- Recent Advances in Preventing Chemotherapy-Induced Nausea and Vomiting. [Journal Article, Review]
- Oncology (Williston Park) 2016 Aug; 30(8)
Chemotherapy-induced nausea and vomiting (CINV) remains an important adverse effect of cancer therapy. The goal of CINV prophylaxis is to reduce the morbidity associated with nausea and vomiting, as well as to preserve quality of life, while maintaining the desired chemotherapy regimen. The US Food and Drug Administration has recently approved new therapies for prevention of CINV, including the neurokinin-1 (NK1) receptor antagonist rolapitant and the fixed-dose combination of the second-generation 5-hydroxytryptamine type 3 receptor antagonist palonosetron with the novel NK1 receptor antagonist netupitant. Alternative agents, like the atypical antipsychotic olanzapine, have also expanded the options available for preventing delayed and refractory CINV. Consensus guidelines for prevention of CINV from several organizations are generally consistent with one another and are updated based on expert review of available clinical trial data. This article will address changes in CINV guidelines over the past 5 years and provide updates on recently approved agents and agents that are expected to be approved, based on published phase III trials. It will also explore other factors affecting optimal CINV control, including the role of patient-related risk factors and the role of physician adherence to antiemetic guidelines in reducing the residual risk of CINV.
- [Comparative Study of the Antiemetic Palonosetron for Lung Cancer Patients Treated with a Divided Dose of Cisplatin]. [English Abstract, Journal Article]
- Gan To Kagaku Ryoho 2016 Aug; 43(8):967-72.
Palonosetron(Palo)is a second-generation 5-hydroxytryptamine 3 receptor antagonist(5-HT3RA)effective in suppressing chemotherapy-induced nausea and vomiting in both acute and delayed phases.Most studies have reported Palo as an effective antiemetic for cisplatin(CDDP)chemotherapy(≥50mg/m2)administered on an intermittent basis.To assess the antiemetic efficacy of Palo, we performed a retrospective study in 16 patients with lung cancer who received Palo with split-dose CDDP, ifosfamide, and irinotecan(CPT-11)triple combination(CIC)therapy at Sapporo Minami-Sanjo Hospital between October 2010 and January 2012.T he CIC regimen consisted of CPT-11(50-60mg/m2)administered on days 1, 8, and 15, in addition to CDDP(15-20mg/m2)and ifosfamide(1,500mg/kg)for 4 consecutive days.On day 1, ramosetron was replaced with Palo in patients who had insufficient antiemetic control in accordance with guidelines on the management of highly emetogenic chemotherapy(HEC).There was a lower incidence of grade 1 or higher nausea(62.5%)in patients in the Palo-combination group than in those in the non-Palo-combination group(87.5%).No incidence of grade 3 or higher nausea was reported in either group.On the fifth day of chemotherapy, the incidence of nausea was significantly lower in the Palo-combination group(43.8%)than in the non-Palo-combination group(81.3%)(p<0.05).In addition, there was a significant decrease in the number of days of incidence and a significant increase in the number of days since the last episode was observed in the Palo-combination group.These results suggest that Palo, in particular, decreases the incidence of nausea and extends the number of days since its occurrence; moreover, it is effective in accelerating recovery.In conclusion, this study suggests that Palo exhibits excellent antiemetic efficacy in patients administered split doses of CDDP.
- Drug in adhesive patch of palonosetron: Effect of pressure sensitive adhesive on drug skin permeation and in vitro-in vivo correlation. [JOURNAL ARTICLE]
- Int J Pharm 2016 Aug 10; 511(2):1088-1097.
Palonosetron (PAL) is recommended for the prevention of chemotherapy-induced nausea and vomiting. The aim of this study was to develop a long-acting PAL transdermal patch to improve patient compliance. We were particularly concerned about the effect of pressure sensitive adhesives (PSAs) on PAL skin permeability. Formulation factors including PSAs, backing films and drug loadings were investigated in the in vitro skin permeation study using rabbit skin. Fourier transform infrared spectrometer study and thermal analysis were conducted to investigate the drug-PSA interaction and thermodynamic activity of PSAs, respectively. The results indicated that high drug skin permeation amount was obtained in PSA DURO-TAK(®)87-2516, which had low interaction potential with PAL and high thermodynamic activity. The optimized patch was composed of PAL of 8 %, DURO-TAK(®)87-2516 as PSA, CoTran™ 9700 as backing film and Scotchpak™ 9744 as release liner. The in vitro skin permeation amount of the optimized patch was 734.0±55.8μg/cm(2) during 3-day administration. The absolute bioavailability of the optimized patch was 43 % in rabbit and a good in vitro-in vivo correlation coefficient was obtained (R(2)=0.989). These results indicated the feasibility of PAL transdermal patch in the prevention of chemotherapy-induced nausea and vomiting.
