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New Therapies for Antiemetic Prophylaxis for Chemotherapy

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New Therapies for Antiemetic Prophylaxis for Chemotherapy Review New therapies for antiemetic prophylaxis for chemotherapy Mellar P Davis, MD, FCCP, FAAHPM Cleveland Clinic Lerner School of Medicine, Case Western Reserve University, and Taussig Cancer Institute, Te Cleveland Clinic, Cleveland, Ohio A number of new advances have occurred over the past 2 years in the management of chemotherapy-related nausea and vomit- ing (CINV). A new neurokinin-1 receptor antagonist (NK1RA), netupitant, has been combined with palonosetron in a single oral tablet for treating the effects of moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC). Rolapitant, another NK1RA, unlike aprepitant, has a long half-life and does not block CYP-3A4 and therefore has fewer drug in- teractions. Olanzapine reduces nausea more effectively than aprepitant in patients who are receiving HEC and is a better rescue antiemetic than is metoclopramide. Ginger lacks effcacy as an antiemetic agent for CINV. Although there was some evidence in a pilot study of gabapentin as an antiemetic, it was no better in reducing CINV than was placebo. Compliance to guidelines in mul- tiple settings ranges from 50%-60% but is improved by computerized order entry of antiemetics and recommendations displayed with chemotherapy. he presence of nausea, vomiting, and antagonist (5HT3RA) used for prophylaxis and anorexia at the end of chemotherapy has is combined with APR and dexamethasone for Ta synergistic detrimental efect on patient HEC;4-8 palonosetron 0.25 mg intravenously (IV) quality of life and signifcantly diminishes the ther- plus APR 125 mg by mouth plus dexamethasone apeutic beneft to palliative chemotherapy.1 Many 20 mg on Day 1, followed by 80 mg of APR on patients present with anorexia, nausea, and vomit- days 2 and 3 and dexamethasone 8 mg twice a day ing before chemotherapy which, if untreated, will through days 2-4. Te standard antiemetic prophy- adversely afect the tolerance to palliative chemo- laxis for MEC is palonosetron 0.25 mg IV or 0.5 therapy.1,2 Tere are multiple risk factors for emesis, mg by mouth plus dexamethasone 20 mg on the including young age, female gender, lack of regular day of chemotherapy only. Requirements for mul- alcohol use, motion sickness, emesis during preg- tiple antiemetics became evident clinically when nancy, and a history of emesis with previous chemo- 5HT3RAs were found to be inefective after 24 therapy.3 Antiemetic guidelines have included only hours. Mechanistically, substance P activation of drug choices based on chemotherapy and emeto- neurokinin-1 receptors (NK1Rs) on vagal aferents, genic classifcation. Choices are based on whether brainstem, and vomiting centers was found to be a chemotherapeutic drug or drug combination is important in generating delayed emesis.9 highly emetogenic (HEC), moderately emetogenic Compliance to guidelines is a problem – a sig- (MEC) or low emetogenic. Patient characteristics nifcant number of patients do not receive standard and their risks for emesis are not included in guide- antiemetics. Patient factors that adversely afect lines. Emesis has been the primary outcome in anti- compliance include the complexity of treatment emetic drug trials. Risk is divided into 2 timeframes; prophylaxis for HEC, polypharmacy, mucositis, and acute (0-24 hours after chemotherapy) and delayed depression. Physicians underestimate nausea and (25-120 hours after chemotherapy). Secondary end- vomiting. Physician work load and poor communi- points include nausea and quality of life.3 cation between physician and patient further reduce Major advances in the management of chemo- compliance.6 As a step forward in an efort to reduce therapy-induced nausea and vomiting (CINV) complexity of the treatment and improve compli- occurred in 2003 when both palonosetron and ance, the development of fosaprepitant eliminates aprepitant (APR) became commercially available. days 2 and 3 of APR for HEC and for adriamycin Palonosetron is the preferred serotonin receptor plus cyclophosphamide (AC) chemotherapy used Accepted for publication November 18, 2015. Correspondence: Mellar P Davis, MD, FCCP, FAAHPM; [email protected]. Disclosures: The author has no disclosures. JCSO 2016;14:11-20. ©2016 Frontline Medical Communications. DOI 10.12788/jcso.0207. Volume 14/Number 1 January 2016 J THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY 11 Review convergence input, which is transmitted to the dorsal vagus complex as the common eferent pathway.13 Besides serotonin, dopamine, substance P, histamine, and acetylcholine are involved in the vomiting refex. Tese neurotransmitters are located on the dorsal vagal complex, area postrema, and gastrointestinal tract.12 Dopamine is found within the chemoreceptor