Chemotherapy-Induced Nausea and Vomiting

BioMed Research International

Guest Editors: Bernardo Leon Rapoport, Alexander Molasiotis, Haralambos Raftopoulos, and Fausto Roila Chemotherapy-Induced Nausea and Vomiting BioMed Research International Chemotherapy-Induced Nausea and Vomiting

This is a special issue published in “BioMed Research International.” All articles are open access articles distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Contents

Chemotherapy-Induced Nausea and Vomiting, Bernardo Leon Rapoport, Alexander Molasiotis, Haralambos Raftopoulos, and Fausto Roila Volume 2015, Article ID 457326, 2 pages

Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors,AnaLucia´ Costa, Catarina Abreu, Teresa Raquel Pacheco, Daniela Macedo, Ana Rita Sousa, Catarina Pulido, Antonio´ Quintela, and Lu´ıs Costa Volume 2015, Article ID 309601, 7 pages

A Randomized, Double-Blind Pilot Study of Dose Comparison of Ramosetron to Prevent Chemotherapy-Induced Nausea and Vomiting, Ka-Rham Kim, Gaeun Kang, Myung-Seo Ki, Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Ik-Joo Chung, Jong-Keun Kim, Seongwook Jeong, and Sang-Hee Cho Volume 2015, Article ID 523601, 7 pages

Management of Chemotherapy Induced Nausea and Vomiting in Patients on Multiday Cisplatin Based Combination Chemotherapy, Praveen Ranganath, Lawrence Einhorn, and Costantine Albany Volume 2015, Article ID 943618, 8 pages

A Review of NEPA, a Novel Fixed Antiemetic Combination with the Potential for Enhancing Guideline Adherence and Improving Control of Chemotherapy-Induced Nausea and Vomiting,PaulJ.Hesketh, Matti Aapro, Karin Jordan, Lee Schwartzberg, Snezana Bosnjak, and Hope Rugo Volume 2015, Article ID 651879, 12 pages

Efficacy of Olanzapine Combined Therapy for Patients Receiving Highly Emetogenic Chemotherapy Resistant to Standard Antiemetic Therapy, Masakazu Abe, Yuka Kasamatsu, Nobuhiro Kado, Shiho Kuji, Aki Tanaka, Nobutaka Takahashi, Munetaka Takekuma, and Yasuyuki Hirashima Volume 2015, Article ID 956785, 6 pages

Prophylactic Management of Radiation-Induced Nausea and Vomiting,PetraFeyer,FranziskaJahn, and Karin Jordan Volume 2015, Article ID 893013, 8 pages

Treatment of Breakthrough and Refractory Chemotherapy-Induced Nausea and Vomiting, Rudolph M. Navari Volume 2015, Article ID 595894, 6 pages

Biological and Pharmacological Aspects of the NK1-Receptor, Susana Garcia-Recio and Pedro Gascon´ Volume 2015, Article ID 495704, 14 pages Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 457326, 2 pages http://dx.doi.org/10.1155/2015/457326

Editorial Chemotherapy-Induced Nausea and Vomiting

Bernardo Leon Rapoport,1 Alexander Molasiotis,2 Haralambos Raftopoulos,3 and Fausto Roila4

1 The Medical Oncology Center of Rosebank, Saxonwold, Johannesburg 2196, South Africa 2School of Nursing, The Hong Kong Polytechnic University, Hong Kong 3Merck & Co., Rahway, NJ 07065, USA 4MedicalOncology,SantaMariaHospital,Terni,Italy

Correspondence should be addressed to Bernardo Leon Rapoport; [email protected]

Received 15 June 2015; Accepted 15 June 2015

Copyright © 2015 Bernardo Leon Rapoport et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In the past two decades, significant advances have been made The current antiemetic guidelines (MASCC/ESMO, ASCO, in the management of chemotherapy-induced nausea and and NCCN) endorse triple therapy treatment for patients vomiting (CINV). These advances are primarily due to a receiving cisplatin- and AC-based chemotherapy regimes [6– greater understanding of the physiological and molecular 8]. pathways underlying CINV,which resulted in major progress The current special issue includes several reviews includ- in the management of patients with CINV. ing the biology and pharmacology of the NK1 receptor and In the early 1990s, CINV treatment consisted of dex- substance P, the antiemetic management of germ cell tumor amethasone [1]. Improvements in the management of patients undergoing multiple days’ chemotherapy treatment, CINV control were achieved with the discovery of 5- radiotherapy induced nausea and vomiting (RINV), CINV hydroxytryptamine (5HT3) receptor and the development of induced by oral cytotoxic agents and targeted therapies in 5HT3 receptor antagonists (RA). This pathway is primarily patients undergoing treatment for solid tumors, adherence to involved in the acute phase of CINV. Subsequent studies CINV guidelines and the benefits of NEPA (a new agent con- demonstrated that the usage of the combination of 5HT3 RA sisting of a combination of netupitant and palonosetron), and and dexamethasone resulted in additional improvements in the treatment of breakthrough and refractory chemotherapy- CINV control [2, 3]. induced nausea and vomiting. Additionally, 2 original clinical Over the last decade, the discovery of the neurokinin-1 papers are presented investigating the ramosetron and olan- receptor antagonists (NK1-RA) and its role in the pathogen- zapine in the management of CINV. esis of delayed phase of CINV has led to significant develop- The review article by S. Garcia and P. Gascon provides an ments in the management of this complication of anticancer extensive overview of the basic knowledge of the NK1 recep- treatment. More importantly, these milestone achievements tor and substance P biology and the pharmacological basis of are significant and resulted in an improvement in anticancer the usage of NK1 receptor antagonists in the management of treatment compliance, as well as an improvement in the delayed phase of CINV. quality of life of patients diagnosed with cancer. The 5-HT3 receptor antagonists play an important role Despite these achievements, nausea, in particular, and in the pathogenesis of the acute phase of CINV. K.-R. vomiting remain a clinically significant problem for patients Kim et al. presented a pilot study with the potential usage receivingbothhighlyemetogenicchemotherapy(HEC)and of ramosetron, a tetrahydrobenzimidazole derivative struc- moderately emetogenic chemotherapy (MEC). Seventy per- turally independent of the previously developed 5-HT3 cent of patients treated with cisplatin-based HEC will achieve receptor antagonists, such as ondansetron, granisetron, and an overall antiemetic complete response when managed with tropisetron. a triple therapy consisting of a NK1 RA aprepitant in combi- Patients with germ cell tumor undergoing 5 days of nation with a 5HT3 RA and corticosteroids prophylaxis [4, 5]. cisplatin-based chemotherapy have a different mechanism 2 BioMed Research International and pattern of CINV compared to those receiving single day References chemotherapy. The efficacy of antiemetic drugs, as observed in single day chemotherapy, is therefore not applicable. In [1] M. S. Aapro and D. S. Alberts, “Dexamethasone as an antiemetic this issue, P. Ranganath et al. from Indiana University discuss in patients treated with cisplatin,” The New England Journal of Medicine,vol.305,no.9,article520,1981. current recommendations and future directions for patients undergoing multiple day treatment. [2] G. Falkson and A. J. van Zyl, “A phase I study of a new 5HT3- receptor antagonist, BRL43694A, an agent for the preven- Depending on the site of irradiation, dosing, fraction- tion of chemotherapy-induced nausea and vomiting,” Cancer ation, irradiated volume, and radiotherapy techniques, the Chemotherapy and Pharmacology,vol.24,no.3,pp.193–196, incidence of nausea and vomiting after radiotherapy is 1989. approximately 50–80%. RINV is a very important and not [3]D.B.Smith,E.S.Newlands,O.W.Spruytetal.,“Ondansetron well researched area often underestimated by physicians. (GR38032F) plus dexamethasone: effective anti-emetic prophy- K. Jordan et al. include an overview of RINV and current laxis for patients receiving cytotoxic chemotherapy,” British guidelines recommendations as well as future directions. Journal of Cancer,vol.61,no.2,pp.323–324,1990. The treatment of nausea and vomiting caused by oral [4] P. J. Hesketh, S. M. Grunberg, R. J. Gralla et al., “The antineoplastic agents is primarily empirical, consisting of the oral neurokinin-1 antagonist aprepitant for the prevention of administration of daily oral antiemetic therapy. The level of chemotherapy-induced nausea and vomiting: a multinational, evidence of prophylactic antiemetics recommended for these randomized, double-blind, placebo-controlled trial in patients agents is low. A. L. Costa et al. discuss the management receiving high-dose cisplatin—the aprepitant protocol 052 of CINV induced by oral cytotoxic agents and targeted study group,” Journal of Clinical Oncology,vol.21,no.22,pp. therapies in patients undergoing treatment for solid tumors. 4112–4119, 2003. This article highlights the differences in the classification of [5] S. Poli-Bigelli, J. Rodrigues-Pereira, A. D. Carides et al., “Addi- emetogenic potential of oral antineoplastic agents between tion of the neurokinin 1 receptor antagonist aprepitant to stan- the different international guidelines, as well as different dard antiemetic therapy improves control of chemotherapy- recommendations for prophylactic antiemetic treatments. induced nausea and vomiting: results from a randomized, double-blind, placebo-controlled trial in Latin America,” Can- NEPA is a new oral single fixed combination agent, cer,vol.97,no.12,pp.3090–3098,2003. containing a highly selective NK1 RA, netupitant with palonosetron. This agent is a pharmacologically and clinically [6] National Comprehensive Cancer Network, “NCNN Guidelines 1.2012: antiemesis 1.2015,” Tech. Rep. 1.2015, 2015. distinct 5-HT3 RA. Palonosetron has a longer half-life com- [7] F. Roila, J. Herrstedt, M. Aapro et al., “Guideline update pared with older 5-HT3 RAs. Palonosetron works synergis- for MASCC and ESMO in the prevention of chemotherapy- tically with netupitant and has the potential to improve the and radiotherapy-induced nausea and vomiting: results of the efficacy in the prevention of the delayed phase of CINV when Perugia consensus conference,” Annals of Oncology,vol.21, used in combination. P. J. Hesketh et al. discuss the use of supplement 5, pp. v232–v243, 2010. NEPA in the context of how NEPA may overcome some of the [8] E. Basch, A. A. Prestrud, P.J. Hesketh et al., “Antiemetics: Amer- barriers interfering with adherence to the various antiemetic ican Society of Clinical Oncology clinical practice guideline guidelines. update,” Journal of Clinical Oncology,vol.29,no.31,pp.4189– Several studies have shown that the antipsychotic agent 4198, 2011. olanzapine is effective in the management of CINV. The pharmacological mechanism of action consists of the blocking of neurotransmitter receptors including dopaminergic at D1,D2,D3,andD4 brain receptors, serotonergic at 5-HT2a, 5-HT2c,5-HT3,and5-HT6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors. In this special issue, R. M. Navari discusses the treatment of breakthrough and refractory chemotherapy-induced nausea and vomiting with special reference to olanzapine in this setting. In another paper, M. Abe et al. retrospectively analyze the role of olanzapine in 50 gynecologic cancer patients receiving cisplatin- basedchemotherapywhohadnauseadespitetheuseof standard therapy. The treatment of CINV is evolving and this special issue highlights some of the recent developments as well as some of the controversies in this important field of oncology.

Bernardo Leon Rapoport Alexander Molasiotis Haralambos Raftopoulos Fausto Roila Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 309601, 7 pages http://dx.doi.org/10.1155/2015/309601

Review Article Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors

Ana Lúcia Costa,1 Catarina Abreu,1 Teresa Raquel Pacheco,1,2 Daniela Macedo,1 AnaRitaSousa,1 Catarina Pulido,1 António Quintela,1 and Luís Costa1,2

1 Oncology Division, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, EPE, Avenida Professor Egas Moniz, 1649-035 Lisbon, Portugal 2Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal

Correspondence should be addressed to Lu´ıs Costa; [email protected]

Received 21 November 2014; Accepted 11 May 2015

AcademicEditor:BernardoL.Rapoport

Copyright © 2015 Ana Lucia´ Costa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances in its prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high, moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one day regimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targeted therapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oral antineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agents is low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the international guidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemetic regimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate risk and low to minimal risk of emetogenicity.

1. Introduction of emesis during pregnancy, impaired quality of life, and previous experience with chemotherapy [2, 3]. Chemotherapy-induced nausea and vomiting (CINV) is still The methodology for this review article was based on a common and debilitating side effect despite recent advances anelectronicsearchofthePubMeddatabasetoobtainkey in its prevention and treatment. literature in prevention of nausea and vomiting in patients At the 2004 Perugia Antiemetic Consensus Guideline undergoing oral anticancer therapies for solid tumors in the meeting, an expert panel used best available data to estab- last 10 years. There was also evaluation of the summary lish rankings of emetogenicity. The anticancer therapy was of product characteristics for each oral antineoplastic agent > divided into four emetic risk groups: high ( 90%), moderate mentioned and clinical trials that referred to the antiemetic < (30–90%), low (10–30%), and minimal ( 10%) [1]. These per- prophylaxis used and the results in the prevention of nausea centages represent the number of patients that will experience and vomiting. emesis after the administration of chemotherapeutic agents if no effective antiemetic prophylaxis has been given. The 2. Antineoplastic Oral Agents Emetogenicity emetogenic potential of the chemotherapeutic agents used is the main risk factor for the degree of CINV [2]andthe Oral chemotherapeutic agents are evaluated separately from onethatinfluencesthechoiceofantiemeticprophylaxis. intravenous agents, because of intrinsic differences in emeto- The other risk factors that can be present are young age, genicity as well as differing schedules of administration [1, 4]. female gender, not having a high alcohol intake, experience Emetogenic classification has been established based on that 2 BioMed Research International

Table 1: Emetogenic potential of oral antineoplastic agents most Table 2: Emetogenic potential of oral antineoplastic agents most used in solid tumors (based on MASCC and ESMO guidelines 2010). used in solid tumors (based on NCCN guidelines 2014).

MASCC and ESMO guidelines 2010 NCCN guidelines 2014 Degree of emetogenicity (incidence) Agent Degree of Hexamethylmelamine emetogenicity Agent High (>90%) Procarbazine (incidence) Cyclophosphamide Hexamethylmelamine Temozolomide Crizotinib Moderate (30–90%) ≥ 2 Vinorelbine Cyclophosphamide ( 100 mg/m /day) Imatinib Estramustine Capecitabine Moderate to Etoposide high Etoposide Lomustine (single day) Low (10–30%) Sunitinib Mitotane Everolimus Procarbazine Lapatinib Temozolomide (>75 mg/m2/day) Methotrexate Vismodegib Gefitinib Minimal (<10%) Axitinib Erlotinib Cabozantinib Sorafenib Capecitabine Cyclophosphamide (<100 mg/m2/day) Dabrafenib of a full course of oral antineoplastic therapy as clinically Erlotinib employed [4]. Everolimus International guidelines such as MASCC, ESMO, and Gefitinib NCCN guidelines give recommendations for antiemetic prophylaxis according to the grade of emetogenicity of oral Imatinib antineoplastic agents. Although there are no prospective Minimal to low Lapatinib clinical trials that can be used to recommend prophylactic Methotrexate antiemetics for oral antineoplastic drugs, all recommenda- Pazopanib tions are based on expert consensus and low levels of evidence Regorafenib [5]. Recommendations based on high levels of evidence are Sorafenib available only for intravenous agents. The tables referring to emetogenic potential of oral anti- Sunitinib 2 neoplastic agents in MASCC and ESMO guidelines published Temozolomide (<75 mg/m /day) in 2010 are slightly different from NCCN guidelines of 2014 Topotecan (Tables 1 and 2). Trametinib In MASCC and ESMO guidelines oral antineoplastic Vandetanib agents are classified into four risk groups as mentioned Vemurafenib above and in NCCN guidelines these agents are grouped into moderate to high risk and minimal to low risk groups. Also, in NCCN guidelines, there are mentioned agents not referred to in MASCC and ESMO guidelines, just like crizotinib, estramustine, lomustine, mitotane, and vis- Cyclophosphamide and temozolomide are classified as modegib in moderate to high risk group. Crizotinib and moderate risk in MASCC and ESMO guidelines and as vismodegib were approved by European Medicines Agency moderate to high risk or minimal to low risk in NCCN (EMA), respectively, in 2012 and 2013, after MASCC and guidelines according to the daily dosage and the association ESMO guidelines had been published. of temozolomide with radiotherapy. Oral vinorelbine is mentioned in moderate risk group Axitinib, cabozantinib, dabrafenib, pazopanib, rego- in MASCC and ESMO guidelines and is not mentioned in rafenib, trametinib, vandetanib, and vemurafenib are clas- NCCN guidelines. Oral vinorelbine is not available in the sified as minimal to low risk group in NCCN guidelines United States. and are not mentioned in MASCC and ESMO guidelines Imatinib is classified as moderate risk in MASCC and because EMA approval occurred between 2010 and 2014, after ESMO guidelines and as minimal to low risk in NCCN publication of these guidelines. guidelines. These small differences between these guidelines maybe Etoposide is classified as low risk in MASCC and ESMO due to little variations in the experience and expertise of the guidelines and as moderate to high risk in NCCN guidelines. panel members that collaborated for each one [6]. The NCCN BioMed Research International 3 guidelines are more recent and more frequently updated 4. Antineoplastic Agents with High but the bibliographic references are identical to MASCC Emetogenic Potential and ESMO guidelines [4]. Considerations about the dose of chemotherapeutic agents are only made on NCCN guidelines There are two oral chemotherapy agents with high emeto- for cyclophosphamide and temozolomide, suggesting that, genic potential, being rarely used in clinical practice [1, 6]. for lower doses of these drugs, the recommended antiemetic Hexamethylmelamine (also known as altretamine) is an prophylaxis for moderate risk of emetogenicity may be alkylating agent that may be used in persistent or recur- excessive. rent epithelial ovarian cancer. The recommended dosage is 2 Usually CINV is classified as acute, delayed, or anticipa- 260 mg/m /day in 4 divided doses for 14 or 21 days of a 28- tory, and these distinctions have important implications for day cycle. patient management [7]. Although with extended regimens Procarbazine is also an alkylating agent used in cen- of daily oral use the distinction between acute and delayed tral nervous system tumors. The PCV regimen includes 2 emesis is less clear, cumulative emesis must be considered, as procarbazine 60 mg/m on days 8 to 21 every 6 weeks (in some of the newer agents may only become emetogenic after combination with lomustine and vincristine) for 6 cycles or 2 a week or more of continuous administration [4, 5]. 75 mg/m on days 8 to 21 every 6 weeks (also in combination with lomustine and vincristine) for up to 4 cycles. 3. Antiemetics NCCN recommendations for antiemetic prophylaxis for moderatetohighemetogenicriskmaybefollowedforthese There are three categories of drugs most efficient forthe agents. management of CINV: type three 5-hydroxytryptamine (5- HT3) receptor antagonists, neurokinin-1 receptor (NK1R) 5. Antineoplastic Agents with Moderate antagonists, and glucocorticoids (especially dexamethasone) [7].Theseagentsareusedalone(glucocorticoids)orincom- Emetogenic Potential binations depending on the specific chemotherapy regimen The moderate risk category covers a wide range of frequencies being administered, as recommended in the MASCC and of emesis from 30% to 90%. The period of risk lasts for at least ESMO guidelines and in the ASCO guidelines [1, 8]. 2 days after the last dose of chemotherapy [6]. The prevention of acute and delayed CINV for intra- The agents included in this category are cyclophos- venous agents and one day regimens is well studied [1, 8], phamide, temozolomide, vinorelbine, and imatinib according although there is little data about management of CINV to MASCC and ESMO guidelines. caused by oral cytotoxic agents and targeted therapies, usually According to NCCN guidelines other agents are also administered in extended regimens of daily oral use. included such as crizotinib, estramustine, etoposide, lomus- NCCN guidelines recommend antiemetic prophylaxis for tine (single day), mitotane, and vismodegib. the following oral agents, classified as having high or moder- Cyclophosphamide is an alkylating agent. The oral ate emetic risk: hexamethylmelamine, crizotinib, cyclophos- 2 cyclophosphamide is used in adjuvant breast cancer reg- phamide (≥100 mg/m /day), estramustine, etoposide, lomus- imens just like cyclophosphamide, methotrexate, and flu- tine (single day), mitotane, procarbazine, temozolomide 2 2 2 orouracil (100 mg/m /dayondays1to14every28days (>75 mg/m /day or ≤75 mg/m /day with concurrent radio- for 6 cycles). In this regimen an antiemetic protocol for therapy), and vismodegib. The antiemetics recommended are high/moderate emetogenic chemotherapy is recommended oral 5-HT3 antagonists (such as dolasetron 100 mg po daily, [9]. The British Columbian Cancer Agency (BCCA) recom- granisetron 2 mg po daily, or 1 mg po bid or ondansetron 16– mends ondansetron 8 mg po and dexamethasone 8–20 mg po 24 mg po daily) with or without lorazepam (0.5–2 mg po or on D1 of chemotherapy and dexamethasone 4 mg po in the sublingualevery4orevery6honasneededbasis)andwith evening of D1 and then 4 mg po bid on D2-D3/4. Prochlor- or without either an H2 blocker or a proton pump inhibitor. perazine 10 mg po or metoclopramide 10–40 mg po could be These antiemetics should be started before chemotherapy and used on as needed basis [10]. In 1993, Buser et al. showed that continue daily during chemotherapy. For oral agents of low ondansetron given orally, 8 mg three times a day for 15 days, or minimal emetic risk no routine premedication is required was safe and effective in the control of emesis induced by oral and recommended antiemetics include oral 5-HT3 antago- multiple-day cyclophosphamide treatment in breast cancer nists, metoclopramide, prochlorperazine, or haloperidol with patients receiving chemotherapy with CMF [11]. or without lorazepam and with or without either an H2 Temozolomide is an alkylating agent used in malignant blocker or a proton pump inhibitor on as needed basis only brain tumors and in malignant melanoma (with brain metas- [6]. tasis). Patients with newly diagnosed malignant gliomas 2 There is no data incorporating NK1 receptor antagonists treated with concomitant temozolomide (75 mg/m po daily with oral regimens [6]. for 6 weeks) and RT should be medicated with ondansetron These antiemetic recommendations apply to oral 8 mg given 30 minutes prior to first dose of temozolomide chemotherapy only. When combined with intravenous and then prochlorperazine 10 mg po 30 minutes prior to each agents in a combination chemotherapy regimen, the anti- subsequent dose of temozolomide [10]. For adjuvant and pal- 2 emetic recommendations for the agent with the highest level liative temozolomide (150 mg/m once daily for 5 days every of emetogenicity should be followed. 28 days) the recommended premedication is ondansetron 4 BioMed Research International