- Prolonged drug-induced myoclonus: is it related to palonosetron? [JOURNAL ARTICLE]
- J Anesth 2016 Aug 10.
We report a case of drug-induced myoclonus possibly related to palonosetron, a second-generation 5-hydroxytryptamine-3 receptor antagonist which was administered as a prophylaxis for postoperative nausea and vomiting in a 28-year-old female. The recurrent episodes of myoclonus jerk involving the head, neck and shoulder persisted for a period of 4 days. The patient also exhibited an episode of severe bradycardia leading to hypotension 7 h after surgery. To our knowledge, this is the first report presenting these adverse events potentially associated with the use of palonosetron.
- Ca(2+) signaling and emesis: Recent progress and new perspectives. [REVIEW, JOURNAL ARTICLE]
- Auton Neurosci 2016 Jul 26.
Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca(2+))-dependent release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca(2+) signaling is triggered by activation of diverse emetic receptors (including tachykininergic NK1, serotonergic 5-HT3, dopaminergic D2, cholinergic M1, or histaminergic H1), whose activation in vomit-competent species can evoke emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein and bacterial toxins can also induce intracellular Ca(2+) elevation. Netupitant is a highly selective neurokinin NK1 receptor (NK1R) antagonist and palonosetron is a selective second-generation serotonin 5-HT3 receptor (5-HT3R) antagonist with a distinct pharmacological profile. An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo(®)) with >85% antiemetic efficacy is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Cannabinoid CB1 receptor agonists possess broad-spectrum antiemetic activity since they prevent vomiting caused by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, 5-HT3R agonists, and D2R agonists. Our findings demonstrate that application of the L-type Ca(2+) channel (LTCC) agonist FPL 64176 and the intracellular Ca(2+) mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca(2+)-ATPase inhibitor) cause vomiting in the least shrew. On the other hand, blockade of LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic efficacy against diverse agents that specifically activate emetogenic receptors such as 5-HT3, NK1, D2, and M1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the non-specific emetogen, cisplatin. In this review, we will provide an overview of Ca(2+) involvement in the emetic process; discuss the relationship between Ca(2+) signaling and the prevailing therapeutics in control of vomiting; highlight the evidence for Ca(2+)-signaling blockers/inhibitors in suppressing emetic behavior in the least shrew model of emesis as well as in the clinical setting; and also draw attention to the clinical benefits of Ca(2+)-signaling blockers/inhibitors in the treatment of nausea and vomiting.
- 2016 Updated MASCC/ESMO Consensus Recommendations: Prevention of Nausea and Vomiting Following High Emetic Risk Chemotherapy. [JOURNAL ARTICLE]
- Support Care Cancer 2016 Jul 22.
This review summarizes the recommendations for the prophylaxis of nausea and vomiting in adults receiving highly emetogenic chemotherapy (HEC) which includes cisplatin, mechlorethamine, streptozocin, cyclophosphamide >1500 mg/m(2), carmustine, dacarbazine, and the combination of an anthracycline and cyclophosphamide (AC) administered to women with breast cancer, as agreed at the MASCC/ESMO Antiemetic Guidelines Update meeting in Copenhagen in June 2015.A systematic review of the literature using PubMed and the Cochrane Database from 2009 to June 2015 was performed.The NK1-receptor antagonists netupitant (300 mg given in combination with palonosetron 0.5 mg as NEPA) and rolapitant have both completed phase II and III programs and were approved by FDA (both) and EMA (NEPA) in 2014-2015. Addition of one of these agents (or of (fos)aprepitant) to a combination of a serotonin (5-HT)3-receptor antagonist and dexamethasone improved the number of patients with a complete response (no emesis and no rescue medication) days 1-5 after AC HEC with 8-9 % and after non-AC HEC by 8-20 %. Olanzapine has improved control of delayed nausea as compared to aprepitant in a randomized open designed study. In the prophylaxis of delayed nausea and vomiting, metoclopramide is an option instead of aprepitant in patients receiving cisplatin-based chemotherapy and dexamethasone is an option instead of aprepitant in patients receiving AC chemotherapy.Two new NK1-receptor antagonists (netupitant and rolapitant) have been included in the updated recommendations as additional options to aprepitant or fosaprepitant. Addition of one of these NK1-receptor antagonists to a combination of a 5-HT3-receptor antagonist and dexamethasone is recommended in both non-AC HEC and AC HEC. Olanzapine is included as an option in HEC in particular if nausea is the main symptom.
- Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study. [Journal Article]
- Ann Oncol 2016 Aug; 27(8):1601-6.
There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC).Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea).Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369).The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point.UMIN000004863.
- Management of chemotherapy-induced nausea and vomiting by risk profile: role of netupitant/palonosetron. [Journal Article, Review]
- Ther Clin Risk Manag 2016.:917-25.