trigger zone. Substance P, which binds to neurokinin-1 (NK1) receptors, is located (colocated) with serotonin in the gastrointestinal tract and can be found in the NTS and area postrema. Te NK1 pathway parallels the serotonin pathway, and substance P is largely responsible for delayed nausea.9 Substance P within enterochromafn cells is released with serotonin substance P, crosses the blood-brain barrier, and binds to NK1 recep- tors within the NTS.14,15 Te symptom cluster of malaise and anorexia caused by cisplatin is not mediated through 5HT3 or NK1 recep- tors and will not respond to standard antiemetics. Cisplatin activates glutamate receptors in the dorsal vagal com- plex, lateral parabrachial nucleus, and central nucleus of the amygdala. In animal models, N-methyl-d-aspartate receptor antagonists reverse cisplatin anorexia and weight loss.16,17 Te unique pharmacology of palonosetron involves interactions with NK1 receptors and unlike other 5HT3 receptors, palonosetron up-regulates protein kinase C FIGURE 1 The emetic center consists of the circumventricular origin area posterior, nucleus tractus solitaries, and dorsal motor nucleus of the vagus. activity while internalizing 5HT3 receptors. Protein kinase A central pattern generator located near the emetic center coordinates the C phosphorylates NK1 receptors, which down-regulates emetogenic response. Multiple neurotransmitters are involved in generating NK1 receptor expression and allows the NK1 receptor emesis. Dopamine and serotonin are emetogenic. Substance P is respon- antagonist netupitant to successfully compete with sub- sible for delayed chemotherapy nausea and vomiting. Cannabinoids block 18 emesis through inhibition of serotonin-receptor responses. stance P for the remaining NK1 receptors. Cisplatin also increases calcium fux through L-type calcium changes. Nifedipine, an L-type calcium channel blocker, has a broad antiemetic activity in the least shrew; for breast cancer. Fosaprepitant is an APR pro-drug which low-dose nifedipine potentiates the antiemetic activity of is converted to active drug by phosphatases.10 palonosetron.19 Tis needs to be explored clinically. Te antiemetic mechanism to corticosteroids is not Pathophysiology of CINV well understood. Several mechanisms have been pro- Multiple neurotransmitters are involved in generating posed. Dexamethasone reduces CNS levels of tryptophan, vomiting. Te pathways and neurotransmitters for nau- a precursor to serotonin. Corticosteroid anti-infammatory sea are less well understood. Prophylaxis is more successful activity reduces serotonin release from the gastrointestinal in preventing emesis than nausea. Certain antiemetics are tract. Corticosteroids block production of prostaglandins more successful than others in preventing nausea.11 and leukotrienes, which are involved in emetogenesis, and In the vomiting refex, cisplatin damages the gastroin- blunt the stress responses and cortisol-releasing hormone. testinal tract leading to calcium dependent exocytic release Recent evidence suggests the corticosteroids enhance of serotonin (5HT) from enterochromafn cells within endocannabinoid and cannabinoid receptor expression mucosa. Serotonin binds to 5HT3 receptors on the dorsal within the dorsal vagus complex and stomach.20,23 vagal complex, which activate signals to the nucleus tractus solitarius (NTS) chemoreceptor trigger zone and central Therapies for CINV pattern generator. Te chemoreceptor trigger zone releases Palonosetron multiple neurotransmitters which activate the central pat- Palonosetron is unique among the 5HT3RAs in part tern generator. Eferent transmission goes to respiratory because of its long half-life and greater afnity for the muscles, vasomotor areas, salivary centers, abdominal mus- 5HT3 receptor relative to frst-generation 5HT3RAs. cles, diaphragm, and esophagus.12,13 Te NTS receives a However, this does not explain palonosetron’s unique 12 THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY g January 2016 www.jcso-online.com Davis benefts in reducing delayed emesis.24 If this were true, then stream activation of multiple kinases within the brainstem. repeated doses of a frst-generation 5HT3RA would have Tese downstream efects include the activation of extra- made up for palonosetron’s long half-life. Palonosetron allo- cellular signal-regulated protein kinase 1 and 2 (ERK1/2), sterically binds to 5HT3 receptors and increases palonose- protein kinase C (PKC), and protein kinase A (PKA). tron afnity for the receptor (called positive cooperativity), NEPA almost completely prevents emesis from cispla- which is unlike the bimolecular binding characteristics of tin in this animal model. Both drugs prevent PKA phos- frst-generation 5HT3RAs. Palonosetron uniquely triggers phorylation, but only the combination prevents the acute 5HT3 receptor internalization.
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