8 mg po 30 minutes prior to each dose of temozolomide mentioned that the severity of nausea and vomiting due to [12, 13].PalonosetronhasbeentestedinaphaseIIstudyin oral etoposide is generally mild to moderate with treatment the adjuvant treatment of glioblastoma patients. A single dose discontinuation required in 1% of patients. Symptoms can of palonosetron 0.25 mg iv before the initiation of multiple usually be controlled with standard antiemetic therapy [23, oral doses of temozolomide, in patients on treatment with 24]. The emetic potential of oral etoposide was studied by steady doses of dexamethasone, provides a good protection Einhorn and Brames in 16 patients with refractory germ cell 2 against CINV throughout the overall phase (0–168 h) [14]. cancer who received daily oral etoposide 50 mg/m for 21 2 In malignant melanoma (temozolomide 200 mg/m /day for consecutive days every 4 weeks [25]. None of the patients 5 days every 28 days) the premedication is also ondansetron received prophylactic antiemetics, 11 of 16 had no nausea or 8 mg po 30 minutes prior to each dose of temozolomide [15]. vomiting, and only two patients required antiemetic support, Vinorelbine is a mitotic inhibitor. Oral vinorelbine is being treated with lorazepam and lorazepam with prochlor- used in non-small-cell lung cancer and in breast cancer in perazine.Theauthorssuggestedthatdailyoraletoposidedoes mono- or polychemotherapy. In monotherapy the starting not require prophylactic antiemetics. 2 dose is 60 mg/m givenondays1and8ofa3-weekcycle Lomustine is an alkylating agent (nitrosourea). It is used 2 in the treatment of recurrent malignant brain tumors. The and thereafter 80 mg/m on D1 and D8. It may induce nausea 2 or vomiting because of local gastrointestinal irritation, so a usual dosage is 130 mg/m (single dose at fasting or at bed- primary prophylaxis with 5-HT3 receptor antagonist 30 min time) once every 6 weeks. Nausea and vomiting may occur 3 before each intake is recommended [16]. In the associations to 6 hours after administration and the duration is generally < with cisplatin or taxanes the antiemetic regimens are chosen 24 hours [26]. BCCA suggests ondansetron 8 mg po plus based on these drugs because of their highest emetic risk. In dexamethasone 12 mg po 30 min before lomustine and then association with capecitabine or trastuzumab, the prophylaxis dexamethasone 4 mg po twice daily during 24 hours [27]. could be done with 5-HT3 receptor antagonist before vinorel- Mitotane is an adrenal cytotoxic agent. It is used in bine intake. adrenocortical carcinoma. The initial dose is 2 to 6 g daily in3 to 4 divided doses, and then it is increased incrementally to 8 Imatinib is a tyrosine kinase inhibitor. In GIST (adjuvant to 10 g daily in 3 to 4 divided doses. BCCA recommends pro- and metastatic) it is used as 400 mg once daily but may be phylactic antiemetic regimens for agents with low/moderate increasedupto800mgdaily(400mgtwicedaily)indisease emetic risk [10]. progression [17, 18]. In MASCC and ESMO guidelines it Vismodegib is a hedgehog pathway inhibitor. It is used is considered as having moderate emetogenic potential and in basal cell cancer (metastatic or locally advanced), 150 mg BCCA recommends antiemetic protocol for low/moderate once daily. BCCA suggests an antiemetic protocol for low emetogenic chemotherapy. In NCCN guidelines it is classified emetogenicity (dexamethasone 4–12 mg po), but antiemetics as minimal to low risk of emetogenicity and so no prophylaxis are not usually required [28]. of emesis is recommended. Crizotinib is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used in treatment of metastatic 6. Antineoplastic Agents with Low or ALK-positive non-small-cell lung cancer. It is administered Minimal Emetogenic Potential as 250 mg twice daily. BCCA does not recommend antiemetic premedication [19]. In the product monograph it is men- There are even less clinical trials of antiemetic prophylaxis tioned that median time to the onset for nausea and vomiting or treatment of emesis associated with agents of low or is 2 to 3 days and most events are mild to moderate in severity minimal emetogenic risk. This creates risk of overtreatment if anddeclinedinfrequencyafter3to4weeksoftreatment.In prophylactic regimens for drugs of moderate emetic potential clinical trials, the most commonly used antiemetic medica- are used [3]. tions were ondansetron and prochlorperazine [20]. For these agents NCCN guidelines recommend no rou- Estramustine is an alkylating agent used in hormone tine antiemetic premedication and suggest oral 5-HT3 antag- refractory and metastatic prostate cancer. The recommended onists, metoclopramide, prochlorperazine, or haloperidol dosage is 14 mg/kg/day (range: 10–16 mg/kg/day) in 3 or 4 with or without lorazepam and with or without either an H2 divided doses [21]. Transient nausea and vomiting may occur blocker or a proton pump inhibitor on as needed basis only during the first two weeks of therapy [22]. [6]. If nausea and vomiting occurs, single agent antiemetics Etoposide is a topoisomerase II inhibitor. It is classified as canbeusedinsubsequentcycles. havinglowemetogenicriskbyMASCCandESMOguidelines When low or minimal emetic risk oral agents are com- andasmoderatetohighriskbyNCCNguidelines.Itisusedin bined with intravenous agents the antiemetic recommenda- small cell lung cancer (first-line in combination, second-line tions for the agent with the highest level of emetogenicity alone or in combination), non-small-cell lung cancer (alone should be followed. or in combination), and testicular cancer (in combination, oral therapy for refractory disease). The usual dosage is 100 2 7. Management of Emetogenicity of to 200 mg/m /day for 5 days. If daily doses are >200 mg they Oral Regimens: Proposed Scheme should be administered in 2 divided doses. Dosage must be modified to take into account the myelosuppressive effects Considering the differences in the classification of of other drugs in the combination. The product monograph emetogenic potential of oral antineoplastic agents and BioMed Research International 5 the prophylactic antiemetic regimens recommended by So, other causes should be sought in these patients. the international guidelines, we propose the following A meticulous history and physical examination should be recommendations. performed. Symptom duration (acute versus chronic), frequency, temporal relationship with the oral antineoplastic General Recommendations agents or other drugs, severity, and the characteristics of vomiting episodes and associated symptoms must be char- (i) The anticancer agent must be taken with food, unless acterized. In some circumstances the etiology can be multi- it is specified differently in summary of product factorial. Most frequent disorders associated with nausea and characteristics. vomiting are listed in the following list. (ii) Choose the antiemetic regimens according to the emetogenic potential of the antineoplastic agent. Differential Diagnosis for Emesis in Patients under (iii) If the antiemetic regimen chosen is insufficient, asso- Oral Antineoplastic Treatment ciateanantiemeticfromadifferentcategory. (i) Tumor related causes are as follows: (iv) Check for possible interactions between each antineoplastic agent and the proposed antiemetic regimens. (a) malignant mechanical obstruction (bowel obstruction, gastric obstruction, and extrinsic Antiemetic Regimens. For oral antineoplastic agents with high compression by hepatomegaly or ascites); or moderate emetic risk we suggest antiemetic prophylaxis (b) increased intracranial pressure: primary or with oral 5-HT3 antagonists, such as ondansetron 8–16 mg secondary brain tumors; 30 minutes before the antineoplastic agent or 8 mg bid during (c) metabolic abnormalities: hypercalcemia, the days in which the oral antineoplastic is administered hyponatremia, and adrenal insufficiency. plus one or two days after it is ended. It may be associated with a glucocorticoid as dexamethasone 4–8 mg 30 minutes (ii) Treatment related causes are as follows: before the antineoplastic agent or 2–4mgbid during oral chemotherapy. The glucocorticoid is especially useful with (a) chemotherapy induced; antineoplastic agents administered one time each week (e.g., (b) anticipatory nausea and vomiting; vinorelbine). Olanzapine 10 mg once daily may be associated (c) radiotherapy induced; with continuous oral regimens (see the following list). (d) postoperative nausea and vomiting. High to Moderate Emetic Risk: Emesis Prevention (iii) Organic causes (generally not tumor related) are Start before chemotherapy and continue daily: as follows: (i) 5-HT3 antagonist: ondansetron 8 mg po bid, (a) acute gastritis/gastroenteritis; ± (ii) glucocorticoid: dexamethasone 2–4 mg po bid, (b) gastroesophageal reflux disease; (iii) ±olanzapine 10 mg po id. (c) functional gastrointestinal disorders; Fororalagentsofloworminimalemeticrisknoroutine (d) acute cholecystitis and acute pancreatitis; antiemetic premedication is required and if necessary dom- (e) constipation; peridone 10 mg 3-4 times daily or metoclopramide 10 mg 3- (f) chronic intestinal pseudo-obstruction; 4 times daily with or without lorazepam 0.5–2 mg every 4–6 (g) vestibular dysfunction; hours as needed is recommended (see the following list). (h) myocardial ischemia; (i) uremia; Low to Minimal Emetic Risk: Emesis Prevention (j) diabetic ketoacidosis; No antiemetic prophylaxis (k) hyperparathyroidism, hypoparathyroidism, Or and hyperthyroidism; (i) domperidone 10 mg po 3-4 times daily, or (l) sepsis; (m) hemorrhage intracranial and abscess (ii) metoclopramide 10 mg po 3-4 times daily, intracranial; ± (iii) lorazepam 0.5–2 mg every 4–6 hours as needed. (n) migraine; (o) pregnancy; 8. Differential Diagnosis for Emesis in Patients (p) psychiatric disease. under Oral Antineoplastic Treatment (iv) Drug-induced causes (may not be tumor related) The oral antineoplastic agents can be responsible for nausea are as follows: and vomiting in patients under treatment, but with the exception of some drugs previously mentioned, most of these (a) analgesics: opioids, tramadol, nonsteroidal drugs are relatively well tolerated. anti-inflammatory drugs, aspirin; 6 BioMed Research International

(b) antidepressants: selective serotonin reuptake [7] P. Hesketh, “Prevention and treatment of chemotherapy- inhibitors and bupropion; induced nausea and vomiting,” UpToDate,2014. (c) anticonvulsants; [8]E.Basch,A.A.Prestrud,P.J.Heskethetal.,“Antiemetics:american Society of Clinical Oncology clinical practice guideline (d) iron supplements; update,” Journal of Clinical Oncology,vol.29,no.31,pp.4189– (e) antibiotics/antivirals: erythromycin, tetracy- 2117, 2011. cline, sulfonamides, and acyclovir; [9] S. Ellard, BCCA Protocol Summary for Adjuvant Therapy (f) cardiovascular medications: digoxin, antiar- for High-Risk Breast Cancer using Cyclophosphamide (oral), rhythmics, antihypertensives, and oral antidia- Methotrexate and Fluorouracil, 2014. betics. [10] P. Hoskins, BBCA Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults,BC Cancer Agency, 2014. 9. Conclusions [11] K. S. Buser, R. A. Joss, D. 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[26] Bristol-Myers Squibb Canada, Lomustine (CeeNU) Product Monograph, Bristol-Myers Squibb Canada, Saint-Laurent, Canada, 2010. [27] B. Thiessen, BCCA Protocol Summary for Lomustine (CCNU) for Treatment of Recurrent Malignant Brain Tumours, 2014. [28] K. Savage, “BCCA Protocol Summary for the Treatment of Metastatic or Locally Advanced Basal Cell Carcinoma Using Vismodegib,” November 2014. Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 523601, 7 pages http://dx.doi.org/10.1155/2015/523601

Clinical Study A Randomized, Double-Blind Pilot Study of Dose Comparison of Ramosetron to Prevent Chemotherapy-Induced Nausea and Vomiting

Ka-Rham Kim,1 Gaeun Kang,2 Myung-Seo Ki,1 Hyun-Jeong Shim,1 Jun-Eul Hwang,1 Woo-Kyun Bae,1 Ik-Joo Chung,1 Jong-Keun Kim,2,3 Seongwook Jeong,4 and Sang-Hee Cho1

1 Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju 519-763, Republic of Korea 2Division of Clinical Pharmacology, Chonnam National University Hospital, Gwangju 519-763, Republic of Korea 3Department of Pharmacology, Chonnam National University Medical School, Gwangju 519-763, Republic of Korea 4Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju 519-763, Republic of Korea

Correspondence should be addressed to Sang-Hee Cho; [email protected]

Received 19 December 2014; Revised 21 January 2015; Accepted 3 February 2015

AcademicEditor:BernardoL.Rapoport

Copyright © 2015 Ka-Rham Kim et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. This study was conducted to determine the optimal dose titration of ramosetron to prevent the Rhodes Index ofNausea, Vomiting, and Retching (RINVR). Methods. Patients treated with folic acid, 5-fluorouracil, and oxaliplatin were randomized into three groups (0.3 mg, 0.45 mg, and 0.6 mg ramosetron before chemotherapy). The pharmacokinetics and pharmacodynamics using RINVR were evaluated. Results. Seventeen, 15, and 18 patients received ramosetron at doses of 0.3 mg, 0.45 mg, and 0.6 mg, 𝑇 𝐶 ⋅ respectively. max (h), max (ng/mL), and AUClast (ng h/mL) were associated with dose escalation significantly, showing a reverse correlation with the RINVR during chemotherapy. Acute CINV was observed in four patients (22.2%), two patients (14.3%), and one (5.6%) patient and a delayed CINV on day 7 was found in eight (47%), three (21.4%), and five (27.8%) patients in each group. The complete response rate was increased with dose escalation (35.3%, 50.0%, and 72.2% in each group) and also showed the tendency for decreasing moderate-to-severe CINV. Conclusions. This study shows a trend regarding the dose-response relationship for ramosetron to prevent CINV, including delayed emesis. It suggested that dose escalation should be considered in patients with CINV in a subsequent cycle of chemotherapy, and an individual approach using RINVR could be useful to monitor CINV.

1. Introduction and substance P/neurokinin-1 receptor (NK-1) systems have played important roles in controlling CINV, and block- Chemotherapy-induced nausea and vomiting (CINV) re- ing both systems has been demonstrated to reduce CINV mains one of the most feared adverse events of chemotherapy in patients receiving chemotherapy [3–5].Basedonthe among cancer patients [1].NotonlyearlyonsetCINV(acute, guidelines of the National Comprehensive Cancer Network, within 24 h after chemotherapy) but also delayed CINV patients receiving a moderately emetogenic chemotherapy ≥ ( 2 days after chemotherapy) can interfere with compli- (MEC) regimen are recommended a 5-HT3 receptor antag- ance of treatment and cause patients to receive delayed onist and dexamethasone, while those receiving a highly chemotherapy, contemplate refusing further treatment, and emetogenic chemotherapy (HEC) regimen are given a 5- develop anticipatory CINV [2]. CINV is an autonomic reflex HT3 receptor antagonist, a corticosteroid, and an NK-1 controlled by multiple neurotransmitter systems. Among receptor antagonist [6]. As shown above, the 5-HT3 receptor them, the serotonin/5-hydroxytrptamine 3 receptor (5-HT3) antagonist is the most crucial drug to control CINV in a 2 BioMed Research International

MEC or HEC regimen. However, even if the standard dose of 0–2 with adequate bone marrow and organ function were of the 5-HT3 receptor antagonist has been used, 20–30% of included in the present study (i.e., absolute neutrophil count patients complain of nausea or vomiting in practice [7, 8], ≥1,500/𝜇L, platelet count ≥100,000/𝜇L, serum bilirubin level and studies concerning the optimal concentration of 5-HT3 <2.0 mg/dL, creatinine level <1.5 mg/dL, and serum transam- receptor antagonists are lacking. inase levels less than twice the upper limit of normal). Patients Ramosetron, a new member in the class of selective were excluded from the study if they had obstructive symp- 5-HT3 receptor antagonists and is a tetrahydrobenzimida- toms due to previous stomach disease or intestinal adhesion, zole derivative structurally independent of the previously received radiotherapy, or sustained vomiting associated with developed 5-HT3 receptor antagonists, such as ondansetron, abnormalities in the central nervous system. Other exclusion granisetron, and tropisetron. Ramosetron is more potent criteria included a history of another malignancy, pregnancy, and has longer-lasting effects than older agents because of a or lactation, a history of or current distant metastasis, a slower rate of dissociation from the target receptor and higher historyofclinicallysignificantcardiacdiseasewithinthelast binding affinity [9]. 5-HT3 antagonists such as granisetron 6 months, active serious infection, or a psychiatric illness that or palonosetron have been investigated extensively regarding would preclude obtaining informed consent. the optimal dose to treat postoperative nausea and vomiting (PONV) or CINV. Generally, the dose required to prevent 2.2. Ethics Statement. The current study was a single center, CINV is two- to threefold higher than that needed for PONV prospective, double-blind, randomized trial conducted at [10–12]. However, a similar dose of ramosetron has been used Chonnam National University Hwasun Hospital and the for both PONV and CINV, and no study has evaluated the protocol was approved by the Institutional Review Board optimal dose titration for ramosetron to prevent CINV. Committee (CNUHH-2012-103). The trial was registered in To evaluate the efficacy of antiemetics, complete response ClinicalTrial.gov (NCT02076529,URL:https://clinicaltrials (CR: no emesis and no rescue medication) and complete .gov/ct2/show/NCT02076529?term=ramosetron&rank=1) protection (CP: no emesis, no use of rescue medication, anditwasconductedincompliancewiththegoodclinical and no significant nausea) have been commonly used as practice guidelines issued by the International Conference on meaningful indices [7, 13, 14]; nevertheless, they do not Harmonization of Technical Requirements for Registration quantify mild-to-severe CINV. The Rhodes Index of Nausea, of Pharmaceuticals for Human Use and the ethical principles Vomiting, and Retching (RINVR) was developed by Rhodes of the Declaration of Helsinki. Written informed consent was and McDaniel to assess nausea or vomiting after surgery or obtained from all patients before the start of any screening the administration of chemotherapy [15]. In this scale, eight procedure. items to evaluate the experience of nausea/vomiting, occurrence of nausea/vomiting, and issues with nausea/vomiting 2.3. Study Design and Treatment. After obtaining informed are listed. A higher point indicates more intense CINV; consent from the patients, they were assigned randomly to therefore, the RINVR is used to assess the severity of CINV receive a single intravenous (IV) dose of 0.3 mg, 0.45 mg, or more precisely. In addition, antiemetics have been widely 0.6 mg ramosetron administered 30 min before the first dose used; the incidence of vomiting has been decreased. In the of chemotherapy on day 1. Dexamethasone 10 mg was also contrary, nausea and retching have been major concerns and administered intravenously within 30 min before ramosetron a new parameter for monitoring CINV is needed. injection to prevent CINV and anaphylaxis from oxaliplatin. We hypothesized that if dose escalation of a 5-HT3 The randomization scheme was determined by the study’s antagonist could be effective against CINV, the frequency biostatistician based on a permuted block design (𝐾=6). or severity of CINV could also be reduced by subsequent The treatment allocation scheme was maintained by the study dose increases in the next cycle of chemotherapy in patients pharmacist who assumed the responsibility for blinded drug who experienced moderate-to-severe CINV in the previous distribution. After antiemetic preparation, all of the patients cycle. Based on this concept, the purpose of the present study received FOLFOX4 chemotherapy consisting of leucovorin, was to evaluate the optimal concentration of ramosetron to 2 200 mg/m /day given as a 2h infusion, followed by a bolus prevent CINV using the RINVR clinical parameter based on 2 of 5-fluorouracil, 400 mg/m , and a 22 h continuous infusion pharmacokinetic (PK) and pharmacodynamic (PD) studies 2 of 600 mg/m 5-fluorouracil, repeated for two consecutive as a pilot trial. 2 days. Oxaliplatin, 85 mg/m , was administered on day 1 only 2. Materials and Methods as a 2 h infusion in 250 mL dextrose 5%, concurrently with leucovorin. Rescue antiemetics were permitted during treat- 2.1. Patients. To evaluate the efficacy of ramosetron for each ment, and the results were recorded. All of the patients were dose, we limited the enrolled patients only to those receiving required to be hospitalized for 2 days to assess RINVR and FOLFOX (folic acid, 5-fluorouracil, and oxaliplatin), which collect blood samples. In addition, follow-up examination does not require inclusion of an NK-1 receptor antagonist was performed on day 8 (range, 6–10 days) to monitor the during the first cycle. Patients were eligible if they were safety. diagnosed with colon cancer and treated with FOLFOX as adjuvant chemotherapy after curative resection or palliation. 2.4. Blood Sample Preparation and Quantification of Ramo- Additionally, patients who were at least 19 years old and had setron. Blood samples for PK analysis were drawn at 10 min, an Eastern Cooperative Oncology Group performance score 1 h, 6 h, 24 h, and 48 h after the injection of ramosetron. The BioMed Research International 3 blood samples were collected into EDTA tubes. Each sample and no use of rescue medication during the first cycle of ∘ was then centrifuged at 1500 g for 10 min at 4 C. At least chemotherapy. ∘ 0.4 mL plasma was harvested and stored at −70 Cuntilanal- Safetywasevaluatedbasedontheresultsoflaboratory ysis. The plasma concentrations of ramosetron were analyzed tests and electrocardiography. The signs and symptoms were using validated high-performance liquid chromatography- graded according to the Common Terminology Criteria for tandem mass spectrometry (HPLC-MS/MS). Briefly, 200 𝜇L Adverse Events (CTCAE), version 4.0. plasma sample was mixed with 20 𝜇Lofaninternalstandard (5 ng/mL risperidone). Next, 1.5 mL methyl tert-butyl ether 2.7. Statistics. This study was planned as a pilot study to was added, and the mixture was vortexed for 2 min and evaluate the efficacy of dose escalation of ramosetron. Since centrifuged at 12,000 rpm for 2 min. The supernatants were thereisnodataontargetpopulationtouseforsamplesize transferred and evaporated under nitrogen. The residue was calculation for pilot study, we adopt sample size that was reconstituted in 100 𝜇L40%acetonitrile,and10𝜇Lofthe used in a previous similar granisetron study [16]. Data are latter mixture was injected into the HPLC-MS/MS system presented as mean ± SD for continuous data and absolute (HPLC system, Shimadzu LC-20A HPLC system (Shimadzu frequencies (n) and percentages for frequency data. To assess Co., Kyoto, Japan); MS/MS system, API 4000Q-TRAP mass the pharmacokinetic linearity, statistical comparisons of spectrometer (AB SCIEX, Framingham, MA, USA)). The the dose-normalized 𝐶max (𝐶max/D), dose-normalized AUC 𝑉 column was a Gemini C18 2.0 × 100 mm (Phenomenex, (AUClast/D), T1/2,CL,and ss among the ramosetron dose Torrance, CA, USA), and the mobile phase consisted of groups were performed using the Kruskal-Wallis test. One- ammonium acetate (10 mM) and acetonitrile (40 : 60, v/v). way analysis of variance (with Bonferroni post hoc test) was The flow rate was maintained at 0.25 mL/minute. Linear utilized to assess the differences in patient characteristics and to compare the RINVR score and concentration of calibration curves were validated in the ranges of 0.1– 2 2 𝜒 100 ng/mL for ramosetron (𝑟 = 0.98). The intra- and ramosetron. test or Fisher’s exact probability test was interday precision and accuracy were verified within 15% and used to compare the proportions of categorical variables. The 85–115%, respectively. number of emetic episodes, severity of nausea, and RINVR were compared among the ramosetron dose groups using the Kruskal-Wallis test. Statistical significance was recognized 2.5. Pharmacokinetic Analysis. The pharmacokinetic param- when the 𝑃 value was less than 0.05. SPSS version 21.0 (IBM, eters of ramosetron were analyzed by noncompartmental Inc., Chicago, IL, USA) was utilized for statistical analyses. methods using WinNonlin version 6.3 (Pharsight Co., Moun- tain View, CA, USA). The maximum concentration (𝐶max) and time to 𝐶max (𝑇max)wereobtaineddirectlyfromthe 3. Results concentration-time data. The area under the concentration- 3.1. Patient Characteristics. From October 2012 to October time curve of ramosetron from zero to the last measurable 2013,fifty-onepatientswereenrolled,andonepatientrefused concentration (AUClast)wascalculatedusingthelineartrape- to participate in the present study; therefore, the data from zoidal rule. From the terminal slope of the concentration 50 patients were analyzed. Seventeen, 15, and 18 patients time curve, the elimination rate constant was estimated using received ramosetron at a dose of 0.3 mg, 0.45 mg, and linear regression, and the terminal half-life (T1/2), clearance 0.6 mg, respectively. Their baseline clinical characteristics are (CL), and volume of distribution at the steady state (𝑉 )were ss summarized in Table 1. There was no difference between calculated. the groups in terms of sex, age, weight, height, or body surface area (BSA). Although female is well known risk factor 2.6. Evaluation of Nausea/Vomiting and Safety. The RINVR, for CINV, thirty-three patients (66%) were male in present used to assess the degree of CINV, comprises eight ques- study. This result is associated with colon cancer prevalence tions, each with a total of five choices rating the frequency which is more common in male than female. Thirty-eight and intensity of symptoms. Among the survey questions, patients (74%) were diagnosed with stage III colon cancer numbers 1, 4, 6, 7, and 8 address the subclass of symptom after curative resection, and 12 patients (26%) with stage IV occurrence, and numbers 2, 3, and 5 address the subclass disease. Patients with nausea, vomiting, or retching despite of symptom distress by assessing the degree of discomfort using ramosetron received metoclopramide, domperidone caused by the symptoms. The scores from all eight questions maleate, or lorazepam as rescue medication. There was no arethensummedtoobtainthesubclassofsymptomexperi- significantdifferenceinthefrequencyoftherescuedose ence points. Therefore, the total sum of the nausea, vomiting, among the ramosetron dose groups. and retching experience points is defined as RINVR point. RINVR was recorded during an interview at 1 h, 6 h, 24 h, 3.2. Pharmacokinetic Analysis. The mean plasma concen- and 48 h after starting chemotherapy. Seven days after start- tration-time profiles of ramosetron at doses of 0.3 mg, ing chemotherapy, the RINVR was reassessed by telephone 0.45 mg, and 0.6 mg are shown in Figure 1. Table 2 shows interview to evaluate the presence of delayed emesis. The the arithmetic mean ± standard deviations (SDs) of the RINVR score was divided into four groups for comprehensive pharmacokinetic parameters determined using noncompart- analysis as follows: none (0), mild (1–8), moderate (9–16), mental analysis. A dose-dependent increase in the mean and severe (17–32). A CR was defined as no emetic episode 𝐶max and AUClast of ramosetron is shown in all three dose 4 BioMed Research International

Table 1: Clinical characteristics. 0.3 mg 0.45 mg 0.6 mg 𝑃 value (𝑁 =17) (𝑁 =15) (𝑁 =18) Male 8 (53.3%) 12 (80.0%) 13 (72.2%) 0.157 Age (year) 58.94 ± 9.74 61.64 ± 7. 76 5 7. 72 ± 10.13 0.547 Weight (kg) 63.82 ± 11.83 62.94 ± 10.34 61.82 ± 9.07 0.385 Height (cm) 162.72 ± 4.92 164.31 ± 7.67 163.62 ± 7.55 0.885 BSA (m2)1.69± 0.18 1.70 ± 0.16 1.67 ± 0.18 0.923 Colon cancer Stage III 12 (71%) 12 (80%) 14 (78%) 0.895 Stage IV 5 (29%) 3 (20%) 4 (22%) Use of rescue antiemetic 3 (17.6%) 5 (33.3%) 3 (16.7%) 0.810 Data are presented as mean ± standard deviation. BSA, body surface area

10 Table 2: Pharmacokinetic parameters of ramosetron after a single intravenous injection of 0.3, 0.45, and 0.6 mg of ramosetron.

