAfter survival, perhaps the most important goal in oncology is limiting avoidable acute care, a goal now used by Medicare to impact cancer reimbursement. This study found that patients treated with highly emetogenic chemotherapy (HEC) regimens had high rates of avoidable acute care use, 1.8 times the risk seen for other chemotherapy. A substantial proportion of the avoidable acute care involved chemotherapy‐induced nausea and vomiting. Results showed that incomplete adherence to national antiemetic guidelines for HEC regimens primarily driven by omission of upfront neurokinin‐1 receptor antagonist use, suggesting that improved adherence can meaningfully resolve this gap in quality and cost of care.     

奥氮平预防高致吐性化疗方案致恶心呕吐的临床观察

目的评价奥氮平预防含顺铂、表阿霉素的高致吐性化疗方案所致恶心呕吐(CINV)的有效性和安全性。方法对符合纳入标准的52例恶性肿瘤患者应用高致吐性方案化疗2个周期,随机交叉应用A→B方案或B→A方案进行预防性止呕处理。A方案(空白对照组):盐酸帕洛诺司琼0.25 mg d_1+地塞米松10 mg d_1~d_3,静推;B方案(奥氮平组):A方案基础上,加用奥氮平10 mg d_(-1)~d_5,睡前口服。主要研究指标为患者化疗后5天内急性(0~24 h)及延迟性(25~120 h)恶心、呕吐的完全缓解(CR)率,同时评估奥氮平治疗的安全性。结果最终完成2个周期化疗并可评价疗效的患者共50例,脱落2例。奥氮平组与空白对照组比较,在急性恶心(88.0%vs.52.0%,P<0.05)、延迟性恶心(72.0%vs.20.0%,P<0.05)、延迟性呕吐(86.0%vs.64.0%,P<0.05)方面CR率更高的,而在急性呕吐方面两组CR率的差异无统计学意义(94.0%vs.86.0%,P>0.05)。奥氮平止呕相关不良反应包括头晕、嗜睡、口干、疲劳、便秘、直立性低血压等,均少见且程度较轻,组间差异无统计学意义(P>0.05)。结论在盐酸帕洛诺司琼和地塞米松的基础上,加入奥氮平可以有效地提高高致吐性化疗方案致急性恶心、延迟性恶心与呕吐的疗效,且安全性较好。     

奥氮平联合格拉司琼控制乳腺癌化疗所致恶心呕吐的疗效观察

目的观察并比较奥氮平联合格拉司琼与单用格拉司琼控制乳腺癌化疗所致恶心呕吐的疗效。方法 120例乳腺癌患者被随机分为研究组（60例）及对照组（60例）,研究组和对照组均在化疗前30 min静脉滴注格拉司琼3 mg,研究组自化疗第1天早晨开始口服奥氮平10 mg,连用3天,第1个周期化疗结束后评价止吐效果。结果研究组的急性恶心呕吐的发生率（33.3%）和迟发性恶心呕吐的发生率（18.3%）均明显低于对照组（53.3%和40%）,差异有统计学意义（P〈0.05）。结论与单用格拉司琼相比,奥氮平联合格拉司琼对于控制乳腺癌化疗所致急性恶心呕吐和延迟性恶心呕吐的效果更好。