As recommended by most recent antiemetic guidelines, the optimal prophylaxis of chemotherapy-induced nausea and vomiting (CINV) requires the combination of 5-HT3 receptor antagonist (RA) with an NK1-RA. Moreover, the major predictors of acute and delayed CINV include: young age, female sex, platinum- or anthracycline-based chemotherapy, nondrinker status, emesis in the earlier cycles of chemotherapy, and previous history of motion/morning sickness. Despite improved knowledge of the pathophysiology of CINV and advances in the availability of active antiemetics, an inconsistent compliance with their use has been reported, thereby resulting in suboptimal control of CINV in several cases. In this scenario, a new anti-emetic drug is now available, which seems to be able to guarantee better prophylaxis of CINV and improvement of adherence to guidelines. In fact, netupitant/palonosetron (NEPA) is a ready-to-use single oral capsule, combining an NK1-RA (netupitant) and a 5-HT3-RA (palonosetron), which is to be taken 1 hour before the administration of chemotherapy, ensuring the coverage from CINV for 5 days. We reviewed the role of NEPA in patients at high risk of CINV receiving highly emetogenic chemotherapy. In these patients, NEPA plus dexamethasone, as compared to standard treatments, achieved superior efficacy in all primary and secondary end points during the acute, delayed, and overall phases, including nausea assessment. Moreover, these results were also achieved in female patients receiving anthracycline plus cyclophosphamide-based chemotherapy. NEPA represents a real step forward in the prophylaxis of CINV.
- Efficacy benefit of an NK1 receptor antagonist (NK1RA) in patients receiving carboplatin: supportive evidence with NEPA (a fixed combination of the NK1 RA, netupitant, and palonosetron) and aprepitant regimens. [JOURNAL ARTICLE]
- Support Care Cancer 2016 Jun 22.
Antiemetic guideline recommendations are inconsistent as to whether a neurokinin-1 receptor antagonist (NK1 RA) should be administered with a 5-hydroxytryptamine-3 (5HT3) RA + dexamethasone (DEX) in patients receiving carboplatin. Patients receiving cisplatin routinely receive an NK1 RA-containing regimen with a resulting 14-22 % benefit in no emesis rates over a 5-HT3 RA/DEX control. Recent studies suggest a similar benefit in patients receiving carboplatin. NEPA is the first fixed antiemetic combination agent and comprises the highly selective NK1 RA, netupitant, and pharmacologically distinct 5-HT3 RA, palonosetron (PALO). This paper presents the efficacy of NEPA in the subset of patients receiving carboplatin in a phase 3 trial (NCT01376297), in the context of aprepitant (APR) data in the carboplatin setting.One hundred ninety-six patients (47 % of all study patients: n = 145 NEPA + DEX; n = 51 APR + PALO + DEX) received carboplatin in a multinational, double-blind, randomized phase 3 study. Complete response (CR: no emesis/rescue) and no significant nausea (NSN: score ≤25 on 100 mm visual analog scale) rates were calculated.Cycle 1-4 overall (0-120 h) CR rates were similar for NEPA (80, 91, 92, and 93 %) and APR (82, 88, 88, and 90 %). Overall NSN rates were also similar (NEPA 84-96 %; APR 82-90 %).Response rates for NEPA and APR regimens were similar and consistent with prior studies evaluating the contribution of adding NK1 RAs in patients receiving carboplatin. Considering such evidence, guideline groups/practitioners should consider giving a NK1 RA antiemetic triplet in patients receiving carboplatin.
- New treatments on the horizon for chemoradiotherapy-induced nausea and vomiting. [Journal Article]
- Expert Opin Pharmacother 2016 Aug; 17(12):1623-9.
Antiemetic prophylaxis for the prevention of chemotherapy-induced nausea and vomiting, and the development of new antiemetic drugs are expanding areas of research. However, studies of antiemetic prophylaxis in chemoradiotherapy have not been prioritised, and little is known about the proper timing, duration, and combination of antiemetic drugs for the prevention of chemoradiotherapy-induced nausea and vomiting (C-RINV).The article summarises the available antiemetic studies, the evidence for antiemetic prophylaxis of C-RINV, and the future perspectives for antiemetic research in chemoradiotherapy.Antiemetic prophylaxis for patients receiving concomitant chemoradiotherapy has, for many years, been an orphan research area. The distinction between acute and delayed nausea and vomiting does not apply to fractionated radiotherapy, and prophylaxis should be considered to cover the entire course of treatment and not only the acute and delayed chemotherapy-induced nausea and vomiting. The best prophylaxis in women receiving fractionated radiotherapy and concomitant weekly cisplatin is a combination of the neurokinin receptor antagonist fosaprepitant with palonosetron and dexamethasone. Even with this three-drug combination nausea is a significant problem and the effect of multi-receptor targeting antiemetics such as olanzapine and amisulpride should be explored in this setting.