8 0.3 mg 0.45 mg 0.6 mg (𝑁 =17) (𝑁 =15) (𝑁 =18)

6 𝐶max (ng/mL) 3.2 ± 1.3 4.9 ± 3.3 7.3 ± 9.3

𝑇max (h) 0.67 0.67 0.67 ⋅ ± ± ± 4 AUClast (ng h/mL) 17.9 6.9 25.9 16.0 35.2 34.8 𝑇1/2 (h) 6.4 ± 2.2 6.5 ± 3.2 6.4 ± 1.8 2 CL (L/h) 17.1 ± 6.6 21.3 ± 13.6 22.5 ± 11.8 𝑉 ± ± ± ss (L) 110.6 38.7 128.5 60.6 142.3 86.6

Ramosetron concentration (ng/mL) concentration Ramosetron ± 0 Data are presented as mean standard deviation. 𝐶max, maximum concentration; 𝐶max/𝐷, maximum concentration/dose; 𝑇 𝐶 0 5 10 15 20 25 max,timeto max;AUClast, area under the concentration-time curve of ramosetron from zero to the last measurable concentration; AUC /𝐷,area Time (h) last under the concentration-time curve of ramosetron from zero to the last 0.3 N = 17) 𝑇 𝑉 mg ( measurable concentration/dose; 1/2, terminal half-life; CL, clearance; ss, 0.45 mg (N = 15) volume of distribution at steady state. 0.6 mg (N = 18)

Figure 1: Mean plasma concentration-time profiles of ramosetron Table 3: Rhodes Index of Nausea, Vomiting, and Retching (RINVR) after a single intravenous injection of 0.3, 0.45, and 0.6 mgof scores among 0.3 mg, 0.45 mg, and 0.6 mg dosing groups at 1 hour, ramosetron. Bars represent standard errors. 6 hours, 1 day, 2 days, and 7 days after starting chemotherapy. 0.3 mg 0.45 mg 0.6 mg (𝑁 =17) (𝑁 =15) (𝑁 =18) groups. The mean 𝐶max ranged from 3.2 to 7.3 ng/mL, and the 1 hr 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 mean AUClast ranged from 17.9 to 35.2 ng⋅h/mL. The mean 6 hr 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 clearance (CL) and volume of distribution at the steady state 1 day 0.78 ± 1.56 0.36 ± 0.93 0.11 ± 0.47 𝑉 ( ss) were in the ranges of 17.1–22.5 L/h and 110.6–142.3 L/h, 2days 1.11± 2.52 0.79 ± 1.12 0.44 ± 1.34 respectively, for the three ramosetron dose groups. There 7days 3.61± 4.80 0.71 ± 1.44 2.39 ± 4.07 were no significant differences in the 𝐶max/D (𝑃 = 0.450), Data are presented as mean ± standard deviation. AUClast/D (𝑃 = 0.301), T1/2 (𝑃 = 0.845), CL (𝑃 = 0.235), or 𝑉 𝑃 ss ( = 0.361) among the ramosetron dose groups, indicating that ramosetron exhibited linear pharmacokinetic properties. significance between the RINVR and dose escalation, buta reverse correlation with RINVR was found at 1 day (𝑃= 3.3. Efficacy of Ramosetron in Dose Escalation. Nausea is 0.237)and7days(𝑃 = 0.377) after starting chemotherapy the most common symptom of CINV (40%), followed by according to dose escalation. Twenty-five patients (80%) had retching (18%) and vomiting (8%). None of the patients CINV of at least one point on the RINVR, among whom had CINV during the first 6 h after starting chemotherapy. nine patients (18%) showed moderate or severe RINVR. One CINV showed an increasing tendency for 7 days. The total day after starting chemotherapy, four patients (22.2%), two RINVR scores at 1 h, 6 h, 24 h, 48 h, and 7 days after starting patients (14.3%), and one (5.6%) patient who received 0.3 mg, chemotherapy are shown in Table 3.Therewasnostatistical 0.45 mg, and 0.6 mg of ramosetron, respectively, showed BioMed Research International 5

Table 4: Treatment related adverse events (𝑛 =50).

Dose of ramosetron 0.3 mg, 𝑛 (%) 0.45 mg, 𝑛 (%) 0.6 mg, 𝑛 (%) Grade 1 Grade 2 Grade 1 Grade 2 Grade 1 Grade 2 AST 1 (6) 1 (6) 0 0 1 (6) 0 ALT 2 (12) 1 (6) 1 (7) 0 2 (11) 0 r-GTP 1 (6) 1 (6) 0 0 1 (6) 0 Constipation 3 (18) 1 (6) 0 0 3 (17) 0 Rash 0 0 1 (7) 0 0 0 ECG QT prolongation 0 0 0 0 1 (6) 0

100 no subjective symptoms, and the condition disappeared on the next cycle of chemotherapy. The incidence and grade of 90 events were similar among the three dose groups (Table 4). 80

70 4. Discussion

60 When the role of chemotherapy is expanded as an adjuvant or for palliation, the willingness to preserve the quality of 50 life and the completion of planned chemotherapy are also increased. Although 5-HT3 antagonists and neurokinin-1 40 inhibitors can provide better supportive care than they did

RINVR (% of patients) RINVR (% of 30 previously [7, 17], limitations of these drugs persist. CINV is associated not only with the chemotherapeutic regimen but 20 also with patient characteristics, such as previous morning sickness, age, gender, performance status score, and smoking 10 or alcohol habits [18]. The standard dose of antiemetics would not be sufficient for high-risk patients, and the precision 0 0.3 0.45 0.6 marker to predict these high-risk patients has not been (mg) identified. Therefore, the meticulous and individual approach used for patients with CINV in the previous cycle would be Moderate-severe None important to prevent further CINV on subsequent cycles. Mild Several studies concerning the dose escalation of antiemetics to prevent CINV have been performed [19, 20]. The Figure 2: Total Rhodes Index of Nausea, Vomiting, and Retching first generation of 5-HT3 antagonists, such as ondansetron, (RINVR) score during 7 days according to ramosetron dose group (𝑛=50). dolasetron, granisetron, and tropisetron, has been very effective in the control of acute emesis but has not been as effective against delayed emesis [21, 22]. Among 5-HT3 antagonists, ramosetron and palonosetron are recently developed agents. CINV. Delayed CINV 7 days after chemotherapy occurred Ramosetron has been shown to have higher selectivity for in eight (47%), three (21.4%), and five (27.8%) patients in the serotonin than other first generation 5-HT3 antagonists respective ramosetron groups. Patients who received a higher showing superior efficacy in the acute and delayed CINV dose of ramosetron showed a greater trend for a CR than did than other first generation 5-HT3 antagonists. Palonosetron, patients who received a lower dose of ramosetron (Figure 2). which is second generation of 5-HT3 antagonists, has been Regarding the severity, all symptoms for 2 days were graded investigated extensively in the setting of PONV and CINV as as mild RINVR. However, five (29%) and three patients (17%) a recommended dose of 0.075 mg IV and 0.25 mg IV, respec- inthe0.3and0.6mgramosetron-treatedgroups,respectively, tively. Compared with palonosetron, the study of ramosetron showed moderate RINVR on day 7. Severe RINVR was seen has been limited, and the recommended dose of ramosetron in only one patient who was treated with 0.3 mg ramosetron. is0.3mgIVinbothPONVandCINV.Inapreviousstudy evaluating the efficacy of different doses of palonosetron 3.4. Safety. Of the 50 patients, there were no grade 3 or 4 (0.075 mg, 0.25 mg, and 0.75 mg IV in each group), CR was adverse events. Constipation and elevated liver enzymes were achieved in 44.4% of the 0.25 mg group and 59.3% of the common symptoms, but most of these were considered to 0.75 mg group in patients receiving Adriamycin/carboplatin beunrelatedtoramosetronandinsteadwereassociatedwith or epirubicin/carboplatin. This was very similar to the current underlying disease or chemotherapy. One patient showed results showing a CR of 35.3% in the 0.3 mg group and 61.1% QT prolongation on electrocardiography; however, he had in the 0.6 mg group. Not only dose escalation but also the 6 BioMed Research International repeated administration of palonosetron improved CINV number of female patients who are more prone to CINV,thus using0.75mgIVondays1and3[23]. As a result, CR diluting the efficacy of the antiemetics. Further large-scale occurred in 76.9% of patients who received MEC or HEC. studies are needed to confirm the efficacy of dose escalation The studies that used high doses of palonosetron up to sixfold in the subsequent chemotherapy for patients who showed the standard dose suggest that dose escalation of a 5-HT3 moderate-to-severe CINV in previous chemotherapy. antagonist could improve CINV. In the present study, twice the standard dose (0.6 mg) of ramosetron resulted in better clinical outcomes compared with the standard dose (0.3 mg) 5. Conclusion in chemotherapy-na¨ıve patients. This suggests that the dose This pilot study showed dose-dependent pharmacokinetics of ramosetron needed to be escalated to control CINV or of ramosetron with a better RINVR trend according to the escalated individually in patients that experienced CINV, dose escalation with a good safety profile. In addition, RINVR despite the prevention using a standard dose of ramosetron. would be a useful tool to assess the quantification of CINV. Although the stratification was not performed according to Based on this pilot trial, further large-scale study is needed gender, age, height, weight, or BSA, there was no significant for more robust clinical outcomes. difference in each dose group. In pharmacokinetic analyses, the current study showed the highest AUClast of ramosetron inthe0.6mggroupamongthethreedosinggroups;therefore, Conflict of Interests the 0.6 mg group had a higher exposure to ramosetron than did the low-dose group when the other conditions were The authors declare that there is no conflict of interests consistent. regarding the publication of this paper. In addition to clinical effectiveness for CINV, the current study revealed that RINVR is a useful tool to monitor CINV. Acknowledgments In addition to CR or CP, the National Cancer Institute- Common Terminology Criteria (NCI-CTC) have been used ThisstudywassupportedbyHealth&MedicalTechnology to monitor nausea or vomiting related to chemotherapy R&D Project from Korea National Enterprise for Clinical toxicities. However, it is not completely sufficient to reflect Trials (A07000112311450100). the CINV based only on its frequency and degree of nausea and vomiting or retching. The current study showed improvement in the RINVR according to the dose of ramosetron with References moderate-to-severe RINVR in six (35%) and three patients [1] C. C. Sun, D. C. Bodurka, C. B. Weaver et al., “Rankings (17%) treated with 0.3 mg and 0.6 mg of ramosetron on day and symptom assessments of side effects from chemotherapy: 7, respectively. 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Scholl et al., “Comparison of the 5- RINVR score showed an increasing tendency over 7 days, hydroxytryptamine3 (serotonin) antagonist ondansetron (GR and47%ofthepatientswhoreceived0.3mgramosetronhad 38032F) with high-dose metoclopramide in the control of CINV at least of one score of RINVR; in contrast, 28% of cisplatin-induced emesis,” New England Journal of Medicine, the patients who received 0.6 mg ramosetron experienced vol. 322, no. 12, pp. 816–821, 1990. CINV on day 7. Although the concentration of ramosetron [5]D.G.Warr,S.M.Grunberg,R.J.Grallaetal.,“Theoral was cleared within the first 2 days according to the phar- NK1 antagonist aprepitant for the prevention of acute and macokinetic data, this result suggested that the control of delayed chemotherapy-induced nausea and vomiting: pooled acute emesis could affect the delayed emesis, and a high dose data from 2 randomised, double-blind, placebo controlled of ramosetron could help to reduce the delayed emesis. 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[9]Y.K.Kang,Y.H.Park,B.Y.Ryooetal.,“Ramosetronforthe [22]J.T.Hickok,J.A.Roscoe,G.R.Morrowetal.,“5-hydrox- prevention of cisplatin-induced acute emesis: a prospective ran- ytryptamine-receptor antagonists versus prochlorperazine for domized comparison with granisetron,” Journal of International control of delayed nausea caused by doxorubicin: a URCC Medical Research,vol.30,no.3,pp.220–229,2002. CCOP randomised controlled trial,” The Lancet Oncology,vol. [10]T.Mihara,K.Tojo,K.Uchimoto,S.Morita,andT.Goto, 6, no. 10, pp. 765–772, 2005. “Reevaluation of the effectiveness of ramosetron for preventing [23] Y. Ikari, K. Ogata, Y. Nakashima et al., “Safety and pharma- postoperative nausea and vomiting: a systematic review and cokinetic evaluation of repeated intravenous administration of meta-analysis,” Anesthesia and Analgesia,vol.117,no.2,pp.329– palonosetron 0.75 mg in patients receiving highly or moderately 339, 2013. emetogenic chemotherapy,” Supportive Care in Cancer,vol.22, [11] R. M. Navari, “Palonosetron for the treatment of chemotherapy- no.7,pp.1959–1964,2014. induced nausea and vomiting,” Expert Opinion on Pharma- cotherapy,vol.15,no.17,pp.2599–2608,2014. [12] G. U. Roh, S. Y. Yang, J. K. Shim, and Y. L. Kwak, “Efficacy of palonosetron versus ramosetron on preventing opioid-based analgesia-related nausea and vomiting after lumbar spinal surgery: a prospective, randomized, and double-blind trial,” Spine,vol.39,no.9,pp.E543–E549,2014. [13] S. Poli-Bigelli, J. Rodrigues-Pereira, A. D. Carides et al., “Addi- tion of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy- induced nausea and vomiting: results from a randomized, double-blind, placebo-controlled trial in Latin America,” Can- cer, vol. 97, no. 12, pp. 3090–3098, 2003. [14] F. Roila, M. Tonato, F. Cognetti et al., “Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone,” Journal of Clinical Oncology,vol.9,no.4, pp.675–678,1991. [15] V. A. Rhodes and R. W. McDaniel, “The Index of Nausea, Vomiting, and Retching: a new format of the lndex of Nausea and Vomiting,” Oncology Nursing Forum, vol. 26, no. 5, pp. 889– 894, 1999. [16] R. de Wit, A. C. de Boer, G. H. M. Vd Linden, G. Stoter, A. Sparreboom, and J. Verweij, “Effective cross-over to granisetron after failure to ondansetron, a randomized double blind study in patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy,” British Journal of Cancer,vol.85,no.8,pp.1099–1101,2001. [17] F. Roila, J. Herrstedt, M. Aapro et al., “Guideline update forMASCCandESMOinthepreventionofchemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference,” Annals of Oncology,vol.21, supplement 5, pp. v232–v243, 2010. [18] I. Sekine, Y. Segawa, K. Kubota, and T. Saeki, “Risk factors of chemotherapy-induced nausea and vomiting: index for personalized antiemetic prophylaxis,” Cancer Science,vol.104, no. 6, pp. 711–717, 2013. [19] Y. Segawa, K. Aogi, K. Inoue et al., “A phase II dose-ranging study of palonosetron in Japanese patients receiving moderately emetogenic chemotherapy, including anthracycline and cyclophosphamide-based chemotherapy,” Annals of Oncology, vol. 20, no. 11, pp. 1874–1880, 2009. [20] M. Maemondo, N. Masuda, I. Sekine et al., “A phase II study of palonosetron combined with dexamethasone to prevent nausea and vomiting induced by highly emetogenic chemotherapy,” Annals of Oncology, vol. 20, no. 11, pp. 1860–1866, 2009. [21] O. Geling and H.-G. Eichler, “Should 5-hydroxytryptamine- 3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic reevaluation of clinical evidence and drug cost implications,” Journal of Clinical Oncology,vol.23,no.6,pp.1289–1294,2005. Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 943618, 8 pages http://dx.doi.org/10.1155/2015/943618

Review Article Management of Chemotherapy Induced Nausea and Vomiting in Patients on Multiday Cisplatin Based Combination Chemotherapy

Praveen Ranganath, Lawrence Einhorn, and Costantine Albany

Indiana University School of Medicine, Indianapolis, IN 46202, USA

Correspondence should be addressed to Praveen Ranganath; [email protected]

Received 25 November 2014; Revised 10 May 2015; Accepted 30 May 2015

Academic Editor: Alexander Molassiotis

Copyright © 2015 Praveen Ranganath et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction of cisplatin based chemotherapy has revolutionized the treatment of germ cell tumors. A common side effect of multiday cisplatin chemotherapy is severe nausea and vomiting. Considerable progress has been made in the control of these side effects since the introduction of cisplatin based chemotherapy in the 1970s. Germ cell tumor which is a model for acurable neoplasmhasalsoturnedintoanexcellenttestinggroundtodevelop effective strategies to prevent chemotherapy induced nausea and vomiting (CINV) in multiday cisplatin based regimens. The use of combination of a 5-hydroxytryptamine (HT)3 receptor antagonist, a neurokinin-1 (NK1) antagonist, and dexamethasone has greatly improved our ability to prevent and control acute and delayedCINV.MechanismandpatternofCINVwithmultidaychemotherapymaydifferfromthoseinsingledaychemotherapyand therefore efficacy of antiemetic drugs as observed in single day chemotherapy may not be applicable. There are only few randomized clinical trials with special emphasis on multiday chemotherapy. Further studies are essential to determine the efficacy, optimal dose, and duration of the newer agents and combinations in multiday cisplatin based chemotherapy.

1. Introduction regimens for patients undergoing multiday cisplatin combination chemotherapy regimen. Germ cell tumor, which Germ cell tumors are rare cancers accounting for only 1% is a model for a curable neoplasm, has also turned into of all malignancies in American males. The introduction an excellent testing ground to develop effective strategies of cisplatin based combination chemotherapy revolution- to prevent chemotherapy induced nausea and vomiting ized the treatment of germ cell tumors. The majority of (CINV) in these regimens. Phases II and III randomized patients with testicular cancer are cured with standard dose clinical trials focusing on multiday chemotherapy regimens cisplatin based combination chemotherapy [1]. A common are summarized in Table 1. The purpose of this paper is side effect of cisplatin based regimens is severe nausea and to review our current understanding of CINV in multiday vomiting. Cisplatin in germ cell tumors is administered for cisplatin regimens and to evaluate clinical agents available for five consecutive days and is appropriately categorized as prevention and treatment of CINV as well as areas of future highly emetogenic chemotherapy (HEC) with patients being research. vulnerable to nausea and vomiting on all five days. Median number of emetic episodes with cisplatin based regimens in 2. Pathophysiology the 1970s and the 1980s for germ cell tumors on day 1 was ten anddecreasingonsubsequentdays[2]. These symptoms were It has been established that different pathways exist in the significantly debilitating for patients. Considerable progress body that induce emesis, each relying on a set of different neu- hasbeenmadeinthecontrolofnauseaandvomitingfrom rotransmitters, including serotonin, dopamine, histamine, those early days but there is still paucity of data on antiemetic and substance P. Receptors for these neurotransmitters are 2 BioMed Research International

Table 1: Selected phases II and III trials of various agents for treatment of chemotherapy induced nausea and vomiting in patients undergoing multiday cisplatin based chemotherapy.

Emesis Study Phase 𝑁 CINV prophylaxis Nausea Day 1 CR Days 1–5 CR Einhorn et al., II 36 Ondansetron 77% 30% NA 1990 [14] Sledge et al., Ondansetron versus 78% versus 14% VAS s cores 8 versus III 45 30%versus9%(𝑝 = 0.002) 1992 [15] metoclopramide (𝑝<0.001) 58.5 (𝑝<0.001) Granisetron versus Bremer, 1992 alizapride (substituted 90% versus 66% III 200 49% versus 35%. NA [17] benzamide) + (𝑝<0.001) dexamethasone Ondansetron + Fox et al., 1993 dexamethasone + VAS s cores 5.5 versus III 45 95%versus82% 55%versus32%(𝑝 = 0.22) [21] chlorpromazine versus 15 (p = 0.046) ondansetron 40% versus 44% Patient Noble et al., Ondansetron versus III 200 NA preference, 34% versus 26% NA 1994 [18] granisetron (𝑝 = 0.048) VAS s core of 0 (no 73% versus 41% (𝑝<0.0001). nausea) day 1: 88% Dolasetron + Fauser et al., CR rates on each study day versus 60% III 210 dexamethasone versus NA 2000 [22] were also significantly higher (𝑝<0.001); day 5: dolasetron (𝑝 = 0.029) 63% versus 37% (𝑝 = 0.017) Einhorn et al., Palonosetron + No or mild nausea, II 41 88% 51% 2007 [23] dexamethasone self-reported 59%

Aprepitant + 5-HT3 RA (other than VAS: aprepitant better Albany et al., palonosetron) + III 69 NA 47% versus 15% (𝑝 = 0.01) than placebo on all 6 2012 [24] dexamethasone versus days aprepitant + dexamethasone Aprepitant + Hamada et al., Mild to no nausea II 30 palonosetron + NA 90% 2014 [25] 70% dexamethasone

CR: complete response (no emesis and no need for rescue medication); VAS: visual analog scale for nausea; 5-HT3 RA: 5-hydroxytryptamine receptor antagonists; NA: not available.

found in high numbers in the dorsal vagal complex, area of emesis [5]. Preclinical studies have shown that NK1- postrema, and gastrointestinal tract [3]. Cisplatin damages receptor antagonists prevent emesis by acting centrally within the GI tract and causes calcium dependent exocytic release the NTS [6]. Evaluation of NK1 receptor antagonists in of 5-hydroxytryptamine (HT)3 from enterochromaffin cells animal emesis models also indicated that they were highly in the GI mucosa. Released 5-HT3 binds to its receptors effective against the delayed phase of emesis caused bycis- on the vagal afferent neurons and this binding activates platin [5, 6]. Dopamine receptors are also present in CTZ and thechemoreceptortriggerzone(CTZ)andvomitingcenter dopamine antagonists like phenothiazines, butyrophenones, (VC). When CTZ is activated, it also releases various neuro- andmetoclopramidehavebeeneffectiveintreatingCINV, transmitters which in turn stimulate the VC. Once activated, although restricted by their side effects. the VC modulates efferent transmission to respiratory, vaso- motor, and salivary centers as well as to abdominal muscles, diaphragm, and esophagus, resulting in emesis [3, 4]. 3. Historical Perspective Substance P is a neurotransmitter of the tachykinin family and is widely located in the central and peripheral nervous Phenothiazines, introduced as antipsychotic medications, system, including gut, the nucleus tractus solitarius (NTS), were the first group of drugs to demonstrate activity in and the area postrema. It acts through the neurokinin-1 chemotherapy induced vomiting and remained the main- (NK1) pathway and has been implicated in the pathogenesis stay of antiemetic therapy for almost 3 decades from their BioMed Research International 3 introduction in the 1950s. Standard agents included chlorpro- 35 patients receiving 4- to 5-day cisplatin based regimens. mazine hydrochloride and prochlorperazine which mainly Ten patients (29%) had no vomiting or retching throughout acted as dopamine antagonists. Low doses were not effective the entire study period and 18 patients (51%) experienced while higher doses carried risk of extrapyramidal reactions, two or fewer emetic episodes during the entire study period. liver dysfunction, marrow aplasia, and excessive sedation. Ondansetron was very well tolerated in all 35 patients [14]. A Theywerealsoineffectiveifpatientfailedtorespondtoitin subsequent phase III study by Sledge Jr. et al. [15]evaluated3 the first course of treatment [7]. intravenous doses of ondansetron 0.15 mg/kg intravenously Metoclopramide, a substituted benzamide, was used in or metoclopramide 1 mg/kg in patients undergoing multi- Europefordecadesforpreventionofmotionsicknessbutwas day cisplatin chemotherapy. Proportion of patients with no considered ineffective against chemotherapy induced nausea. emetic episodes throughout the entire study period was But in the 1980s, it was discovered that massive doses of the higher in the ondansetron arm (30% versus 9%, 𝑝 = 0.077). drug (2 mg/kg given before and after chemotherapy) helped Significantly fewer antiemetic treatment failures (more than to minimize nausea and vomiting in most patients treated five emetic episodes or withdrawal from the study) occurred with cisplatin. However, high doses of metoclopramide were with patients given ondansetron (9%) than with those associated with troublesome Parkinsonian symptoms which given metoclopramide (50%) during the entire study period were somewhat dissipated with addition of diphenhydramine (𝑝 = 0.002). Although ondansetron clearly demonstrated [8]. superiority over metoclopramide as a single agent, 70% of Steroids, particularly dexamethasone, were tried alone patients treated with ondansetron in this study experienced and in various combinations with older agents with good at least one emetic episode during the 5-day treatment control of nausea and vomiting. In combination with meto- period. Ondansetron was very efficacious on the first day clopramide and other agents like lorazepam, it was noted of chemotherapy and its effect diminished over subsequent that 50–60% of patients experienced no emesis compared days. to around 20% with either of the agents alone [9]. CINV Other 5-HT3 receptor antagonists, such as granisetron prophylaxis with combination of dexamethasone and meto- and dolasetron, were subsequently approved by the FDA and clopramide was the mainstay of treatment in the 1980s till have demonstrated equivalent efficacy and toxicity relative introduction of ondansetron. At Indiana University, metoclopramide or lorazepam in combination with dexamethasone to ondansetron [16]. A single blind prospective study by before and after cisplatin for the first 2 days, followed the granisetron study group evaluated efficacy of prophylac- by chlorpromazine on the other 3 days, was utilized with tic intravenous granisetron versus alizapride (a substituted adequate antiemetic efficacy in patients undergoing multiday benzamide) with dexamethasone in patients receiving frac- cisplatin based chemotherapy. tionated chemotherapy (cisplatin or ifosfamide) for 5 days. Based on observations that smoking marijuana helps Granisetron was superior to the combination in preventing to alleviate CINV, tetrahydrocannabinol as an antiemetic nausea and vomiting, 54% versus 43% complete responders, agent was evaluated by Sallan et al. Antiemetic effect was respectively, in the cisplatin group. Adverse events were observed in 14 of 20 tetrahydrocannabinol courses and in also lower in the granisetron group [17]. A subsequent, 0 of 22 placebo courses. No patient had vomiting episodes double-blind, randomized, and crossover comparison of while experiencing a subjective “high” [10]. Subsequently, in single daily intravenous doses of granisetron compared with a double-blind prospective study, Einhorn et al. demon- three daily intravenous doses of ondansetron in 5-day frac- strated superiority of nabilone, a synthetic cannabinoid, com- tionated chemotherapy demonstrated equal efficacy, safety, pared to prochlorperazine in patients undergoing multiday and patient preference, with both agents achieving good cisplatin chemotherapy. In patients treated with prochlor- control of emetic symptoms with 5-day complete response perazine, the mean number of emetic episodes on the first rates of 44.0% with granisetron compared to 39.8% in the day of multiple-day cisplatin therapy was 10.3 compared with ondansetron arm [18]. 7.05 on nabilone. It was however associated with significant Single agent 5-HT3 receptor antagonists were ineffective dry mouth and dysphoria [11]. This has not been replicated in prevention of delayed CINV, which is a major issue with in the era of 5-HT3 receptor antagonists. A study by Meiri multiday cisplatin based chemotherapy. A meta-analysis of 5 et al. evaluating dronabinol, ondansetron, or combination studies comparing a 5-HT3 receptor antagonist as monother- demonstrated equivalent efficacy between all groups and did apy compared to placebo showed no clinical evidence of not show any benefit from addition of cannabinoids to a 5- improvement of control of delayed emesis with addition HT3 receptor antagonist [12]. of 5-HT3 receptor antagonists [19]. In early clinical trials, addition of dexamethasone consistently improved efficacy 4. 5-HT Receptor Antagonist compared to 5-HT3 receptor antagonist alone, making it 3 the standard for patients receiving cisplatin based therapy. Just as cisplatin revolutionized the cure rate for germ cell In a multicenter trial looking at ondansetron plus dexam- tumors, ondansetron, the first 5-HT3 receptor antagonist, ethasone compared to ondansetron alone in cisplatin based greatly mitigated the severe cisplatin-associated nausea and chemotherapy, patients who received the combination had vomiting [13]. In 1990, Einhorn et al. piloted ondansetron higher complete antiemetic response rate (61% versus 46%) 0.15 mg/kg intravenously for 3 doses in a phase II study with and less nausea as per visual analog scale (18% versus 33%) 4 BioMed Research International

Table 2: Antiemetic prophylaxis regimen for multiday cisplatin chemotherapy for germ cell tumors, Indiana University protocol.

Day 1 Day 2 Day 3 Day 4 Day 5 Days 6–8 Dexamethasone Dexamethasone Palonosetron Palonosetron Dexamethasone 20 mg IV 20 mg IV 0.25 mg IV 0.25 mg IV 4mgBIDPO ∗ Palonosetron Fosaprepitant Fosaprepitant 0.25 mg IV 150 mg IV 150 mg IV ∗ Alternatively, ondansetron 16 mg orally daily can be utilized from days 1–5 if palonosetron is not available.

[20].Foxetal.conductedaphaseIIItrialin44patients the nausea they experienced had no significant effect on daily comparing ondansetron with combination of ondansetron, functioning. Recently, two studies have demonstrated that dexamethasone, and chlorpromazine in multiday cisplatin single dose (0.25 mg IV) of palonosetron maintains response chemotherapy. There was a reduction in total number of rates for acute and delayed CINV over repeated courses emetic episodes in favor of the combination arm but this did of chemotherapy in patients on HEC [30, 31]. An open- not reach statistical significance (55 versus 32%, 𝑝 value = label, single-arm, and multicenter study was performed in 0.22). Mean change of nausea control measured by visual ana- patients with testicular germ cell tumor who were scheduled log scale (VAS) was superior with the combination regimen. to receive 5-day cisplatin based combination chemotherapy. It isunsurewhatrolechlorpromazineplayed inthisstudy and The antiemetic therapy consisted of palonosetron 0.75 mgon it is questionable that it added much value to the ondansetron day 1, aprepitant 125 mg on day 1, 80 mg on days 2 to 5, dexam- and dexamethasone combination [21]. A bigger phase III ethasone 9.9 mg on day 1, and 6.6 mg on days 2 to 8. Complete trial demonstrated that adding dexamethasone to dolasetron response (CR) rate, which was defined as no vomiting and no significantly increased effectiveness in preventing nausea rescue medication use, was achieved in 90% of the patients in and vomiting related to fractionated cisplatin chemotherapy. the first chemotherapy course, and high CR rates were also Complete response rates were significantly better in all 5 days observed in the second and third courses (82.1 and 78.3%, in the combination arm compared to dolasetron alone [22]. resp.) [25].ThistrialwasconductedinJapan,where0.75mg These studies clearly established the superiority of 5-HT3 intravenous dose of palonosetron is the commonly used receptor antagonist-dexamethasone combination in multiday dose. Trials evaluating single dose (0.25 mg intravenously) of cisplatin based chemotherapy and soon became the standard palonosetron or head to head comparison of palonosetron of care. compared to ondansetron in multiday cisplatin chemother- However optimal duration of dexamethasone has never apy have not been performed. Our antiemetic prophylaxis been clearly established. Side effects of 5 consecutive days recommends palonosetron 0.25 mg IV on days 1, 3, and 5, of dexamethasone during cisplatin administration and three basedonthephaseIItrialresults.Ondansetron16mgorally additional days for delayed nausea and vomiting and repeated dailyondays1–5canbealternativelyusedinpatientswhoare courses every 3 weeks are going to be substantial [26]. In unable to get palonosetron due to insurance reasons or other a retrospective study evaluating dexamethasone toxicity in issues (Table 2). patients receiving moderately emetogenic chemotherapy, all patients received dexamethasone (10 or 20 mg intravenously) 5. NK1 Receptor Antagonists and oral dexamethasone for delayed prophylaxis (4 mg twice daily for 2-3 days). In this study, 45% of patients reported Introduction of NK1 receptor antagonists substantially inc- moderate to severe problems with insomnia, 27% had indi- reased our ability to control nausea and vomiting and is gestion or epigastric discomfort, and 27% had agitation [27]. now an important component of antiemetic management Late toxicity from dexamethasone is of particular concern, strategies in multiday cisplatin based chemotherapy. In particularlywithavascularnecrosisofthehiponlongterm the first multicenter, double-blind, and placebo-controlled dexamethasone [26, 28]. Our antiemetic prophylaxis regimen trial conducted by Navari et al., addition of NK1 receptor antagonists (aprepitant) to granisetron and dexamethasone for cisplatin chemotherapy in germ cell tumors restricts resulted in significant decrease in acute CINV and delayed dexamethasone to days 1 and 2 of cisplatin administration emesis for single day HEC [32]. In 3 studies comparing the (Table 2). addition of aprepitant (125 mg on day 1, 80 mg on days 2 Palonosetron is a unique 5-HT3 receptor antagonist with and 3) to intravenous ondansetron 32 mg (on day 1) and oral activity at both central and GI sites and also has a long dexamethasone (12 or 20 mg on days 1 and 8 or 16 mg on days plasma terminal phase elimination half-life of approximately 2 and 3), addition of aprepitant resulted in absolute increase in 40 hours [29]. A phase II trial by Einhorn et al. [23]evaluated complete response rate from 11% to 20%, favoring aprepitant. palonosetron 0.25 mg IV on chemotherapy days 1, 3, and 5 Also there was a significant benefit observed in prevention of plus dexamethasone in patients receiving multiday cisplatin delayed emesis [33–35]. chemotherapy for germ cell tumor. Majority of patients had Albany et al. (see Table 1)conductedthefirstrandomized, no emesis at any time throughout days 1–5 (51%) or days double-blind, placebo-controlled, and phase III crossover 6–9(83%),hadnomoderateorseverenausea,anddid study evaluating the oral NK1 antagonist aprepitant in com- not require rescue medication. Most patients reported that bination with several 5-HT3 receptor antagonists (except BioMed Research International 5

palonosetron) and dexamethasone in patients with germ cell selective NK1 receptor antagonist, netupitant, and the 5-HT3 tumors receiving 5-day cisplatin combination chemotherapy receptor antagonist, palonosetron. Hesketh et al. conducted [24]. Patients were randomly assigned to aprepitant 125 mg a phase II randomized double-blind study in 694 patients on day 3 and 80 mg per day on days 4 through 7 or to placebo undergoing cisplatin based chemotherapy with combination with initial course and crossover to opposite treatment with of NEPA. Different oral doses of netupitant (100, 200, and thesecondcourse.Among69patientsinthestudy,42% 300mg) and palonosetron 0.50mg, all given on day 1, achieved complete response for days 1–8, defined as no emetic were compared to a standard 3-day regimen of aprepitant, episodes with no use of rescue medication with aprepitant, with ondansetron as an additional exploratory arm. All compared with 13% in the placebo group (𝑝 value < 0.01). NEPA doses showed superior overall complete response Only 16.2% of patients who got aprepitant had one or rates compared with palonosetron (87.4%, 87.6%, and 89.6% more emetic episodes compared to 47.1% with placebo. No for NEPA100, NEPA200, and NEPA300, resp., versus 76.5% statistically significant difference was noted in visual analog palonosetron; 𝑝 value < 0.050) with the highest NEPA300 scale(VAS)fornausea,butitwasnumericallysuperiorwith dose studied showing an incremental benefit over lower aprepitant. Also patient preference was higher for aprepitant NEPA doses for all efficacy endpoints. NEPA showed superi- cycle compared to placebo. Dexamethasone was used only ority for all key efficacy end points of no emesis, no significant on days 1 and 2 for the acute phase to decrease the adverse nausea, and complete protection (no emesis and no signifi- effects of corticosteroids. This may have contributed tothe cant nausea) rates even during the delayed (25–120 h) phase. loss of control on days 3 through 5 during the acute phase Safety profile was similar to aprepitant and ondansetron and on days 6 through 8 in the delayed phase. Utilizing [40]. This trial specifically excluded patients getting multiday dexamethasone in patients receiving three to four cycles cisplatin chemotherapy but appears to be a promising therapy ofBEPchemotherapywouldputthemathigherriskfor warranting further evaluation with randomized clinical trials multiple complications including insomnia, hyperglycemia, in multiday cisplatin chemotherapy. and avascular necrosis of hip. Palonosetron, with its longer Olanzapine is an atypical antipsychotic medication which half-life, is probably more attractive in this setting and is blocks multiple neurotransmitter receptors including dopa- included in our antiemetic prophylaxis regimen (Table 2). minergic, serotonergic, adrenergic, and histamine receptors. Pharmacokinetics interactions of aprepitant should be Two phase III clinical trials have been conducted to evaluate carefully evaluated in clinical practice. It has been noted efficacy and safety of olanzapine compared with 5-HT3 to decrease plasma concentrations of other agents that are receptor antagonists. In a study by Tan et al., 229 patients metabolized by CYP3A4 or CYP2C9 [36]. Aprepitant has receiving moderately emetogenic chemotherapy (MEC) and been shown to cause a twofold increase in the area under the highly emetogenic chemotherapy (HEC) were randomly plasma concentration curve (AUC) of dexamethasone, which assigned to azasetron, dexamethasone, and olanzapine or to is a sensitive substrate of CYP3A4 and therefore oral steroid azasetron and dexamethasone. Complete response rate in dose should be reduced by 50% when used in combination HEC group was significantly improved for both the delayed with aprepitant. There might also be interaction with warfarin period (69.64% versus 30.43%, 𝑝 < 0.05)andtheoverall and it would require close monitoring [37]. period (69.64% versus 28.26%, 𝑝 < 0.05), but no differ- Fosaprepitant is a water-soluble phosphoryl prodrug for ence was noted in the acute phase. Patients reported better aprepitant which is administered intravenously and rapidly quality of life on olanzapine [41]. Navari et al. conducted converts to aprepitant within 30 minutes of administration an additional phase III study in patients receiving HEC. 249 [38]. Single dose fosaprepitant (150 mg intravenously) in patients were randomized to either olanzapine or aprepitant combination with granisetron 40 𝜇g/kg intravenously on day in combination with palonosetron and dexamethasone. Rate 1 and dexamethasone on days 1–3 was evaluated in a phase of control of chemotherapy induced emesis was comparable II trial against control regimen of placebo plus intravenous between the two regimens while nausea was significantly bet- granisetron and dexamethasone. Complete response (no ter controlled with olanzapine arm particularly in the delayed emesis and no rescue therapy) was significantly higher in phase [42]. Both these studies did include cisplatin based the fosaprepitant group than in control group (64% versus chemotherapy but excluded multiday cisplatin chemother- 47%, resp.). The fosaprepitant regimen was more effective apy. So it is difficult to draw any conclusions about the than the control regimen in both the acute phase (94% versus effectiveness of olanzapine in patients undergoing multiday 81%, 𝑝 = 0.0006)andthedelayedphase(65%versus49%, cisplatin chemotherapy without further trials. Other newer 𝑝 = 0.0025)[39]. Currently, the Hoosier Clinical Research agents like rolapitant and gabapentin have also not yet been Network (HCRN) is conducting a multicenter, phase II studiedinmultidaychemotherapysetting. study of fosaprepitant with 5-HT3 receptor antagonists and dexamethasone in patients with germ cell tumors undergoing 7. Practice Guidelines and Our Practice 5-day cisplatin based chemotherapy. Practice guidelines (from the National Comprehensive Can- 6. Novel Agents and Emerging Therapies cer Network (NCCN), Multinational Association of Support- ive Care in Cancer/European Society for Medical Oncol- Netupitant and palonosetron (NEPA) is the first antiemetic ogy (MASCC/ESMO), and American Society of Clinical combination agent developed, comprised of a new, highly Oncology (ASCO)) recommend a combination of antiemetic 6 BioMed Research International agents for the prevention of CINV with HEC, specifically [7] G. Wampler, “The pharmacology and clinical effectiveness of “triple therapy” with an NK1 receptor agonist, a 5-HT3 phenothiazines and related drugs for managing chemotherapy- receptor agonist, and dexamethasone [43–45], to be given induced emesis,” Drugs, vol. 25, supplement 1, pp. 35–51, 1983. prophylactically on all days of chemotherapy regimen. [8] A. Stoudemire, P. Cotanch, and J. 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Review Article A Review of NEPA, a Novel Fixed Antiemetic Combination with the Potential for Enhancing Guideline Adherence and Improving Control of Chemotherapy-Induced Nausea and Vomiting

Paul J. Hesketh,1 Matti Aapro,2 Karin Jordan,3 Lee Schwartzberg,4 Snezana Bosnjak,5 and Hope Rugo6

1 Lahey Hospital & Medical Center, 41 Mall Road, Burlington, MA 01805, USA 2Institut Multidisciplinaire d’Oncologie, Clinique de Genolier, Case Postale 100, Route du Muids 3, 1272 Genolier, Switzerland 3Department of Internal Medicine IV, Hematology/Oncology, Martin-Luther-University Halle/Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany 4TheWestClinic,100HumphreysBoulevard,Memphis,TN38120,USA 5Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia 6University of California San Francisco Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, P.O.Box1710,SanFrancisco,CA94115,USA

Correspondence should be addressed to Paul J. Hesketh; [email protected]

Received 18 November 2014; Revised 20 February 2015; Accepted 25 February 2015

Academic Editor: Min Li

Copyright © 2015 Paul J. Hesketh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Combination antiemetic regimens targeting multiple molecular pathways associated with emesis have become the standard of care for prevention of chemotherapy-induced nausea and vomiting (CINV) related to highly and moderately emetogenic chemotherapies. Antiemetic consensus guidelines from several professional societies are widely available and updated regularly as new data emerges. Unfortunately, despite substantial research supporting the notion that guideline conformity improves CINV control, adherence to antiemetic guidelines is unsatisfactory. While studies are needed to identify specific barriers to guideline use and explore measures to enhance adherence, a novel approach has been taken to improve clinician adherence and patient compliance, with the development of a new combination antiemetic. NEPA is an oral fixed combination of a new highly selective NK1 receptor antagonist (RA), netupitant, and the pharmacologically and clinically distinct 5-HT3 RA, palonosetron. This convenient antiemetic combination offers guideline-consistent prophylaxis by targeting two critical pathways associated with CINV in a single oral dose administered only once per cycle. This paper will review and discuss the NEPA data in the context ofhow this first combination antiemetic may overcome some of the barriers interfering with adherence to antiemetic guidelines, enhance patient compliance, and offer a possible advance in the prevention of CINV for patients.

1. Introduction of a 5-HT3 receptor antagonist (RA) (targeting serotonin) and dexamethasone (DEX) represents the foundation of The pathophysiology of chemotherapy-induced nausea and antiemetic prophylaxis for both MEC and HEC settings, vomiting (CINV) is known to be a complex multifactorial with the addition of a neurokinin-1 (NK1)RA(targeting process involving numerous neurotransmitters and recep- substance P), being uniformly recommended by antiemetic tors [1]. Consequently, combination antiemetic regimens guidelines when administering HEC or anthracycline- targeting multiple molecular pathways associated with eme- cyclophosphamide (AC) chemotherapy [3–5]. sis have become the standard of care for prevention of Unfortunately, despite substantial research supporting CINV in patients receiving moderately (MEC) or highly the fact that guideline conformity will improve CINV control emetogenic chemotherapy (HEC) [2–5]. The combination for patients, adherence to antiemetic guidelines is inadequate 2 BioMed Research International

[6–9]. With the goal of improving the quality of care and emetogenicity of this chemotherapy combination but also quality of life for cancer patients undergoing emetogenic becauseACiscommonlyusedinyoung,femalebreast chemotherapy treatment, the Multinational Association of cancer patients. These patient-related factors of female gen- Supportive Care in Cancer (MASCC), in particular, continues der and younger age can add to the emetogenicity of the to strive to educate clinicians on the importance and value of chemotherapy. Recently, guideline groups either established appropriate antiemetic prophylaxis. While studies are needed a separate category/recommendation for AC chemotherapy to identify specific barriers to guideline use within individual (MASCC/ESMO) or reclassified AC from the previous cate- clinics and hospitals and to explore measures that can be gory of being moderately emetogenic to being highly emeto- taken to enhance adherence, an interesting approach has been genic (ASCO/NCCN). Regardless of the specific approach to taken with the development of a new combination antiemetic. classification, all committees now recommend that patients NEPA is an oral single dose, fixed combination agent, receiving AC should receive the triplet combination of an containing a new highly selective NK1 RA (netupitant) with NK1 RA plus 5-HT3 RA plus dexamethasone (Table 1). thepharmacologicallyandclinicallydistinct5-HT3 RA, Whether or not guideline committees integrate patient- palonosetron (PALO), thereby offering guideline-consistent related risk factors with chemotherapy emetogenicity, clin- prophylaxis while targeting two critical pathways associated icians need to give patient risk factors consideration when with emesis. Palonosetron was selected for the combination determining the optimal antiemetic prophylaxis for a given over older generation 5-HT3 RAs due to its distinctive phar- patient [16]. macological properties [10, 11], its longer half-life compared Despite the fact that antiemetic guidelines are widely with older 5-HT3 RAs, and its proven clinical efficacy2 [ , 12– available and data supports the notion that guideline con- 14]. Its ability to work synergistically with netupitant suggests formity improves CINV control for patients [6, 7], clinical the potential to enhance prevention of delayed CINV when utilization of guidelines remains unacceptably low. Recently, used in combination [10, 11]. Aapro and colleagues showed guideline adherence of only This paper will briefly discuss the current antiemetic 29% in a large 1000-patient European observational study guideline recommendations and review the recently pub- [6]. Better CINV control and less utilization of health care lished NEPA data and discuss how this first combination resources were also observed in patients receiving guideline- antiemetic may overcome some of the barriers interfering consistent antiemetic prophylaxis, suggesting a clear need with adherence to antiemetic guidelines and improve preven- for greater adherence to the guideline recommendations. tion of CINV for patients. In a subsequent study conducted in US oncology prac- tices, Gilmore and colleagues similarly showed adherence to NCCN guidelines to be low, particularly in patients receiving 2. Updates to Antiemetic Guidelines, HEC (29% adherence HEC, 73% in MEC) [7]. As in the Importance of Adherence, and Aapro study, adherence to guidelines was associated with Consideration of Patient-Related significantly better CINV control in HEC and MEC settings. Risk Factors In a recent analysis of IMS Health Inc. data from 5 European countries between January and December 2013, only about Evidence-based guidelines for the prevention of CINV have 12%ofpatientsreceivingHEC,14%ofpatientsreceiving been developed by several international professional soci- AC, and 47% of patients receiving non-AC MEC were eties [MASCC, the European Society for Clinical Oncology prophylactically administered antiemetics in accordance with (ESMO), and the American Society of Clinical Oncology the MASCC/ESMO guidelines [19]. (ASCO)]. The National Comprehensive Cancer Network Inadequate adherence to practice guidelines is not spe- (NCCN) in the United States has also developed antiemetic cific to antiemetics; it is common across all fields of medicine guidelines,andthesameistrueinmanycountries.These with numerous factors playing a role. A key aspect related to guideline committees meet regularly to review and discuss utilizing guidelines is the behavior of the clinician, and often new data warranting revisions and updates to their rec- changing behavior is difficult. Physician knowledge, clinician ommendations [3–5]. While the guidelines of the various and institutional education, attitudes toward guidelines, clin- organizations vary to some extent, they are all reasonably ician agreement with them, awareness of and familiarity with consistent with their key recommendations (Table 1). them, lack of confidence in their ability to implement them, It is important to realize that antiemetic guideline com- and expectations may all impact use [20–22]. In addition, mittees continue to group their recommendations based in many countries local regulations do not allow access to on the emetogenicity of the chemotherapy, notwithstanding antiemetic agents recommended by international guidelines. awareness of well-established patient-related risk factors that Only a small number of studies have evaluated approaches to increase patients’ emetic risk. These risk factors include improving adherence with antiemetic guidelines, and some female gender, younger age, history of low alcohol intake, were hindered by methodological shortcomings [23–26]. motion sickness, experience of emesis during pregnancy, Nevertheless, some important messages can be derived from anxiety, impaired performance status, and previous exposure these studies. Single approaches to addressing adherence have to chemotherapy [15–18]. little, if any, impact [21]. Multiple strategies need to be used Patients receiving treatment with a combination of an concurrently in order to improve adherence and implemen- anthracycline and cyclophosphamide may present a partic- tation of antiemetic guidelines. These can include guideline ularly challenging population not only due to the intrinsic dissemination, use of opinion leaders, interactive educational BioMed Research International 3

Table 1: Key recommendations of antiemetic guideline groups.

Emetic risk MASCC/ESMO (2010) [3] ASCO (2011) [4]NCCN(2014)[5] category Day 1 Days 2-3 Day 1 Days 2-3 Day 1 Days 2-3 Same as MASCCc or NK RA + Same as Same as NK RAa +DEXd High 1 NK RAa +DEX olanzapine + PALO + 1 5-HT RA + DEX 1 MASCC MASCC or olanzapinee 3 DEX Same as MASCCc or NK RA + Same as Same as MASCCd AC 1 NK RAa DEX + NK RAa olanzapine + PALO + 5-HT RA + DEX 1 MASCCb 1 or olanzapineg 3 DEX Same as MASCCc or Same as Same as Moderate PALO + DEX DEX NK RA + 5-HT RA + 5-HT RAh or DEX MASCC MASCC 1 3 3 DEXf (in select patients) DEX or No routine Same as Low 5-HT RA or DEX Same as MASCCi Same as MASCC 3 prophylaxis MASCC DRA No routine No routine Same as Same as Minimal Same as MASCC Same as MASCC prophylaxis prophylaxis MASCC MASCC a NK1 RA (aprepitant) is given only if aprepitant was given on Day 1; if fosaprepitant was used then no follow-up NK1 RA is administered. bAC is classified as highly emetogenic. c Palonosetron is preferred 5-HT3. dGiven on Days 2–4 (i.e., an additional day). eIf olanzapine regimen was given on Day 1. f As per highly emetogenic recommendations an NK1 regimen should be administered with certain MEC agents (e.g., carboplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, and methotrexate). gIf olanzapine was given on Day 1. h Only an option if a 5-HT3 otherthanPALOwasusedonDay1. iSpecifically metoclopramide or prochlorperazine. AC:anthracyclinecyclophosphamide;NK1 RA: neurokinin 1 receptor antagonist; 5-HT3 RA: serotonin receptor antagonist; DEX: dexamethasone; DRA: dopamine receptor antagonist; PALO: palonosetron. workshops, therapeutic reminders in the form of preprinted also triggers receptor internalization and inhibits signaling orders, clinical interventions by pharmacists for inappropri- crosstalk between 5-HT3 and NK1 receptors [10]. Most ate antiemetic orders, and physician audit and feedback. A recently, in vitro studies have shown that the combination of key approach appears to be communication of patients’ CINV netupitant and palonosetron exhibits a synergistic effect in outcomes to physicians. Patient-mediated approaches and preventing the NK1 receptor response against its endogenous computerized decision-support systems may be promising agonist, substance P [11], and an additive effect on NK1 approaches to be utilized in the future, possibly in combina- receptor internalization [28]. The plasma elimination half- tion with the multifaceted strategies described above [16]. A lives of palonosetron (>40 hours) and netupitant (∼96 hours) practical approach to better implementation of the guidelines are long, likely contributing to the extended efficacy during is crucially needed to improve antiemetic care and outcomes thedelayedphase(25–120hours)followingchemotherapy for patients undergoing emetogenic chemotherapy. administration [10]. Netupitant is a substrate and moderate inhibitor of the 3. NEPA Pharmacology cytochrome P450 isoenzyme 3A4 (CYP3A4) and therefore, as is the case with another NK1 RA, aprepitant, coadmin- Netupitant is a highly selective NK1 RA with a high degree of istration with drugs that are substrates of CYP3A4 may receptor occupancy. A positron emission tomography (PET) require dose adjustments [29–31]. Notably, the dose of dex- study showed NK1 receptor occupancy ≥90% in the majority amethasone should be reduced when used in combination of the brain regions tested at 𝐶max, with a long duration of with NEPA [30]; this was done in the NEPA clinical tri- receptor occupancy at doses of 100–450 mg. The netupitant als. However, unlike aprepitant, netupitant does not result minimal plasma concentration predicted to achieve an NK1 in clinically relevant interactions with oral contraceptives, RA of 90% in the striatum was 225 𝜇g/mL. Netupitant 300 mg and interactions with CYP2C9 substrates (e.g., warfarin, was the lowest oral dose reaching this value [27]. tolbutamide) are unlikely based on in vitro interaction Palonosetron is a “new-generation” 5-HT3 RA with a data [31]. While the potential for netupitant interactions longer half-life and distinct pharmacological properties com- with chemotherapy agents metabolized by CYP3A4 has pared with older agents in the 5-HT3 RA class. Mechanism not been fully established, no interaction or no clinically of action studies have shown that unlike other 5-HT3 RAs, relevant interaction has been observed between aprepitant palonosetron exhibits allosteric interactions, positive coop- and the commonly administered chemotherapeutic agents erativity, and persistent inhibition of receptor function; it (cyclophosphamide, docetaxel, and intravenous vinorelbine) 4 BioMed Research International

Table 2: NEPA study designs.

Patient Single versus Study Study design Treatment groups Study objective population/chemotherapy multiple cycle NEPA +DEX 100 Identify best dose Double-blind, NEPA +DEX 200 of NETU + PALO; Study 1 randomized, Chemotherapy-na¨ıve NEPA +DEX 300 demonstrate [Hesketh et al.] dose-ranging, parallel Cisplatin-based Oral PALO + DEX Single cycle superiority of [33] group Phase 2 chemotherapy (HEC) APR + IV OND + NEPA over oral (𝑁 = 694) DEX (included as PALO exploratory) Double-blind, Demonstrate Study 2 Chemotherapy-na¨ıve randomized, parallel NEPA + DEX superiority of [Aapro et al.] Anthracycline- Multiple cycle group Phase 3 Oral PALO + DEX NEPA over oral [34] cyclophosphamide (𝑁 = 1455) PALO Double-blind, NEPA + DEX Demonstrate Study 3 Chemotherapy-na¨ıve randomized 3 : 1, parallel APR + oral PALO + multiple cycle [Gralla et al.] Any HEC or MEC (except Multiple cycle group Phase 3 DEX safety and describe [35] AC) (𝑁 = 413) (3 : 1 randomization) efficacy of NEPA HEC: highly emetogenic chemotherapy; MEC: moderately emetogenic chemotherapy; AC: anthracycline cyclophosphamide; DEX: dexamethasone; PALO: palonosetron; NETU: netupitant; APR: aprepitant; OND: ondansetron; NEPA100: NETU 100 mg + oral PALO 0.50 mg; NEPA200:NETU200mg+oralPALO 0.50 mg; NEPA300: NETU 300 mg + oral PALO 0.50 mg; IV: intravenous.

[32].Otheragentsthatareknowntobemetabolizedby 12 mg PO on Day 1 and additionally 8 mg on Days 2–4 in the CYP3A4 include paclitaxel, etoposide, irinotecan, ifosfamide, HEC setting. The dexamethasone doses with palonosetron imatinib, vinblastine, and vincristine. were20mgonDay1and16mgonDays2–4(withHEC). Blinding of treatment groups was maintained in all studies with the use of matching identical placebos. 4. NEPA Efficacy in Prevention of CINV The primary efficacy endpoint of interest was proportion 4.1. Overview of Studies. The efficacy of NEPA has been of patients with a complete response (CR: no emesis and evaluated in 3 pivotal registration trials, all in chemotherapy- no rescue medication). Other efficacy endpoints included proportion of patients with no emesis, no significant nausea na¨ıve patients with predominantly solid tumors receiving a < variety of highly and moderately emetogenic chemothera- [defined as a maximum score of 25 mm on a 100 mm visual peutic agents (Table 2). analogscale(VAS)],andcompleteprotection(CR+nosig- Two studies (07-07 [Study 1] and 08–18 [Study 2]) nificant nausea). In the Phase 3 NEPA superiority trial (Study were designed to demonstrate superiority of NEPA over 2), patients also completed a functional living index emesis oral palonosetron. Study 1 was a pivotal, dose-ranging trial (FLIE) questionnaire, a validated 18 item VAS-based, patient- designed to identify the best dose combination for NEPA in reported outcome measure that assesses the impact of CINV patients receiving cisplatin-based HEC. Study 2 was designed on patients’ daily lives/functioning. All efficacy endpoints to show superiority of the selected NEPA dose over oral were evaluated during the acute (0–24 h), delayed (25–120 h), palonosetron in patients receiving AC. While the third study and overall (0–120 h) phases after chemotherapy administra- (10–29 [Study 3]) in patients receiving a variety of HEC tion. Details of the study designs, inclusion/exclusion criteria, and MEC (excluding breast cancer patients receiving AC) patient demographics, and statistical analyses are reported in was designed primarily to evaluate the safety of NEPA over the individual publications [33–35]. multiple cycles, efficacy was also assessed and described. This study included an aprepitant treatment arm; however, as the 4.2. Dose Selection. Study 1 was a phase 2, pivotal, dose- inclusion of this arm was intended to help interpret any ranging trial in 694 patients receiving cisplatin-based unexpected safety finding, no formal efficacy comparisons chemotherapy. It was designed to evaluate 3 different oral were prospectively planned and performed. doses of netupitant (100, 200, and 300 mg) coadministered Inall3trialsasingledoseofNEPAwasadministered60 with oral palonosetron 0.50 mg to determine the most appro- minutes prior to chemotherapy on Day 1. Oral palonosetron priate clinical dose for the NEPA combination [33]. The (Studies 1 and 2) and aprepitant (Studies 1 and 3) were 0.50 mg oral palonosetron dose was selected as it repre- administered at this same time on Day 1; aprepitant was also sents the approved oral dose of palonosetron [36]. While giveninthemorningofDays2and3.Dexamethasonewas all coadministered doses provided superior prevention of administered 30 minutes prior to chemotherapy on Day 1 CINV compared with oral palonosetron, netupitant 300 mg + and according to the MASCC/ESMO antiemetic guideline palonosetron 0.50 mg was the best combination dose when recommendations (i.e., administered on Days 1–4 for patients considering all efficacy endpoints. There was no difference receiving HEC and on Day 1 only in patients receiving MEC). in safety between doses of netupitant. The 300 mg netupitant The dexamethasone doses with NEPA (and aprepitant) were dose was also the minimal dose tested in the PET study BioMed Research International 5

∗∗ 100 98.5 100 ∗ ∗∗ ∗ 90 89.7 90.4 89.6 90 88.4 85.0 80.1 ∗∗ 80 80 ∗∗ 76.5 76.9 74.3 69.5 70 70 66.6 60 60

50 50

Patients (%) Patients 40 (%) Patients 40

30 30

20 20

10 10

0 0 Acute (0–24 hr) Delayed (25–120 hr) Overall (0–120 hr) Acute (0–24 hr) Delayed (25–120 hr) Overall (0–120 hr) Study 1 Study 2

NEPA + DEX (n = 136) NEPA + DEX (n=724) Oral PALO + DEX (n = 135) Oral PALO + DEX (n=725) ∗P < 0.05 ∗P < 0.05 ∗∗ P ≤ 0.01 ∗∗ P ≤ 0.01

(a) (b)

Figure 1: Cycle 1 complete response (no emesis, no rescue medication) rates: NEPA versus oral palonosetron (Studies 1 and 2).

resulting in receptor occupancy of 90% in the striatum [27]. In the Phase 3 safety study (Study 3), the overall CR This level of receptor occupancy has been used historically in rates for NEPA in Cycle 1 were high; 81% for the total studies with aprepitant to predict antiemetic efficacy. population, 84% in the subgroup of patients receiving HEC, This oral fixed combination of 300 mg netupitant + and 80% for the subgroup of patients receiving MEC [35, 37]. 0.50 mg palonosetron was subsequently developed and eval- Similar results were seen with the proportion of patients with uated in the NEPA Phase 3 clinical development program. no significant nausea (84% overall population, 82% HEC subgroup, and 85% MEC subgroup) [37]. 4.3. Cycle 1 Efficacy. In both of the trials comparing NEPA and oral palonosetron (Studies 1 and 2), NEPA showed 4.3.1. Efficacy in Gender/Age Risk Subgroups. Female gender superior prevention of CINV during the overall phase as and young age are well-established patient-related risk factors demonstrated by significantly higher CR ratesFigure ( 1)as increasing the emetogenic potential of chemotherapy. In well as absence of emesis, absence of significant nausea, and order to evaluate the effect of gender and age on treatment complete protection rates (Table 3)[33, 34]. Superiority of response, data was combined from Phase 2 and 3 comparative NEPA over oral palonosetron was also seen for the same trials 1 and 2 as well as a third trial which included oral four efficacy endpoints during the delayed phase in both palonosetron [38, 39]. Overall CR rates were calculated for trials. During the acute phase, NEPA was superior to oral females and males and for patients < 55 years and ≥ 55 years. palonosetron for all endpoints in the HEC study and for CR As expected, in both NEPA and oral palonosetron treat- andnoemesisintheAC-MECstudy(Figure 1; Table 3). ment groups, overall CR rates were numerically lower in In Study 2, this better prevention of both nausea and females (82% NEPA, 69% oral PALO) compared with males vomiting correlated with a quality-of-life benefit for patients. (91% NEPA, 78% oral PALO) and also lower in those < 55 yrs For the FLIE assessment, significantly more NEPA-treated (85% NEPA, 70% oral PALO) compared with those ≥ 55 yrs patients (79%) reported no impact on daily functioning for (89% NEPA, 77% oral PALO), although no formal statistical the total combined domains of nausea and vomiting during comparison was performed. However, the beneficial effect of the 5 days after chemotherapy compared with those treated NEPA over oral palonosetron was seen in both gender and with oral palonosetron (72%; 𝑃 = 0.005)[34]. A significantly age groups as evidenced by a similar absolute difference of greater proportion of NEPA-treated patients also had no 12–15%. impact on functioning due specifically to nausea (72% NEPA Toevaluatethecombinedeffectofgenderplusage, versus 66% oral PALO, 𝑃 = 0.015) and due specifically to patients were divided into 4 emetic risk groups (females < 55 vomiting (90% NEPA versus 84% oral PALO, 𝑃 = 0.001). years [high risk], females ≥ 55 years [moderate risk], males 6 BioMed Research International

Table3:Cycle1EfficacyofNEPA+DEXcomparedwithoralpalonosetron+DEX.

Study 1 (Cisplatin HEC) Study 2 (AC) Patients (%) NEPA + DEX Oral PALO + DEX 𝑃 value1 NEPA + DEX Oral PALO + DEX 𝑃 value2 (𝑁 = 136) (𝑁 = 135) (𝑁 = 724) (𝑁 = 725) No emesis Acute (0–24 h) 98.5 89.7 0.007 90.9 87.3 0.025 Delayed (25–120 h) 91.9 80.1 0.006 81.8 75.6 0.004 Overall (0–120 h) 91.1 76.5 0.001 79.8 72.1 <0.001 No significant nausea Acute 98.5 93.4 0.050 87.3 87.9 0.747 Delayed 90.4 80.9 0.027 76.9 71.3 0.014 Overall 89.6 79.4 0.021 74.6 69.1 0.020 Complete protection Acute 97.0 87.5 0.006 82.3 81.1 0.528 Delayed 84.4 73.5 0.027 67.3 60.3 0.005 Overall 83.0 69.9 0.010 63.8 57.9 0.020 1𝑃 value from logistic regression versus oral palonosetron; not adjusted for multiple comparisons. 2𝑃 value from two-sided Cochran-Mantel-Haenszel test including treatment, age class, and region as strata. HEC: highly emetogenic chemotherapy; AC: anthracycline cyclophosphamide; NEPA: netupitant/palonosetron; PALO: palonosetron; DEX: dexamethasone.

Table4:EfficacyofNEPAingender/ageemeticriskgroups. 4.3.3. Efficacy in Patients Receiving Cisplatin Plus Con- comitant Chemotherapy. It has been previously shown that Overall (0–120 h) CR NEPA + Oral PALO + % Difference antiemetic efficacy is reduced when concomitant emetogenic % of patients DEX DEX (95% CI) chemotherapy is administered concurrently with cisplatin Females <55 years − [43]. To evaluate whether emetic prevention differed for (high risk) 80.0 69.0 11.0 ( 1.0; 23.0) NEPA with the addition of concomitant chemotherapy, (𝑁 = 100/100) ≥ NEPA groups from the Phase 2 dose-ranging trial (Study Females 55 years 1) were combined [44]. Complete response and no sig- (moderate risk) 84.5 69.4 15.0 (3.9; 26.2) nificant nausea rates were then calculated for two groups (𝑁 = 108/103) of patients: those receiving cisplatin plus no/minimal/low Males <55 years emetic risk chemotherapy or those receiving cisplatin plus (low risk) 89.7 71.4 18.3 (7.6; 29.0) (𝑁 = 91/126) moderate/high emetic risk chemotherapy. CR and no significant nausea rates were similar for the Males ≥55 years (lowest risk) 92.8 81.1 11.7 (5.0; 18.5) acute, delayed, and overall intervals for both groups, regard- (𝑁 = 206/153) less of the emetogenicity of the additional chemotherapy administered with cisplatin. NEPA: netupitant/palonosetron; PALO: palonosetron; CR: complete response; CI: confidence interval. Overall (0–120 h) CR rates were 88% and 87% for the lower and higher emetic risk groups, respectively, while no significant nausea rates were 86% and 85%, respectively. < ≥ 55 years [low risk], and males 55 years [lowest risk]). 4.3.4. Efficacy in Patients Receiving Carboplatin. As there is A clear trend existed across the risk groups with (older) limited data supporting a guideline recommendation for the males exhibiting numerically higher CR rates than (younger) addition of an NK1 RA to a 5-HT3 RA/DEX regimen with females and CR rates numerically higher for NEPA than oral platinum agents other than cisplatin, a post hoc analysis from palonosetron in all gender/age risk groups (Table 4). Study 3 was performed to assess the effectiveness of NEPA in 149 patients receiving carboplatin [45]. The overall CR 4.3.2. Efficacy in Older Patients. Prevention of CINV in older rates for NEPA were 80%, 91%, 92%, and 94% for cycles 1– cancer patients is critical, as these patients tend to be more 4, respectively. Similar results were seen for no emesis, with sensitive to the adverse effects of cytotoxic therapy and thus ratesof83%,91%,92%,and95%forcycles1–4,respectively. more likely to experience dehydration and anorexia related to CINV [40, 41]. NEPA data from the 3 pivotal trials was 4.4. Multiple Cycle Efficacy. Most antiemetic trials assess combined to evaluate the efficacy in an older subgroup of CINV control in only a single cycle of treatment. However, patients (𝑛 = 214 ≥65 years old) [42]. CR rates for NEPA preservation of benefit over repeated cycles of chemother- in the older patients were generally higher than those seen in apy is essential for optimal supportive care during can- the overall study population (Table 5). cer treatment. Two studies in the NEPA clinical program BioMed Research International 7

Table 5: Efficacy of NEPA in older patients. % of patients Study 1 (HEC) Study 2 (AC) Study 3 (non-AC MEC/HEC) ≥ ≥ ≥ Time period 65 yrs Overall population 65 yrs Overall population 65 yrs Overall population (𝑁=20) (𝑁 = 135) (𝑁 = 116) (𝑁 = 724) (𝑁=78) (𝑁 = 309) Acute (0–24 h) 100 98.5 94.0 88.4 97.4 92.9 Delayed (25–120 h) 100 90.4 81.0 76.9 80.8 83.2 Overall (0–120 h) 100 89.6 79.3 74.3 78.2 80.6 HEC: highly emetogenic chemotherapy; AC: anthracycline cyclophosphamide; MEC: moderately emetogenic chemotherapy. evaluated the effectiveness of NEPA over multiple cycles of events was as expected for the 5-HT3 RA and NK1 RA chemotherapy. The Phase 3 Study 2 in patients receiving AC classes and for patients undergoing cytotoxic chemotherapy. comparing NEPA with oral palonosetron included a multiple NEPA had a similar adverse event profile to oral palonosetron cycle extension [46]. The multiple cycle safety Study 3 also and the aprepitant-based regimen [33–35]. The most fre- assessed efficacy over cycles [35]. quent treatment-related adverse events were headache and 1033 NEPA-treated patients participated in 4428 total constipation. Aapro et al. [47]presentedacomprehensive chemotherapy cycles in these two trials; 75% of patients overview of the safety of NEPA, pooling data from the completed at least 4 cycles. In Study 2, the proportion of studies in the development program. The percentages of patients with an overall CR was significantly greater for patients with at least 1 treatment-emergent adverse event NEPA compared with oral palonosetron during cycles 1–4 (TEAE) in Cycle 1 and in all cycles were generally similar (Figure 2(a))[46]. NEPA was also significantly more effective for NEPA, oral palonosetron, and the aprepitant groups as than oral palonosetron in preventing no emesis and no were the percentages of patients reporting AEs considered significant nausea over cycles 1–4. While no formal efficacy to be treatment-related (Table 6). Few patients in any group comparisons with aprepitant were intended in Study 3, the experienced serious AEs or AEs leading to discontinuation overall CR rates were high and were maintained across or death. There were no deaths in the clinical program cycles for both NEPA and the aprepitant/palonosetron/DEX considered to be related to the NEPA treatment. regimen, with NEPA showing a small but consistent numer- A similar frequency of cardiac AEs was reported in each ical advantage (2%–7%) over aprepitant during each cycle treatment group during all cycles of treatment [47]. The (Figure 2(b))[35]. Response rates for NEPA were similar in mean changes from baseline in the ECG parameters assessed the subgroups of patients who received HEC and non-AC (heart rate, PR, QRS, QT, QTcB, and QTcF) were small MEC. Similar results were seen for no significant nausea in and generally similar across the treatment groups at each the overall population as well as the emetogenicity subgroups study time point. Neither netupitant or oral palonosetron has of HEC and MEC. shown any signals for effects on corrected QT interval (QTcl), heart rate, PR, or QRS intervals compared to placebo in 4.5. Comparison with Aprepitant Regimen. An aprepitant/5- separate ICH E14 QT trials in healthy volunteers [48, 49]. This HT3 RA/DEX regimen was included for exploratory pur- has also been shown for palonosetron in studies in patients poses in the dose-ranging trial (Study 1) and to help with cancer [50–52]. interpret any unexpected safety finding in the multiple cycle HEC/MEC Study 3. In Study 1, Hesketh and colleagues reported that the aprepitant/ondansetron/DEX arm 6. Discussion and Conclusions showed higher CR and no emesis rates compared with oral palonosetron during the overall and delayed phases, but not With the introduction of the NK1 RA class into the antiemetic the acute phase [33]. It also resulted in numerically higher armamentarium, the last decade of research has focused no significant nausea and complete protection rates, but on better understanding the pathophysiology of CINV and these were not significantly different from oral palonosetron identifying effective antiemetic combinations which target during any time interval after chemotherapy. Although no multiple molecular pathways associated with emesis. Accord- formal comparisons were performed and the differences were ingly, CINV can now be prevented and/or minimized suc- small, the NEPA combination selected for development had cessfully for the majority of patients. However, this control numerically higher response rates than the multiday aprepi- can only be achieved if appropriate antiemetic prophylaxis is tant regimen for all efficacy endpoints and time intervals. As administered to patients. mentioned previously, while no formal efficacy comparisons While there are some differences between the vari- were performed, NEPA also showed numerically higher CR ous antiemetic guidelines, they all provide evidence-based rates than the aprepitant/palonosetron/DEX regimen over reasonably consistent recommendations to guide clinicians multiple cycles in Study 3 [35]. on the optimal use of antiemetics. Unfortunately, barriers exist which continue to interfere with administration of 5. Safety of NEPA guideline-based antiemetic prophylaxis [6–9, 20–22], despite compelling research indicating that nonadherence leads to In each of the individual studies, the overall incidence, diminished CINV control for patients [6, 7]. In the large type, frequency, and intensity of treatment-emergent adverse studies by Aapro and Gilmore [6, 7], it was discouraging that 8 BioMed Research International

100 100 ∗∗ ∗∗ 90.7 90.1 90 ∗∗ 90 86.1 86.7 87.7 ∗ 80.3 83.8 83.8 80.6 81.3 80 74.3 74.6 80 75.7 70.3 70 66.6 66.7 70 60 60 50 50 40 40 Patients (%) Patients Patients (%) Patients 30 30 20 20 10 10 0 0 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 1 Cycle 2 Cycle 3 Cycle 4 NEPA + DEX N = 724 635 598 551 NEPA + DEX N =309 280 259 233 Oral PALO + DEX N =725 651 606 560 APR + PALO + DEX N = 103 96 90 81 Study 2 Study 3 NEPA + DEX NEPA + DEX Oral PALO + DEX APR + PALO + DEX ∗P = 0.001 ∗∗ P < 0.0001

(a) (b) Figure 2: Overall (0–120 h) complete response (no emesis, no rescue medication) rates over multiple chemotherapy cycles: NEPA versus oral palonosetron (Study 2) and NEPA versus aprepitant regimen (Study 3).

Table 6: Overview of adverse events. ∗ Cycle 1 All cycles Number (%) of patients NEPA + DEX IV or oral PALO + APR + OND/PALO NEPA + DEX Oral PALO + APR + oral PALO with the following (𝑁 = 1442) DEX (𝑁 = 1600) +DEX(𝑁 = 238) (𝑁 = 1033) DEX (𝑁 = 725) +DEX(𝑁 = 104) Any treatment-emergent 944 (65.5%) 945 (59.1%) 135 (56.7%) 1127 (78.2%) 1080 (67.5%) 166 (69.7%) AE (TEAE) Treatment-related AE 138 (9.6%) 105 (6.6%) 29 (12.2%) 194 (13.5%) 134 (8.4%) 32 (13.4%) (TRAE) Serious TEAE 33 (2.3%) 87 (5.4%) 4 (1.7%) 87 (6.0%) 99 (6.2%) 19 (8.0%) Serious TRAE 2 (0.1%) 2 (0.1%) — 3 (0.2%) 2 (0.1%) — TEAE leading to death 8 (0.6%) 20 (1.3%) — 17 (1.2%) 21 (1.3%) 1 (0.4%) TEAE leading to 14 (1.0%) 6 (0.4%) 4 (1.7%) 44 (3.1%) 20 (1.3%) 13 (5.5%) discontinuation TRAE leading to 2 (0.1%) 2 (0.1%) — 1 (0.1%) 4 (0.3%) — discontinuation ∗ Allcycles:Cycle1fromallPhase2/3studies+Cycles2andbeyondfromthePhase3multiplecycletrials. Treatment-emergent adverse event (TEAE): any AE reported after first study drug intake. TRAE: AEs deemed possibly, probably, or definitely related to study drug. DEX: dexamethasone, PALO: palonosetron, and APR: aprepitant.

the patients at highest risk for CINV (i.e., those receiving may have contributed to the underutilization of the NK1 HEC or AC chemotherapy) were the ones where the inci- RA, the complexity and inconvenience of the oral aprepitant dence of guideline inconsistent prophylaxis was highest. As regimen (e.g., 3 days aprepitant plus 1–3 days 5-HT3 RA plus these are the patients most likely to benefit from appropriate 1–4 days of dexamethasone) may have also played a role. In antiemetics, it is critical that continued efforts are taken light of this, it is interesting to speculate if the development to identify multifaceted strategies that can be employed to of the convenient single day antiemetic combination, NEPA, improve guideline adherence. The Aapro study also suggested will offer physicians a possible solution to address this that the absence of an NK1 RA in these high risk groups particular gap. was a predominant gap in guideline-consistent care. While The data in the clinical program offer unequivocal evi- economic constraints of hospitals and government payers dence that NEPA plus dexamethasone provides superior BioMed Research International 9

CINV control over oral palonosetron plus dexamethasone in historical carboplatin subset analysis and more recently a settings where an NK1 RA/5-HT3 RA/DEX “triplet” is recom- Phase 3 trial in patients receiving a paclitaxel/carboplatin mended (i.e., HEC and AC-based MEC). This is supported regimen where an aprepitant regimen showed a >10% incre- bythepharmacologicalsynergyseenwithnetupitantand mental benefit over a 5-HT3 RA/DEX control [59, 60]. Given palonosetron. The consistent superiority of NEPA over oral this consistent evidence, MASCC/ESMO and ASCO guide- palonosetron across the multiple efficacy endpoints in two line groups, in particular, should evaluate this dataset and comparative studies is particularly noteworthy considering emerging data with rolapitant [61] and give consideration to that palonosetron is regarded as a clinically distinct 5-HT3 the addition of an NK1 RA in patients receiving carboplatin. RA. NCCN includes carboplatin as one of the chemotherapies, Future trials could be considered to explore how NEPA like AC, where an NK1 RA should be added to the 5-HT3 compares clinically to an aprepitant-based triplet regimen. RA/DEX regimen (Table 1). The limited data generated thus far suggests that NEPA shows The multiple cycle data generated for NEPA is perhaps slightly higher response rates than a 3-day aprepitant regimen themostrobustmulticycledatasetgeneratedthusfarforany in both the single cycle study in patients receiving cisplatin- approved antiemetic. In Studies 2 and 3, 1033 patients were based HEC (Study 1) [33] and over multiple cycles in patients treated with NEPA for a total of 4428 chemotherapy cycles receiving either MEC or HEC (Study 3) [35]. However, as with 75% of these patients completing at least 4 cycles [37]. neither of these trials were designed specifically to compare Overall CR and no significant nausea rates were high and theefficacyofNEPAwiththatoftheaprepitantregimen,a were maintained across 4 cycles of chemotherapy in both formal trial would be needed to address this. studies and in the subsets of patients receiving the various Study 3 offers evidence that NEPA is effective in a non- types of chemotherapies. This provides confidence in the AC-based “pure” MEC population, although further studies preservation of benefit with NEPA over repeated cycles and are needed to evaluate the superiority of NEPA over a 5-HT3 reinforces the value of administering appropriate prophylaxis RA/DEX regimen in this setting. starting at Cycle 1, rather than waiting to introduce an NK1 With the appropriate use of current antiemetics, emesis RA after the patient has failed (i.e., experienced CINV). can be prevented in nearly all patients. However, there is still The safety profile for NEPA is consistent with that room for improving control of nausea, particularly during expected for these drug classes with the type and incidence thedelayedphasefollowingchemotherapy.Asnoconsistent of adverse events also being typical for a diverse cancer superiority has been seen with the addition of aprepitant population receiving cytotoxic chemotherapy. As expected, over 5-HT3 RAs+DEXinprevioustrialsevaluatingnausea the most common treatment-related adverse events were [53–57], it was encouraging to see that a nausea benefit headache and constipation. While there has been safety was demonstrated with NEPA over oral palonosetron in two concerns associated with QTc prolongation with older 5-HT3 pivotal trials. High levels of protection against nausea were RAs such as ondansetron and dolasetron [62–64], the cardiac also maintained in multiple cycles (i.e., in the extension of adverse events and QTc data for NEPA from the pivotal the Study 2 and also in Study 3) (Table 3). Notwithstanding studies indicate no cardiac safety concerns. Reassuringly, this benefit, further research is needed to better understand neither netupitant nor palonosetron have shown any signals nausea and how to optimize control of this bothersome for effects on corrected QT intervals in individual QT trials symptom, particularly in subgroups of patients who may be [48–52]. more prone to it. Because netupitant is a moderate inhibitor of CYP3A4, In the subset of older patients ≥65 years, it was reassuring the oral dexamethasone dose should be reduced when used in to see that CINV control with NEPA was at least as good conjunction with NEPA. The dexamethasone doses adminis- as that seen in the overall population in the individual teredintheNEPAclinicaltrialswere12mgPOonDay1(for pivotal trials. In the gender/age analysis, it was not surprising HEC and AC) and additionally, 8 mg on Days 2–4 in the HEC that males had higher CR rates than females as did older setting. The administration of dexamethasone on Day 1 only patients compared with younger patients. It was somewhat in the AC trial was consistent with the MASCC/ESMO guide- surprising, however, that despite these differences in response line recommendations. In contrast, the ASCO and NCCN by gender and age the beneficial effect of NEPA over oral guidelines recommend dexamethasone dosing through Day palonosetron was consistent in males and females (13% in 3 or 4 in the AC setting. However, as dexamethasone may both) and in older (12%) and younger (15%) patients. This is be associated with a range of side effects, there is interest in contrast to previously reported aprepitant data where the in minimizing its dose and frequency, particularly in those beneficial effect of an aprepitant/ondansetron/DEX regimen patients who experience dexamethasone-related side effects over ondansetron/DEX was greatest in women (14%) and in or in those with preexisting conditions that may be exacer- those < 55 years (19%) compared with men (4%) and those batedbycorticosteroiduse.TheNEPAdatainStudy2provide ≥ 55 years (6%) [58]. It is encouraging that NEPA offers an encouraging evidence that a Day 1 only regimen of NEPA plus improved response regardless of age and gender and also dexamethasone is effective. As concomitant administration of regardless of the combined risk factors of young age/female NEPA may increase the plasma concentration for drugs that (high risk) versus older/males (lowest risk) where the NEPA are mainly metabolized via CYP3A4, coadministration with benefit seen ranged from 11% to 18%. other drugs that are substrates of CYP3A4 may require dose The data in the subset of 149 patients receiving carboplatin adjustments. While these potential drug-drug interactions is interesting. The response rates are consistent with a similar were a possible source of concern regarding aprepitant, a 10 BioMed Research International review by Aapro and colleagues concluded that the majority [2] P. Feyer and K. Jordan, “Update and new trends in antiemetic of drug-drug interactions with aprepitant have little or no therapy: the continuing need for novel therapies,” Annals of clinical consequence [32]. 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Clinical Study Efficacy of Olanzapine Combined Therapy for Patients Receiving Highly Emetogenic Chemotherapy Resistant to Standard Antiemetic Therapy

Masakazu Abe, Yuka Kasamatsu, Nobuhiro Kado, Shiho Kuji, Aki Tanaka, Nobutaka Takahashi, Munetaka Takekuma, and Yasuyuki Hirashima Division of Gynecology, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan

Correspondence should be addressed to Masakazu Abe; [email protected]

Received 21 November 2014; Revised 22 January 2015; Accepted 3 February 2015

AcademicEditor:BernardoL.Rapoport

Copyright © 2015 Masakazu Abe et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. Olanzapine is proved to be effective for chemotherapy induced nausea and vomiting (CINV). But its efficacy in combination with standard antiemetic therapy is unknown. The purpose of this study is to prove the preventive effect of olanzapine for the prevention of CINV caused by highly emetogenic chemotherapy when used with standard antiemetic therapy. Method. Gynecologic cancer patients receiving cisplatin-based chemotherapy who had grade 2 or 3 nausea in overall phase (0–120 h after chemotherapy) despite standard therapy were assigned to this study. From the next cycles to cycles in which patients developed grade 2 or 3 nausea, they received olanzapine with standard therapy. 5 mg oral olanzapine was administered for 7 days from the day before chemotherapy. The effectiveness of preventive administration of olanzapine was evaluated retrospectively. The primary endpoint was nausea control rate (grade 0 or 1) with olanzapine. Results. Fifty patients were evaluable. The nausea control rate with olanzapine was improved from 58% to 98% in acute phase (0–24 h after chemotherapy) and 2% to 94% in delayed phase (24– 120 h after chemotherapy). In overall phase, the nausea control rate improved from 0% to 92%, and it was statistically significant (𝑃 < 0.001). Conclusion. Preventive use of olanzapine combined with standard antiemetic therapy showed improvement in control of refractory nausea.

1. Introduction These guidelines recommend triple therapy consisted of 5-HT3 receptor antagonist, NK-1 receptor antagonist, and Chemotherapy induced nausea and vomiting (CINV) is dexamethasone as a standard antiemetic therapy toward one of the most harmful adverse effects even though there highly emetogenic chemotherapy (HEC) [1, 2]. Multiple is a significant progress in antiemetics nowadays. CINV reports proved the effect of this therapy [3–6]. Complete could bring anorexia, malnutrition, dehydration, and anxiety response (no vomiting, no rescue, and any nausea) to HEC toward chemotherapy to patients and for that it is important is reported to be around 80% in acute phase (0–24 h after to reduce symptoms of CINV as possible. National Com- chemotherapy) and 60–70% in delayed phase (24–120 h after prehensive Cancer Network (NCCN), American Society of chemotherapy).However,thereisnoeffectivetherapytoward Clinical Oncology (ASCO), and Multinational Association CINV which is resistant to standard antiemetics reported. of Supportive Care in Cancer (MASCC) have developed In guidelines above, olanzapine, the atypical antipsy- antiemetic guidelines based on evidence. In Japan, the first chotic, is mentioned as a usable agent for CINV refractory guideline for proper use of antiemetics was provided by Japan for standard antiemetic therapy. Olanzapine is reported to be Society of Clinical Oncology in 2010 based on guidelines equal or more effective for CINV compared to aprepitant and written above. dexamethasone [7, 8]. Moreover, olanzapine is reported as an 2 BioMed Research International effective and tolerable agent which can be used as a salvage and olanzapine. Adverse effects and laboratory data were therapy to standard therapy refractory CINV [9]. However, evaluated based on CTCAE ver. 4.0. preventive administration of olanzapine for standard therapy refractory CINV has not been proved effective or safe so 2.4. Statistical Analysis. We compared cycles in which far. In this study, we administered olanzapine with standard patients developed grade 2 or 3 nausea with standard therapy antiemetic therapy as a preventive therapy to patients treated and cycles in which they received olanzapine with standard with HEC containing cisplatin who had grade 2 or 3 nausea therapyforthefirsttime.WeusedMcNemartesttoevaluate (Common Terminology Criteria for Adverse Events; CTCAE the improvements in each parameter. 𝑃 < 0.05 was consid- ver. 4.0) in spite of receiving standard antiemetic therapy. The ered statistically significant in this study. control of nausea and vomiting was evaluated retrospectively. 3. Results 2. Methods Patient’s characteristics are shown in Table 1. Regimens with 2.1. Patients. Fifty patients were assigned to this study. They 2 cisplatin more than 50 mg/m were used in 45 patients and were gynecological cancer patients who were treated with 2 HEC regimen containing cisplatin and had symptoms of regimens with cisplatin less than 50 mg/m were used in 5 grade 2 or 3 nausea in overall phase (0–120 h after chemother- patients.InFPtherapy,weeklyCDDP,andweeklyTPtherapy, apy) in spite of receiving standard antiemetic therapy. There radiation therapy (external pelvic irradiation, 1.8 Gy/day) was were 32 patients of grade 3 and 18 patients of grade 2. used simultaneously. The mode of the number of cycles in All patients were informed of drug information and the which patients developed grade 2 or 3 nausea though they consent of using olanzapine was obtained. Since olanzapine is were treated with standard antiemetic therapy was cycle 1 and contraindicated in patients with diabetes mellitus, their blood there were 29 cases. sugar level and hemoglobin A1c were checked to confirm that The changes of nausea grades with the usage of olanzapine they do not have glucose intolerance. are shown in Table 2. There were no patients who had heavier 2 Regimens with less than 50 mg/m cisplatin were included nausea. In most of the patients, their nausea improved after in this study because ASCO, MASCC, and Japanese guide- they started to use olanzapine. lines include these regimens in HEC although NCCN classi- The nausea control rate is shown in Table 3.Thenausea fies them as moderate emetogenic chemotherapy (MEC). control rate with olanzapine improved from 58% to 98% in We conducted this study in accordance with ethical acute phase and 2% to 94% in delayed phase. In overall phase, the nausea control rate improved from 0% to 92%, and it was principles based on the Declaration of Helsinki. All the 𝑃 < 0.001 data and information of patients were processed considering statistically significant ( ). privacy and patients were not identifiable. No vomiting rate, no rescue therapy rate, complete response rate, complete control rate, and total control rate of cycles before using olanzapine and those with olanzapine 2.2. Treatment Plans. As a standard antiemetic therapy, 5- are shown in Table 4. In the cycle where patients developed HT3 receptor antagonist (palonosetron 0.75 mg or granis- grade 2 or 3 nausea, 19 patients vomited and 49 had rescue etron 3 mg on day 1), NK-1 receptor antagonist (aprepitant 125 mg on day 1, 80 mg on days 2-3), and dexamethasone therapy in overall phase. As this result, complete response (9.9 mg on day 1, 6.6 mg on days 2–4) were administered. rate of overall phase in group of patients without olanzapine Olanzapine was given with standard antiemetic therapy from was only 2%. No vomiting rates of cycles using olanzapine the cycles next to cycles in which patients developed grade inacutephase,delayedphase,andoverallphasewere100%, 2 or 3 nausea in overall phase though they were treated 96%, and 96%, respectively. In each phase, improvement was with standard antiemetic therapy. 5 mg of oral olanzapine statistically significant (𝑃 < 0.05). No rescue therapy rates was given for 7 days starting at the day before cisplatin was of cycles using olanzapine in acute phase, delayed phase, administered. andoverallphasewere98%,82%,and82%,respectively.In each phase, improvement was statistically significant (𝑃< 0.001 2.3. Parameters Assessed. The grades of nausea through acute ). Complete response rate and complete control rate phase, delayed phase, and overall phase were evaluated of cycles using olanzapine were 82–98% in all phases and according to medical record written by doctors, nurses, and they improved significantly compared with cycles without 𝑃 < 0.001 pharmacists using CTCAE ver. 4.0. The primary endpoint olanzapine ( ). Total control rate using olanzapine was nausea control rate. It was defined as the rate of patients was 86% in acute phase, 42% in delayed phase, and 40% in whose grade of nausea was controlled within 0 or 1. The sec- overall phase, but all rates improved significantly𝑃 ( < 0.001). ondary endpoints were no vomiting rate (the rate of patients As adverse effects, grade 1 or 2 drowsiness was seen in who did not have any vomiting), complete response rate (no 26 patients. There were 18 patients of grade 1 (36%) and 8 vomiting, no rescue, and any nausea), complete control rate patients of grade 2 (16%). Six patients had to reduce the dose (no vomiting, no rescue, and nausea grade 0 or 1), and total of olanzapine to 2.5 mg because of grade 2 drowsiness, but control rate (no vomiting, no rescue, and no nausea). We no patients had to stop taking it. There were no grade 3- compared cycles containing only standard antiemetic therapy 4 adverse effects. Forty-nine patients out of 50 wished to with cycles containing both standard antiemetic therapy continue taking olanzapine and used olanzapine through BioMed Research International 3

Table 1: Characteristics of patients.

Variables ∗ Age 53 ± 12.3 years (26–71 years) Gender Male 0 Female 50 ECOG performance status 0 24 1 18 2 8 ∗∗ Height 155.6 ± 3.7 cm (150–162 cm) ∗∗ Body weight 55.1 ± 11.2 kg (42–84 kg) ∗∗ Body mass index 22.8 ± 4.4 (16.2–33.8) The cycle in which patients developed grade 2 or 3 nausea despite standard antiemetic therapy 1 29 2 11 3 6 4 4 Type of cancer Uterine cervical cancer 23 Uterine corpus cancer 22 Uterine carcinosarcoma 2 Ovarian cancer 2 Vaginal cancer 1 Regimen of anticancer chemotherapy AP (adriamycin 60 mg/m2,cisplatin50mg/m2)22 CPT-11/CDDP (irinotecan 60 mg/m2,cisplatin60mg/m2)8 CDDP (cisplatin 50 mg/m2) 5 ∗∗∗ FP (5-fluorouracil 700 mg/m2 × 4days,cisplatin70mg/m2) 3 TP (paclitaxel 135 mg/m2,cisplatin50mg/m2)3 EP (etoposide 100 mg/m2 × 3days,cisplatin80mg/m2)2 IP (ifosphamide 1.5 g/m2 × 4days,cisplatin80mg/m2)2 ∗∗∗ weekly CDDP (cisplatin 40 mg/m2) 4 ∗∗∗ weekly TP (paclitaxel 50 mg/m2,cisplatin30mg/m2) 1 ECOG: Eastern Cooperative Oncology Group; CDDP: cisplatin. ∗ Median ± S.D. (range). ∗∗ Mean ± S.D. (range). ∗∗∗ Combined with external pelvic irradiation (1.8 Gy/day). whole cycles of chemotherapy. One patient had to stop wasimprovedmorethan90%inthosepatientsbycombined receivingchemotherapybecauseoftheprogression. use of olanzapine. The improvement was statistically significant. This shows the possibility of preventive administration of olanzapine becoming a new effective choice toward CINV 4. Discussion resistant to standard antiemetic therapy. Second,thenauseaandvomitingwerealsocontrolled As far as we know, this is the first study to report the preven- indelayedphaseinalmostthesamelevelofacutephase, tiveeffectofolanzapineusedwithstandardantiemeticther- although delayed phase is known to be more difficult in terms apy toward CINV caused by highly emetogenic chemother- of controlling these symptoms. It is very interesting that the apy. nausea control rate was 94% in delayed phase while it was First, the most important point in this study is that using 98% in acute phase. There is a possibility that olanzapine is olanzapine combined with standard antiemetic therapy was effective to the mechanism of nausea in delayed phase which effective for preventing nausea and vomiting in patients with is refractory to standard antiemetic therapy. Even in patients CINV resistant to standard antiemetic therapy. Although who had grade 2 or 3 nausea, complete response rate was 82% olanzapine was given to patients who had grade 2 or 3 nausea indelayedphasebecauseboththenauseacontrolrateandthe despite standard antiemetic therapy, the nausea control rate vomiting control rate significantly improved. 4 BioMed Research International

Table 2: The changes in nausea grade before/after using olanzapine.

Acute phase (0–24 h) Delayed phase (24–120 h) Overall phase (0–120 h) NauseagradewithOLN NauseagradewithOLN NauseagradewithOLN 012301230123 Nausea grade without OLN 0 1700000000000 1 930010000000 2 13 1 0 0 6 13 1 0 6 11 1 0 3 4 2 1 0 14 13 2 0 14 15 3 0 OLN: olanzapine.

Table 3: Changes of nausea grade and nausea control rate after receiving olanzapine combined with standard antiemetic therapy.

Acute phase (0–24 h) Delayed phase (24–120 h) Overall phase (0–120 h) WithoutOLN WithOLN WithoutOLN WithOLN WithoutOLN WithOLN Nausea grade 0 17 (34%) 43 (86%) 0 (0%) 21 (42%) 0 (0%) 20 (40%) 1 12 (24%) 6 (12%) 1 (2%) 26 (52%) 0 (0%) 26 (52%) 2 14 (28%) 1 (2%) 20 (40%) 3 (6%) 18 (36%) 4 (8%) 3 7 (14%) 0 (0%) 29 (58%) 0 (0%) 32 (64%) 0 (0%) ∗ Nausea control rate 58% 98% 2% 94% 0% 92% ∗∗ 𝑃 value 𝑃 < 0.001 𝑃 < 0.001 𝑃 <0.001 ∗ ∗∗ OLN: olanzapine, nausea grade 0 or 1 (CTCAE ver. 4.0), and McNemar test.

Table 4: Changes of complete response rate, complete control rate, and total control rate after receiving olanzapine combined with standard antiemetic therapy.

Acute phase (0–24 h) Delayed phase (24–120 h) Overall phase (0–120 h) ∗ ∗ ∗ Without OLN With OLN 𝑃 value Without OLN With OLN 𝑃 value Without OLN With OLN 𝑃 value No vomiting 44 (88%) 50 (100%) 0.03 35 (70%) 48 (96%) <0.001 31 (62%) 48 (96%) <0.001 No rescue therapy 27 (54%) 49 (98%) <0.001 1 (2%) 41 (82%) <0.001 1 (2%) 41 (82%) <0.001 CR 26 (52%) 49 (98%) <0.001 1 (2%) 41 (82%) <0.001 1 (2%) 41 (82%) <0.001 CC 24 (48%) 49 (98%) <0.001 0 (0%) 41 (82%) <0.001 0 (0%) 41 (82%) <0.001 TC 17 (34%) 43 (86%) <0.001 0 (0%) 21 (42%) <0.001 0 (0%) 20 (40%) <0.001 ∗ McNemar test. OLN: olanzapine. CR: complete response (no vomiting, no rescue, and any nausea). CC: complete control (no vomiting, no rescue, and nausea grade 0 or 1). TC: total control (no vomiting, no rescue, and nausea grade 0).

It is reported that complete response rate of standard both genders. However, the difference of effect in gender antiemetic therapy is 80% in acute phase and 60–70% in became bigger as they continued the chemotherapy. The delayed phase [3–6], which are thought to be relatively good percentage of the female patients with no emesis in 6th course results. However we must pay attention to the fact that these of chemotherapy was only 44% where 60% of male patients studies include both male and female patients. The results hadnoemesis[11]. Therefore we need stronger antiemetic with a group consisted of only female patients are worse therapy in female patients and that is the reason we have compared to those with a group consisted of both sexes expectation in efficacy of olanzapine. because women have higher risk of CINV. In particular, Olanzapine is classified as an atypical antipsychotic and complete response rate in delayed phase is as low as 50% it is used to treat schizophrenia and bipolar disorders. Olan- in gynecologic cancer patients [10]. In phase III randomized zapine is called MARTA (multi-acting-receptor-targeted control trial which compared the effect of antiemetic therapy antipsychotics) and its main characteristic is that it is an toward cisplatin-based chemotherapy between both genders, antagonist of multiple chemoreceptors such as dopamine (D1, there were no differences in male patients and female patients D2,D3,D4,andD5),serotonin(5-HT2a,5-HT2c,5-HT3,and in first cycle when they were treated with triple therapy. 5-HT6), histamine (H1), adrenalin (𝛼1), and acetylcholine- The percentage of patients who had no emesis was 70% in muscarine (Achm1–Achm5) [12]. Olanzapine is not originally BioMed Research International 5 antiemetic agent, but, due to its strong antiemetic effect, there who had their olanzapine reduced to 2.5 mg. Meanwhile, are many studies reporting its efficacy toward CINV, nausea there was one patient who had to take 10 mg of olanzapine due to opioids, and nausea and vomiting in terminal stage in due to strong nausea. We have to verify the optimal dose patients with malignant tumors. of olanzapine used with standard antiemetic therapy. Finally, Acetylcholine-muscarine (Achm), dopamine (D2), his- there are only gynecological cancer patients in this study. We tamine (H1), serotonin (5-HT2, 5-HT3), and neurokinin- also have to verify if this is also effective for patients using 1 (NK-1) are known as main neurotransmitters related to regimens for other kinds of malignant tumors. CINV. There are chemoreceptors of these transmitters in We now have an ongoing prospective phase II trial to central nervous system. There are H1 and Achm in vestibular prove the efficacy and safety of olanzapine used with standard apparatus, 5-HT3, NK-1, and D2 in CTZ, and 5-HT2, 5-HT3, antiemetic therapy toward CINV caused by HEC. NK-1, D2, H1, and Achm in vomiting center and it is thought that the network between these receptors causes nausea and 5. Conclusion vomiting [13]. Olanzapine is a medication which can be an antagonist of those 4 receptors except NK-1 receptor and We treated patients using cisplatin containing HEC regimen relatedtoallofthevestibularapparatus,CTZ,andvomiting with 5 mg of olanzapine who had grade 2 or 3 nausea center. Theoretically, by using both standard antiemetic although they were receiving standard antiemetic therapy. therapy and olanzapine, all chemoreceptors affecting CINV Using olanzapine combined with standard antiemetic therapy can be blocked because olanzapine can be an antagonist improved nausea control rate to more than 90% and it was of chemoreceptors which cannot be blocked using only statistically significant. There was grade 1 or 2 drowsiness in standard antiemetic therapy. Also, olanzapine is known to half of the patients but it was feasible. have less adverse effects such as extra pyramidal symptoms It is suggested that using olanzapine as a preventive and akathisia compared with conventional antipsychotics antiemetic agent combined with recommended standard (prochlorperazine, haloperidol, etc.) and metoclopramide antiemetic therapy could be useful antiemetic regimen. whichhavebeenusedforCINV[14]. Moreover, this could improve quality of life in patients with There are several phase III randomized control trials on cancer who are receiving chemotherapy. efficacy of olanzapine towards CINV. In the study which comparedtheolanzapinewithaprepitantinpatientsusing regimen containing cisplatin or AC therapy (doxorubicin, Conflict of Interests cyclophosphamide), complete control rates were almost the The authors declare that there is no conflict of interests sameinbothacutephaseanddelayedphase.Butrateof regarding the publication of this paper. patientswhohadnonauseaatallwas69%inolanzapine group while it was 38% in aprepitant group [7]. Therefore olanzapinewasprovedtobecomparableorevenmore Acknowledgment effective compared with aprepitant. The study compared olanzapine and dexamethasone with patients using HEC or There was a support from Sayaka Otani M.D. with translation MEC; complete control rates in acute phase were almost the and proofreading of this paper. same in both groups. However in delayed phase, olanzapine group had significantly better complete response rate in both References HEC and MEC regimens (HEC: nausea 69% versus 30%, vomiting 78% versus 56%; MEC: nausea 83% versus 58%, [1] M. G. Kris, M. Tonato, E. Bria et al., “Consensus recommenda- vomiting 89% versus 75%) [8]. In the study which compared tions for the prevention of vomiting and nausea following high- olanzapine with metoclopramide used as salvage therapy emetic-risk chemotherapy,” Supportive Care in Cancer,vol.19, for patients who had CINV resistant to standard antiemetic no. 1, supplement, pp. S25–S32, 2011. therapy, the rates of patients without vomiting were 70% [2] E. Basch, A. A. Prestrud, P.J. Hesketh et al., “Antiemetics: Amer- versus 31% and the rates of those without nausea were 68% ican Society of Clinical Oncology clinical practice guideline update,” Journal of Clinical Oncology,vol.29,no.31,pp.4189– versus 23% within 72 hours after salvage. By this result, 4198, 2011. olanzapine was proved to be a stronger salvage therapy agent [9]. There were no grade 3 or 4 adverse effects in these studies. [3] S. Poli-Bigelli, J. Rodrigues-Pereira, A. D. Carides et al., “Addi- tion of the neurokinin 1 receptor antagonist aprepitant to stan- The limitation of this study is that, firstly, this isa dard antiemetic therapy improves control of chemotherapy- retrospective before-after comparative study with only small induced nausea and vomiting: results from a randomized, number of patients. A prospective study should be conducted double-blind, placebo-controlled trial in Latin America,” Can- in the future. Second, the evaluation of nausea was done cer,vol.97,no.12,pp.3090–3098,2003. by doctors, nurses, and pharmacists based on objective [4]H.J.Schmoll,M.S.Aapro,S.Poli-Bigellietal.,“Comparison indicator. We believe that there is no big divergence with of an aprepitant regimen with a multiple-day ondansetron the self-evaluations of patients but to evaluate the true regimen, both with dexamethasone, for antiemetic efficacy in therapeutic effect, evaluation tool such as patient diary is high-dose cisplatin treatment,” Annals of Oncology,vol.17,no. needed as subjective self-evaluation. Third, we do not know 6, pp. 1000–1006, 2006. the optimal dose of olanzapine yet. The rate of drowsiness was [5] D. Campos, J. R. Pereira, R. R. Reinhardt et al., “Prevention of quite high such as 52% in this study, so there were 6 patients cisplatin-induced emesis by the oral neurokinin-1 antagonist, 6 BioMed Research International

MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone,” Journal of Clinical Oncology,vol. 19, no. 6, pp. 1759–1767, 2001. [6]P.J.Hesketh,S.M.Grunberg,R.J.Grallaetal.,“The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group,” JournalofClinicalOncology,vol.21,no.22,pp. 4112–4119, 2003. [7]R.M.Navari,S.E.Gray,andA.C.Kerr,“Olanzapineversus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial,” Journal of Support- ive Oncology,vol.9,no.5,pp.188–195,2011. [8] L. Tan, J. Liu, X. Liu et al., “Clinical research of Olanzapine for prevention of chemotherapy-induced nausea and vomiting,” Journal of Experimental and Clinical Cancer Research,vol.28, no. 1, article 131, 2009. [9] R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy,” Supportive Care in Can- cer,vol.21,no.6,pp.1655–1663,2013. [10] N. Takeshima, M. Matoda, M. Abe et al., “Efficacy and safety of triple therapy with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin- based chemotherapy for gynecological cancer: KCOG-G1003 phase II trial,” Supportive Care in Cancer,vol.22,no.11,pp.2891– 2898, 2014. [11] P. J. Hesketh, S. M. Grunberg, J. Herrstedt et al., “Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response,” Supportive Care in Cancer,vol.14,no. 4, pp. 354–360, 2006. [12] F.Bymaster,K.W.Perry,D.L.Nelsonetal.,“Olanzapine:abasic science update,” The British Journal of Psychiatry. Supplement, no.37,pp.36–40,1999. [13] B. J. Pleuvry, “Physiology and pharmacology of nausea and vomiting,” Anaesthesia and Intensive Care Medicine,vol.4,no. 10, pp. 349–352, 2003. [14] S. D. Passik, J. Lundberg, K. L. Kirsh et al., “A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain,” Journal of Pain and Symptom Management,vol.23,no.6,pp.526–532,2002. Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 893013, 8 pages http://dx.doi.org/10.1155/2015/893013

Review Article Prophylactic Management of Radiation-Induced Nausea and Vomiting

Petra Feyer,1 Franziska Jahn,2 and Karin Jordan2

1 Department of Radiotherapy, Vivantes Medical Center Berlin-Neukolln,RudowerStraße48,12351Berlin,Germany¨ 2Department of Internal Medicine IV, Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany

Correspondence should be addressed to Karin Jordan; [email protected]

Received 25 November 2014; Accepted 7 March 2015

AcademicEditor:FaustoRoila

Copyright © 2015 Petra Feyer et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The incidence of nausea and vomiting after radiotherapy is often underestimated by physicians, though some 50–80%of patients may experience these symptoms. The occurrence of radiotherapy-induced nausea and vomiting (RINV) will depend on radiotherapy-related factors, such as the site of irradiation, the dosing, fractionation, irradiated volume, and radiotherapy techniques. Patients should receive antiemetic prophylaxis as suggested by the international antiemetic guidelines based upon a risk assessment, taking especially into account the affected anatomic region and the planned radiotherapy regimen. In this field the international guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/European Society of Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) guidelines as well as the National Comprehensive Cancer Network (NCCN) are widely endorsed. The emetogenicity of radiotherapy regimens and recommendations for the appropriate use of antiemetics including 5-hydroxytryptamine (5-HT3) receptor antagonists, steroids, and other antiemetics will be reviewed in regard to the applied radiotherapy or radiochemotherapy regimen.

1. Introduction similar to that of CINV.The treatment of CINV has therefore guided that for RINV [2]. Progress in understanding the RINV still can be a debilitating and distressing side effect pathophysiology of chemotherapy-induced emesis led to for patients receiving radiotherapy, which is often underes- the development of agents that form also the basis for the timated by clinicians. Depending on the site of irradiation, treatment of RINV. 50–80% of patients undergoing radiotherapy will experience nausea and vomiting. The pathophysiology of RINV is not completely understood, but progress in understanding the 3. Incidence of RINV pathophysiology and treatment of CINV has greatly influ- As there is a large amount of literature regarding antiemetic enced that of RINV. Uncontrolled nausea and vomiting can therapies to prevent CINV the body of evidence related to lead to patients delaying or refusing further radiotherapy, thereby compromising their treatment plan [1]. The inci- RINV is noticeably smaller [3]. Two prospective observa- dence, classification of risk, and prophylactic management of tional studies provide information on the frequency of RINV radiation therapy induced nausea and vomiting (RINV) will and antiemetic measures. be discussed in this paper. The Italian Group for Antiemetic Research in Radiother- apy (IGARR) analyzed the incidence of RINV in 1020 patients 2. Pathophysiology receiving various kinds of RT without concurrent chemotherapy [4]. Overall, nausea and/or vomiting were reported by 28 The pathophysiology of radiotherapy-induced nausea and percent. The median time to the first episode of vomiting was vomiting (RINV) is not well understood but is thought to be three days. Antiemetic drugs were administered to 17 percent 2 BioMed Research International

Table 1: Risk categories adapted from [1].

Emetogenic potential Risk of emesis without antiemetic prophylaxis Location High Risk > 90 percent Total-body irradiation (TBI), total nodal irradiation (TNI) Upper abdominal irradiation, hemibody irradiation Moderate Risk 60 to 90 percent (HBI), and upper body irradiation (UBI) Cranium (all), craniospinal, head and neck, lower thorax Low Risk 30 to 60 percent region, pelvis Minimal Risk < 30 percent Breast and extremities

of the patients, including 12 percent treated prophylactically Table 2: Individual risk factors adapted from [1]. and 5 percent given rescue therapy. In a second study of 368 patients receiving RT again Risk factor Risk score without concurrent chemotherapy, the overall incidence rates Age for nausea and vomiting were 39 and 7 percent [5]. Nausea >55 years 0 was more frequent in those receiving RT to the lower <55 years 1 abdomen or pelvis (66 percent) compared to the head and Sex neck area radiated patients (48 percent). Male 1 Female 2 Alcohol consumption 4. Risk Classification Yes (>100 g/day) 0 The occurrence of radiotherapy-induced nausea and vom- No 1 iting (RINV) will depend on radiotherapy-related factors, Previous nausea & vomiting such as the site of irradiation, dosing, fractionation, irra- Yes 1 diated volume, and radiotherapy techniques. Fractionated No 0 radiotherapy, for instance, with as many as 40 fractions over Anxiety a 2-month period, may lead to ongoing, debilitating nausea Yes 1 and vomiting. As a result, patients may delay or refuse and No 0 therefore compromise their antineoplastic treatment [4, 5]. Risk profile (4 = normal risk |5-6 high risk)

4.1. Emetogenicity of Radiotherapy. Amajordifficultyin ensuring effective antiemetic treatment has been the lack of 5. Prevention and Treatment agreement on the emetic potential of different radiotherapy There have been only a few randomized clinical trials evalu- techniques and doses. The extent of irradiation is one of ating the efficacy of antiemetic drugs for treating RINV. Evi- the determinants of risk for RINV. MASCC/ESMO and the dence shows that prevention of these symptoms is better than ASCO guidelines divide the RINV risk into four categories intervention on an as-needed basis. Of course overtreatment basedupontheradiationfield[2, 6, 7](Table 1). has also to be avoided to prevent side effects coming from Intensity-modulated radiation therapy (IMRT), which is the antiemetics themselves. The most studied agents in these becoming the treatment of choice, for example, many head settings seem to be 5-hydroxytryptamine (5-HT3)receptor and neck cancers, reduces toxicity by reducing radiation antagonists, proving good response and activity. Other agents dosestouninvolvednormaltissueinthevicinityoftumour such as the tachykinin NK-1 receptor antagonist may play a targets. However, previously unaffected tissues, such as the role but these agents need to be further studied in randomized brainstem, may receive clinically significant doses that lead controlled trials. to side effects such as nausea and vomiting [8]. Individual patient characteristics also affect the potential 5.1. 5-HT3 Receptor Antagonist. The 5-HT3 RA class of for RINV. Apart from those seen in Table 2, general health, antiemetics has been used more extensively in clinical prac- concurrent or recent chemotherapy, psychological status, tice to treat RINV over the last two decades. Tables 3 and tumour stage, field size, dose per fraction, and overall length 4 show randomised trials with 5-HT3 RAs and/or corticos- of treatment time may all increase or decrease the chance teroids in patients treated with single or fractionated regi- ofnauseaandvomiting.Thisisinaccordancewiththedata mens of radiotherapy. Different compounds and a wide range of the Italian study group. They showed that the statisti- of doses and schedules were used. Trials in Table 3 reported cally significant patient related risk factors were concomi- that, in patients receiving upper abdominal irradiation, 5- tant chemotherapy and a previous experience of vomiting HT3 RAs provided significantly greater protection against induced by chemotherapy [4]. RINV than metoclopramide, phenothiazines, or placebo. BioMed Research International 3 ]. 1 DOL better than placebo OND + DEX better than OND alone OND better than placebo PAL & PRED insufficient for this treatment regimen vomiting) OND better than placebo GRAN better than placebo TRO better than MCP Prophylactic TRO better than rescue TRO AL = palonosetron; PRED = prednisolone; OND = ) b b c b d b c d 𝑃 = 0.001 78 12 23 During cycle 1, 42% nausea-free, after 5 cycles only 23% nausea-free 71 Incidence of vomiting was 2.19 times higher in TRO rescue arm ( 3/day p.o. for 5 days 46 3/day p.o. 50 3/day p.o. for 5 days 97 2/day p.o. 67 3/day p.o. 61 OND better than placebo (for 3/day p.o. 35 × × × × × × DOL 0.6 mg/kg i.v. 93 OND 8 mg b.i.d. + DEX 4 mg for 5 days OND 8 mg MCP 10 mg PAL 0.25 mg + PRED 100PRED mg 50 o.d. mg on day on 1, day plus 2,days and 3 PRED and 4 25 mg on DOL 1.2 mg/kg i.v.Placebo 83 54 DOL 0.3 mg/kg i.v. 100 PCP 10 mg OND 8 mg Placebo 45 OND 8 mg TRO 5 mg/day p.o.OND 8 mg b.i.d. for 5 days + placebo for 5 days TRO5mgdailystartingfrom1daybeforeRT 91 until 7 days after RT MCP 10 mg TRO 5 mg on an as-needed basis (rescue) RAs and/or steroids in patients undergoing upper abdominal irradiation adapted from [ 3 on day 1 2 and not recommended elsewhere (MASCC guidelines 2013). 10 fractions ≥ 6 Gy single fraction 15 fractions to the upper abdomen to a dose 8–10 Gy single fraction ≥ Radiotherapy regimens1.8 Gy/day for at least 5 fractions 1.7 Gy/day for Antiemetic treatment2Gy/dayto30Gyin15fractions CR (% of patients)10–30 fractions(1.8–3 Gy/fraction)≥ of 20 or more Gy Result Fractionated radiotherapy of moderate or high emetogenic potential GRAN Placebo5 2 fractions/wk, mg/day 1.8–2.0 Gy/fraction on days 0–4 + cisplatin 40 mg/m 57.5 42 𝑛 23 82 50 111 211 135 288 260 ] Table 3: Randomised clinical trials with 5-HT ] ]48 32 ] ] 18 38 ] 12 41 ] 15 ] ] 20 39 40 [ a ´ en et al. (1996) [ Secondary end point: CR days 1–15. CR: complete plus major response. Dolasetron i.v.: no longer available in the USA (FDA 2010) Primary end point: CR days 1–5. Study Priestman et al. (1990) [ Priestman et al. (1993) [ Franz Bey et al. (1996) Aass et al. (1997) [ Lanciano et al. (2001) [ Wong et al. (2006) [ Mystakidou et al. (2006) [ Ruhlmann et al. (2013) [ a b c d ondansetron; PCP = prochlorperazine; TRO = tropisetron. p.o. = orally; i.v. = intravenously; b.i.d. = twice daily; wk = week; DEX = dexamethasone; DOL = dolasetron; GRAN = granisetron; MCP = metoclopramide; P 4 BioMed Research International OND better than CLP + DEX OND + DEX better than paspertin + DEX Result GRAN better than MCP + DEX +LOR OND better than placebo No difference OND better than placebo mide;OND=ondansetron;TBI=total-body ]. 1 a a 0 13 61 53 47 50 34 20 84 CR 50 90 (% of patients) 3p.o. i.v. + LOR × 2 1/day p.o. 3p.o.+DEX6mg 2p.o. 3/day p.o. 3/day p.o. × × × × × RAs in patients undergoing TBI and HBI adapted from [ 3 OND 8 mg i.v. Placebo OND 8 mg versus CLP 25 mg GRAN 3 mg i.v. versus MCP 20 mg i.v. + DEX 6 mg/m OND 8 mg i.v. + DEXversus 10 mg MCP10mg+DEX10mg OND 8 mg OND 8 mg Placebo versus GRAN 2 mg 2mgi.v. ). 2 3/day 3/day × × Table 4: Randomised clinical trials with 5-HT 10.5 Gy TBI single fraction 8–12.5 Gy HBI single fraction Radiotherapy regimens7. 5 G y TBI single fraction 1.2 Gy Antiemetic treatment 7–7.7 Gy 1.2 Gy TBI 11 fractions to a total dose of 13.2 Gy TBI 11 fractions to a total dose of 13.2 Gy 𝑛 ]30 11 ]34 ]20 ]116 ]66 ]20 13 43 45 44 42 All patients received i.v. dexamethasone (8 mg) and phenobarbitone (60 mg/m Study Grant Prentice et al. (1995) [ Tiley et al. (1992) [ Spitzer et al. (1994) [ Sykes et al. (1997) [ Huang et al. (1995) [ Spitzer et al. (2000) [ irradiation; p.o. = orally; i.v. = intravenously. CLP = chlorpromazine; CR = complete response; DEX = dexamethasone; GRAN = granisetron; HBI = half-body irradiation; LOR = lorazepam; MCP = metoclopra a BioMed Research International 5

In patients treated with TBI or HBI, 5-HT3 RAs provided radiochemotherapy patients with cervical cancer [24]. Data significantly greater protection against RINV than conven- from a small clinical trial (𝑛=59patients) presented tional antiemetics or placebo (Table 4). at the MASCC meeting 2011 provides the first hint that Side effects were evaluated by Goodin and Cunningham tachykinin NK-1 receptor antagonists in combination with [9]. The side effects of 5-HT3 RAs are usually reported 5-HT3 receptor antagonists and dexamethasone proved to as being mild, with headache, constipation, diarrhoea, and be advantageous in the prophylaxis of acute and delayed weakness [10–13]. Also 5-HT3 RAs sometimes seem to reduce nausea during simultaneous radiochemotherapy compared the frequency of diarrhoea, a debilitating side effect of acute with the standard antiemetic treatment. More patients on enteric radiation toxicity [14, 15]. the emetic prophylaxis containing tachykinin NK-1 receptor The 5-HT3 RA palonosetron and the transdermal antagonists reached a complete response [25]. Dennis et al. granisetron patch (Sancuso) might be a useful option for showed the combination of granisetron and aprepitant being patients receiving radiotherapy, although to date only a safe and efficacious for the prophylaxis of RINV in single few studies have been undertaken on their use [1, 16, 17]. and multiple fraction moderately emetogenic radiotherapy Ruhlmann et al. evaluated antiemetic therapy in 48 gynaeco- for thoracolumbar bone metastases evaluating only a very logical patients receiving fractionated radiotherapy and con- 2 small sample size with 19 patients [26]. comitant weekly cisplatin (40 mg/m )[18]. Antiemetic treatment was palonosetron and prednisolone. Results showed the probability of completing 5 cycles without emesis was 57%. 5.4. Other Agents. Less specific antiemetic drugs, such as During cycle 1, 42% of patients were nausea-free, but by the fifth cycle only 23% of patients were continuously nausea- prochlorperazine, metoclopramide, and cannabinoids, have free.Halfofthepatientsusedrescueremedyatleastoncedur- beenshowntohavelimitedefficacyinthepreventionand ing the 5 cycles. The study concluded that palonosetron and treatment of RINV, and this is generally in patients with prednisolone alone were insufficient antiemetic treatment in milder symptoms. The use of THC was slightly more benefi- these patients and that investigations of the addition of a NK-1 cial than the use of prochlorperazine [27]butgenerallyshows RA to antiemetic treatment under some circumstances would an inferior safety profile, including sedation and eupho- be valuable. ria/dysphoria. Salvo et al. showed in a meta-analysis from 2012 the superiority of 5-HT3 receptor antagonist not only 5.2. Corticosteroids. Steroids are interesting antiemetic drugs to placebo but also to metoclopramide and other antiemetic because of their widespread availability, low cost, and drugs [28]. reported benefits. One trial has recorded dexamethasone use as a single agent for the prophylaxis of RINV. This double-blind study [19] reported patients who underwent 5.5. Duration of Prophylaxis. The appropriate duration of fractionated radiotherapy to the upper abdomen and received antiemetic prophylaxis for patients receiving fractionated × either oral dexamethasone (2 mg 3/day) or placebo during radiotherapy is not clear. There have been no randomized the first week only of a six-week course of radiotherapy. A trials using 5-HT3 receptor antagonists that compared a five- trialbyWongetal.[20](Table 3)showedanonsignificant day course of treatment with a more protracted course. A trend towards improved complete control of nausea (50% systematic review including 25 randomized and nonrandom- versus 38% with placebo) and vomiting (78% versus 71%) (i.e., ized trials revealed that 5-HT3 receptor antagonists were most primary end point was not reached). However, the effects of commonly administered for the entire duration of a course of dexamethasone extended beyond the initial period: complete radiotherapy. Thus we still lack evidence related to duration control of emesis was achieved by significantly more patients and timing of 5-HT3 receptor antagonist therapy [1]. over the entire course of radiotherapy (23% versus 12% with placebo) (i.e., secondary end point was reached). Although Despite this lack of evidence the current guidelines rec- thestudydidnotshowastatisticallysignificantbenefitforthe ommendedthatthedecisiononwhetherornottocontinue primary end point, the results for the secondary end points antiemetic prophylaxis beyond the first week should be based and quality of life data strongly suggest that the addition of uponanassessmentoftheriskofemesisaswellasrelevant dexamethasone does provide benefits. individual factors. In a recent article it was noted that patients As the majority of episodes of nausea and vomiting occur had significantly greater proportions of RINV during the first early in the course of radiotherapy, it could be suggested andsecondweekoftreatment[29]. that antiemetics may only be necessary for the first week of treatment [19, 21, 22]. 5.6. Rescue Therapy. The benefit of 5-HT3 receptor antago- 5.3. Neurokinin-1 (NK-1) Receptor Inhibitors. The role of NK-1 nistsoncenauseaorvomitingoccurshasbeensuggestedinall RAs in the management of CINV is well established; however, studies, but there are no trials specifically in this setting [30– neither aprepitant nor fosaprepitant or the newer NK1-RAs 32]. The emerging role of olanzapine in breakthrough emesis have been studied widely in patients with RINV [23]. A useful in patients with CINV has not been studied in RINV yet [33]. option in high-risk patients might be the combination of However, as the pathophysiology of RINV is thought to be a5-HT3 receptor antagonist and a NK-1 receptor inhibitor. similar to that of CINV, a treatment attempt with olanzapine A trial is ongoing which is looking at this combination in might be useful. 6 BioMed Research International

Table 5: Key recommendations of antiemetic guideline groups adapted from [1, 7].

Risk category Dose Schedule High emetic risk

5-HT3 receptor antagonist before each fraction 5-HT3 receptor antagonist throughout XRT, continued for at least 24 hours after completion of XRT ∗ Granisetron 2 mg orally; 1 mg or 0.01 mg/kg i.v. ∗ 8 mg orally twice daily; 8 mg or 0.15 mg/kg Ondansetron i.v. † Palonosetron 0.50 mg orally; 0.25 mg i.v. Dolasetron 100 mg orally only Tropisetron 5mgorallyori.v. Corticosteroid Dexamethasone 4 mg orally or i.v. During fractions 1–5 Moderate emetic risk Any of the above listed agents are 5-HT receptor antagonist before each fraction 5-HT receptor antagonist † 3 3 acceptable; note preferred options throughout XRT Corticosteroid Dexamethasone 4 mg i.v. or orally During fractions 1–5 Lowemeticrisk 5-HT receptor antagonist as either rescue or Any of the above listed agents are 3 5-HT receptor antagonist prophylaxis; if rescue is used, then prophylactic therapy 3 acceptable; note preferred options should be given until the end of XRT Minimal emetic risk Patients should be offered either class as rescue therapy; Any of the above listed agents are 5-HT receptor antagonist if rescue is used, then prophylactic therapy should be 3 acceptable; note preferred options given until the end of XRT Dopamine receptor antagonist Metoclopramide 20 mg orally Prochlorperazine 10 orally or i.v. ∗ † Preferred agents; no data are currently available on the appropriate dosing frequency with palonosetron in this setting. The Update Committee suggests that dosing every second or third day may be appropriate for this agent. 5-HT3 = 5-hydroxytryptamine-3; i.v., = intravenously; XRT = radiation therapy.

6. Guidelines and Patient Management the addition of short course dexamethasone to the 5-HT3 receptor antagonist may be offered during fractions 1–5. The development of new antiemetic agents and a better For patients at low risk of developing RINV (Table 5), understanding of their activity as a function of the emeto- either prophylaxis with a 5-HT3 receptor antagonist or genicity of different RT regimens have led to the generation observation with rescue treatment is suggested. of guidelines for patient management. The most recent guide- For patients at minimal risk of developing RINV (Table 5), lines were promulgated by the Multinational Association a prophylactic antiemetic treatment is not necessary. If for Supportive Care in Cancer (MASCC) and European patients develop RINV, treatment with a dopamine receptor SocietyforMedicalOncology(ESMO)in2009[1]whichwere antagonist or a 5-HT3 receptor antagonist might be appropri- subsequently endorsed by the American Society of Clinical ate. Oncology (ASCO) in 2011 [7]. A brief summary of these For patients being treated with concomitant RT and guidelines is presented in Table 5. chemotherapy, antiemetic prophylaxis should be based upon For patients at high risk of developing RINV (Table 5), the higher chemotherapy or RT risk category. aprophylaxiswitha5-HT3 receptor antagonist is recom- The NCCN guidelines do not follow the separation in four mended by the guidelines. Based upon results from patients risk categories and are therefore less specific [34]. receiving highly emetogenic chemotherapy, the addition of dexamethasone to the 5-HT3 receptor antagonist is sug- 7. Conclusion gested. For patients at moderate risk of developing RINV Radiation-induced nausea and vomiting (RINV) is a frequent (Table 5), prophylaxis with a 5-HT3 receptor antagonist is complication of radiation therapy. Its effect on patients’ the prophylaxis of choice. However, in this risk group, quality of life should not be underestimated, especially as BioMed Research International 7 such effects may compromise or delay treatments. Therefore, head and neck intensity-modulated radiation therapy,” Medical patients at risk of RINV should always be offered the Dosimetry,vol.36,no.1,pp.41–45,2011. most effective antiemetic prophylaxis as suggested by the [9] S. Goodin and R. Cunningham, “5-HT3-receptor antagonists international guidelines. However, it has to be acknowledged for the treatment of nausea and vomiting: a reappraisal of their that the implementation of these guidelines in practice varies side-effect profile,” Oncologist,vol.7,no.5,pp.424–436,2002. regarding risk estimation and different countries35 [ , 36]. 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Review Article Treatment of Breakthrough and Refractory Chemotherapy-Induced Nausea and Vomiting

Rudolph M. Navari1,2

1 IndianaUniversitySchoolofMedicine,SouthBend,IN46617,USA 2South Bend Medical Services Corporation, 202 Lincoln Way East, Mishawaka, IN 46544, USA

Correspondence should be addressed to Rudolph M. Navari; [email protected]

Received 18 November 2014; Accepted 31 December 2014

AcademicEditor:BernardoL.Rapoport

Copyright © 2015 Rudolph M. Navari. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Despite significant progress in the prevention of chemotherapy-induced nausea and vomiting (CINV) with the introduction of new antiemetic agents, 30–50% of patients receiving moderately or highly emetogenic chemotherapy (MEC or HEC) and guideline directed prophylactic antiemetics develop breakthrough CINV. International guidelines recommend the treatment of breakthrough CINV with an agent from a drug class that was not used in the prophylactic antiemetic regimen and recommend using the breakthrough medication continuously rather than using it on an as needed basis. There have been very few studies on the treatment of breakthrough CINV. A recent double-blind, randomized, phase III study suggested that olanzapine may be an effective agent for the treatment of breakthrough CINV. Refractory CINV occurs when patients develop CINV during subsequent cycles of chemotherapy when antiemetic prophylaxis has not been successful in controlling CINV in earlier cycles. Patients who develop refractory CINV should be considered for a change in their prophylactic antiemetic regimen. If significant anxiety exists, a benzodiazepine may be added to the prophylactic regimen. If a refractory patient is receiving HEC, olanzapine may be added to the prophylactic regimen. If the patient is receiving MEC, olanzapine or an NK-1 receptor antagonist may be added to the prophylactic regimen.

1. Introduction The use of 5-hydroxytryptamine-3 (5-HT3)receptor antagonists has improved the control of CINV [4, 5]. Addi- Chemotherapy-induced nausea and vomiting (CINV) tional improvement in the control of CINV has occurred adversely affects patients’ quality of life and may affect with the use of aprepitant, the first agent available in the patients’ treatment decisions [1–3]. The emetogenicity of the drug class of neurokinin-1 (NK-1) receptor antagonists [6], chemotherapy administered and specific patient characteris- and olanzapine, an antipsychotic agent which blocks multiple tics such as female gender, age, and history of amount of alco- neurotransmitters in the central nervous system [7–9]. hol intake affect patients’ risk factors for CINVTable ( 1)[3]. The primary endpoint used for studies evaluating various Significant and uncontrolled CINV may result in patients agents for the control of CINV has been complete response returning to the chemotherapy treatment facility one to (CR) (no emesis, no use of rescue medication) over the three days after chemotherapy for rehydration or emesis or acute (24 hours after chemotherapy), delayed (24–120 hours), nausea control. If CINV cannot be controlled in an outpatient and overall (0–120 hours) periods [3]. The combination of facility, patients may subsequently be treated in an emergency a5-HT3 receptor antagonist, dexamethasone, and a NK-1 department or require hospitalization [1, 3]. Patients who receptor antagonist has improved the control of emesis in have an electrolyte imbalance or those who have recently patients receiving either highly emetogenic chemotherapy undergone surgery or radiation therapy are at greater risk of (HEC) or moderately emetogenic chemotherapy (MEC) over experiencing serious complications from CINV [1–3]. a 120-hour period following chemotherapy administration 2 BioMed Research International

Table 1: Patient-related risk factors for emesis following chemother- receptors and the NK-1 receptor antagonists have been apy. effective in the prevention of delayed CINV6 [ ]. Significant predictive factors include the dose and the emetogenicity of Major Factors Minor factors the chemotherapeutic agent, patient’s gender and age, and Female History of motion sickness protection against nausea and vomiting in previous cycles of Age <50 years Emesis during past pregnancy chemotherapy [1, 15]. History of low prior chronic alcohol intake (<1ounceof Anxiety alcohol/day) 2.3. Anticipatory CINV. Patients may develop a conditioned History of previous response known as anticipatory nausea and/or emesis if they chemotherapy-induced emesis experience CINV after chemotherapy administration despite prophylactic antiemetics. Emesis and/or nausea which occurs prior to the administration of chemotherapy in future [5, 6]. Many of these same studies have measured nausea as chemotherapy cycles and is attributed to the adverse memory a secondary endpoint, but nausea has not been well controlled of prior CINV is considered anticipatory CINV. Incidence [10, 11]. rates for this type of nausea and vomiting range from 10 to The use of effective antiemetic agents in various clinical 45%, with nausea occurring more frequently [1, 15]. settings has been described in established guidelines from the Multinational Association of Supportive Care in Can- 2.4. Breakthrough CINV. Breakthrough CINV is vomiting cer (MASCC), the European Society of Medical Oncology and/or nausea that occurs within five days of chemotherapy (ESMO) [12], the American Society of Clinical Oncology administration after the use of guideline directed prophy- (ASCO) [13], and the National Comprehensive Cancer Net- lactic antiemetic agents. This type of CINV usually requires work (NCCN) [14]. immediate treatment or requires “rescue” with additional Thepurposeofthisreviewistoprovideaclinical antiemetics. approach to treatment of breakthrough CINV and refractory CINVbasedontheavailabledataintheliteratureaswellas 2.5. Refractory CINV. Refractory CINV is defined as vom- the recommendations provided by established guidelines [12– iting and/or nausea occurring after chemotherapy in subse- 14]. quent chemotherapy cycles after guideline directed prophylactic antiemetic agents have failed in earlier cycles [1, 12– 2. Types of CINV 14, 17]. CINV can be attributed to several treatment-related factors, including the environment in which chemotherapy is admin- 3. Treatment of Breakthrough CINV istered, the emetogenicity of the chemotherapy, the dosage Breakthrough CINV, nausea and emesis which occur despite of the emetogenic agents, and patient-related factors [15–17]. adequate antiemetic prophylaxis, remains a significant clini- There are multiple mechanisms involved in the development cal patient problem [16–19]evenwiththeimprovedcontrol of CINV,and the mechanisms appear to be different for CINV of acute and delayed CINV.There have been very few clinical occurring in the first 24 hours after chemotherapy in contrast trials on the treatment of breakthrough CINV [12–14]. When to that which occurs in the period of one to five days after breakthrough CINV occurs, treatment may be considered chemotherapy. In order to differentiate these mechanisms, with agents such as dopamine antagonists or benzodiazepines five categories are used to classify CINV: acute, delayed, [12, 13], metoclopramide may be substituted for the 5HT3 anticipatory, breakthrough, and refractory. receptor antagonist in the prophylactic regimen, or a different 5-HT3 maybeusedintheprophylacticregimenaccording 2.1. Acute CINV. CINV occurring in the first 24 hours to the MASCC [12]andASCO[13] guidelines. The NCCN after chemotherapy is considered acute CINV and is pri- [14] guidelines suggest treating breakthrough CINV with an marily due to the activation of the serotonin receptors in agent from a drug class that was not used in the prophylactic the gastrointestinal tract. The combination of the 5-HT3 regimen and recommend continuing the breakthrough med- receptor antagonists, dexamethasone, and the NK-1 receptor ication if nausea and vomiting are controlled. antagonists has been very effective in the prevention of acute The treatment of established nausea and vomiting has CINV [3–5, 12–14]. not been well studied [20, 21], and the agents that have been used for the prevention of CINV have not demonstrated 2.2. Delayed CINV. Delayed emesis and/or nausea and/or significant efficacy in the treatment of20 CINV[ , 21]. In 2012, vomiting that develop more than 24 hours after chemother- the National Cancer Institute Physician Data Query (PDQ) apy administration are known as delayed emesis and/or forsupportivecarestatesthatthereisnoknowneffective nausea. For many chemotherapy agents such as cisplatin, therapy for treatment of nausea and vomiting which occurs doxorubicin, or cyclophosphamide, delayed CINV intensity after chemotherapy21 [ ]. peaksattwotothreedayspostchemotherapyadministration and may persist for five days after chemotherapy [1, 12– 3.1. Phase II Studies. The prevention of breakthrough CINV 15]. Delayed CINV is mediated primarily by substance P has slowly improved with the introduction of the serotonin BioMed Research International 3 receptor antagonists [22–24], the addition of dexamethasone CINV and 108 were evaluable. Thirty-nine of 56 (70%) [24, 25], and the addition of NK-1 receptor antagonists [26] patients receiving olanzapine had no emesis compared to 16 to the prophylactic regimens. There have been few studies, of 52 (31%) patients with no emesis for patients receiving however, on the treatment of breakthrough CINV. metoclopramide (𝑃 < 0.01)duringthe72-hourobservation Jones et al. [27]reportedinaphaseIIstudyon96patients period. Patients with no nausea (0, 0–10 visual analogue scale) who received MEC or HEC and guideline directed pro- during the 72-hour observation period were: olanzapine: 68% phylactic antiemetics. Thirty-nine patients (41%) developed (38 of 56); metoclopramide 23% (12 of 52) (𝑃 < 0.01). During breakthrough nausea and/or vomiting requiring treatment. the 72-hour observation period, there were no observed or Twenty-seven of the 39 patients completed a questionnaire reported Grade 3 or 4 toxicities. For patients receiving HEC on the effectiveness of either oral prochlorperazine (24 who were given guideline directed prophylactic antiemetics patients) or an oral 5-HT3 receptor antagonist (3 patients) and subsequently developed breakthrough CINV, the use of as a treatment for breakthrough CINV. There was a median olanzapine was significantly better than metoclopramide in nauseareductionof75%foreithertreatmentafterfourhours. thetreatmentofnauseaandemesisovera72-hourperiod No data were reported after the four-hour period. [30]. In an additional phase II study, 33 patients who developed breakthrough nausea and/or emesis after receiving MEC or 3.3. Olanzapine. Olanzapinehasbeenreportedtobean HEC and antiemetic prophylaxis applied a transdermal gel effective agent in the treatment of acute and chronic nau- consisting of lorazepam, diphenhydramine, and haloperidol sea [31–34]. Fifteen advanced cancer patients with opioid- to the palmar surface of their wrists [28]. They were ret- induced nausea were treated effectively with olanzapine [31]. rospectively interviewed with a questionnaire, and 27 of 33 A patient’s chronic nausea was improved with the use of patients reported a decrease in their nausea and/or vomiting olanzapine [32], and, in six patients receiving palliative care, within a four-hour period. Data beyond four hours were not Jackson and Tavernier [33] found olanzapine to be effective reported. for intractable nausea due to opioids, neoplasm, and/or Chanthawong et al. [29] recently reported a phase II medications. Olanzapine was reported to be very effective in prospective open label clinical trial in which cancer patients controlling refractory nausea and vomiting in two patients diagnosed with solid tumors were enrolled to receive at least with advanced cancer [34]. one cycle of HEC. Each patient received ondansetron, corti- The mechanism of action of olanzapine involves the costeroids, and metoclopramide as prophylactic antiemetics. blocking multiple neurotransmitter receptors including dop- Forty-six patients developed breakthrough CINV and were aminergic at D1,D2,D3,andD4 brain receptors, sero- treated with olanzapine, 5 mg orally every 12 hours for two tonergic at 5-HT2a,5-HT2c,5-HT3,and5-HT6 receptors, doses. Patients were evaluated every six hours for 24 hours. catecholamines at alpha1 adrenergic receptors, acetylcholine The CR of breakthrough emesis, the control of retching, and at muscarinic receptors, and histamine at H1 receptors [35, nausea control were 60.9%, 71.7%, and 50.0%, respectively. 36]. Olanzapine has five times the affinity for 25-HT receptors Adverse events were mild and tolerable including dizziness, compared to D2 receptors [35, 36]. Dopamine and serotonin fatigue, and dyspepsia. are known mediators of CINV [35, 36]. Olanzapine appears to have activity in controlling both acute and delayed emesis 3.2. Phase III Study. Olanzapine and metoclopramide are and nausea and may exert much of its antiemetic effect in the two agents that have been recommended by the international central nervous system at multiple cortical receptors. It is not guidelines [12–14] for the treatment of breakthrough CINV. known whether a peripheral effect may also exist. Olanzapine These two agents were studied and compared in a double- blocks the serotonin mediated 5-HT2c receptor, a receptor blind, randomized phase III trial [30]. Chemotherapy na¨ıve which has been shown to mediate antiemetic activity in 2 patients receiving HEC (cisplatin, ≥70 mg/m ,ordoxoru- animal models (ferret cisplatin-induced emesis and cisplatin- 2 2 bicin, ≥50 mg/m ,andcyclophosphamide,≥600 mg/m )and induced anorexia in the hypothalamus of rats) [37, 38]. The guideline directed prophylactic antiemetics, dexamethasone effect of olanzapine on this receptor as well as other dopamine (12 mg IV), palonosetron (0.25 mg IV), and fosaprepitant and serotonin receptors may explain its efficacy. (150 mg IV) before chemotherapy and dexamethasone (8 mg In a number of phase II and phase III studies [8, 9, 39– p.o. daily, days 2–4) after chemotherapy, who developed 41], olanzapine has also been shown to be a safe and effective breakthrough CINV, were randomized to receive olanzap- agent for the prevention of CINV. A phase II trial involving ine, 10 mg orally daily for three days, or metoclopramide, 30 patients receiving MEC and HEC demonstrated that a 10 mg orally TID for three days. In July, 2013, in order combination of olanzapine, granisetron, and dexamethasone to reduce neurological toxicities, the European Medicines was effective in controlling emesis and nausea [39]. In Agency recommended that the adult dose of metoclopramide forty patients receiving MEC or HEC, the combination of be restricted to ≤30 mg/day for five days. Patients were olanzapine, palonosetron, and dexamethasone was effective monitored for emesis and nausea for the 72 hours after in the prevention of CINV [40]. initiating the olanzapine or the metoclopramide. Tan et al. [8] studied the use of olanzapine as a prophylac- Two hundred seventy-six patients (median age 56 yrs, tic agent in patients receiving either MEC or HEC by adding range38–79;43females;ECOGPS0,1)consentedtothepro- olanzapine to a prophylactic regimen of azasetron and dex- tocol. One hundred twelve patients developed breakthrough amethasone. In a total patient group of 229 patients receiving 4 BioMed Research International either MEC or HEC, CR was significantly improved in the with a three-day regimen of oral olanzapine based on the patients receiving olanzapine, azasetron, and dexamethasone results of a phase III clinical trial [30]. This recommendation compared to patients receiving azasetron and dexamethasone was supported by a recent review by Bradford and Glode [44]. in the delayed and overall periods. Olanzapine improved the It is important to note that aprepitant has been approved CR of delayed and overall CINV and quality of life in patients as an additive agent to a 5-HT3 receptor antagonist and receiving MEC and HEC [8]. dexamethasone for the prevention of CINV. It has not been International guidelines have recommended the use of studied and should not be used to treat breakthrough nausea a5-HT3 receptor antagonist, dexamethasone, and an NK-1 and vomiting. receptor antagonist as the prophylactic antiemetic regimen for patients receiving HEC [12–14]. In order to further investigate the effectiveness of olanzapine as a prophylactic 4. Clinical Approach to Refractory CINV antiemetic for patients receiving HEC, a phase III study was Patients who develop CINV during subsequent cycles of performed to compare the effectiveness of olanzapine versus chemotherapy when antiemetic prophylaxis has not been aprepitant for the prevention of CINV in patients receiving successful in controlling CINV in earlier cycles should HEC [9]. be considered for a change in the prophylactic antiemetic Chemotherapy na¨ıve patients receiving HEC (cisplatin regimen. If anxiety is considered to be a major patient or an anthracycline plus cyclophosphamide) were random- factor in the CINV, a benzodiazepine such as lorazepam or ized to a prophylactic antiemetic regimen of olanzapine, alprazolam can be added to the prophylactic regimen. If the palonosetron, and dexamethasone or to a prophylactic reg- patient is receiving HEC, olanzapine (days 1 to 4) can be imen of aprepitant, palonosetron, and dexamethasone. For substituted for aprepitant or fosaprepitant in the prophylactic the 121 patients receiving the olanzapine regimen and the antiemetic regimen [9]. If the patient is receiving MEC, 120 patients receiving the aprepitant regimen, there was no aprepitant or fosaprepitant can be added to the palonosetron significantdifferenceinCRintheacute,delayed,oroverall and dexamethasone antiemetic regimen [45]. period. The number of patients with no nausea (0, scale 0– Vig et al. [46] reported a retrospective study on the 10, M.D. Anderson Symptom Inventory) was significantly efficacy of the addition of olanzapine in adults experiencing higher in the delayed and overall periods for the patients refractory CINV.Thirty-three adults who experienced CINV who received the olanzapine regimen. Olanzapine appeared refractory to guideline directed prophylactic antiemetics to be an effective agent for the control of nausea in patients and experienced breakthrough treatment with dopamine receiving HEC [9]. antagonists and benzodiazepines received olanzapine, 5– In a randomized, double-blind, placebo-controlled trial, 10 mg as an addition to the prophylactic antiemetics in a 44 patients scheduled to receive MEC or HEC received subsequent chemotherapy cycle. Failure was defined as >5 a5-HT3 receptor antagonist, dexamethasone, and a NK-1 emesis events in 24 hours or more than 10 cumulative doses receptor antagonist. Patients were then randomized to receive of rescue antiemetics following the first olanzapine dose per 5 mg of olanzapine daily for 6 days beginning on the day treatment cycle. The addition of olanzapine demonstrated before chemotherapy or placebo. CR and no nausea were an overall success rate of 70%. The success rate appeared to significantly improved in the patients receiving olanzapine be independent of the chemotherapy emetogenicity (HEC [41]. versus MEC), age, or prophylaxis with a serotonin antagonist, Recent reviews [7, 42, 43] have concluded that antiemetic plus a corticosteroid, and aprepitant or a serotonin antagonist regimens including olanzapine are more effective in reducing alone. CINV compared to regimens that do not include olanzapine. NCCN guidelines [14] have recommended the use of olanzapine, palonosetron, and dexamethasone [42]asan 3.4. Guideline Recommendations. Current guidelines suggest alternative first-line prophylactic antiemetic regimen for the use of a phenothiazine, metoclopramide, dexamethasone, patients receiving HEC. This regimen may be useful in butyrophenones, cannabinoids, anticholinergics, or olanzap- patients who experience refractory CINV and need a revision ine for the treatment of breakthrough nausea and vomiting in their prophylactic antiemetic regimen [42, 46]. [14]. A 5-HT3 receptor antagonist may also be effective unless a patient presents with nausea and vomiting which was 5. Conclusions developed following the use of a 5-HT3 receptor antagonist as prophylaxis for chemotherapy- or radiotherapy-induced Breakthrough CINV can occur in 30–40% of patients receiv- emesis. It is very unlikely that breakthrough nausea and ing MEC or HEC despite the use of guideline directed vomiting will respond to an agent in the same drug class prophylactic antiemetics. Guidelines [12–14]haverecom- after unsuccessful prophylaxis with an agent with the same mended treatment with phenothiazines, metoclopramide, mechanism of action. Agents which are successful in treating butyrophenones, corticosteroids, cannabinoids, anticholin- a patient’s breakthrough CINV should be given routinely for ergics, 5-HT3 receptor antagonists, and olanzapine. Agents aperiodoftimeratherthanonanasneededbasis. which have not been part of the prophylactic antiemetic The NCCN guidelines [14] state that patients who develop regimenshouldbeemployedandgivencontinuouslyrather nausea or vomiting after chemotherapy (days 1 to 5) despite than on an as needed basis. A recent randomized, double- adequate prophylaxis should be considered for treatment blind, phase III clinical trial demonstrated that olanzapine BioMed Research International 5

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receiving high-dose cisplatin—the Aprepitant Protocol 052 [42] X.-F.Wang, Y.Feng, Y.Chen, B. L. Gao, and B.-H. Han, “Ameta- Study Group,” JournalofClinicalOncology,vol.21,no.22,pp. analysis of olanzapine for the prevention of chemotherapy- 4112–4119, 2003. induced nausea and vomiting,” Scientific Reports,vol.4,article [27] J. M. Jones, R. Qin, A. Bardia, B. Linquist, S. Wolf, and C. L. 4813, 2014. Loprinzi, “Antiemetics for chemotherapy-induced nausea and [43] C. M. Hocking and G. Kichenadasse, “Olanzapine for chemo- vomiting occurring despite prophylactic antiemetic therapy,” therapy-induced nausea and vomiting: a systematic review,” Journal of Palliative Medicine,vol.14,no.7,pp.810–814,2011. Supportive Care in Cancer, vol. 22, no. 4, pp. 1143–1151, 2014. [28] J. Bleicher, A. Bhaskara, T. Huyck et al., “Lorazepam, diphen- [44] M. V.Bradford and A. Glode, “Olanzapine: an antiemetic option hydramine, and haloperidol transdermal gel for rescue from for chemotherapy-induced nausea and vomiting,” Journal of the chemotherapy-induced nausea/vomiting: results of two pilot Advanced Practitioner in Oncology,vol.5,no.1,pp.24–29,2014. trials,” Journal of Supportive Oncology,vol.6,no.1,pp.27–32, [45] B. L. Rapoport, K. Jordan, J. A. Boice et al., “Aprepitant for 2008. the prevention of chemotherapy-induced nausea and vomit- [29] S. Chanthawong, S. Subongkot, and A. Sookprasert, “Effec- ing associated with a broad range of moderately emetogenic tiveness of olanzapine for the treatment of breakthrough chemotherapies and tumor types: a randomized, double-blind chemotherapy induced nausea and vomiting,” Journal of the study,” Supportive Care in Cancer,vol.18,no.4,pp.423–431, Medical Association of Thailand,vol.97,pp.349–355,2014. 2010. [30] R. M. Navari, C. K. Nagy, and S. E. Gray, “The use of olanzapine [46] S. Vig, L. Seibert, and M. R. Green, “Olanzapine is effective versus metoclopramide for the treatment of breakthrough for refractory chemotherapy-induced nausea and vomiting chemotherapy-induced nausea and vomiting in patients receiv- irrespective of chemotherapy emetogenicity,” Journal of Cancer ing highly emetogenic chemotherapy,” Supportive Care in Can- Research and Clinical Oncology,vol.140,no.1,pp.77–82,2014. cer,vol.21,no.6,pp.1655–1663,2013. [31] S. D. Passik, J. Lundberg, K. Kirsh et al., “A pilot exploration of the antiemetic activity of olanzapine (Zyprexa) for the relief of nausea in patients with advanced cancer and pain,” Journal of Pain and Symptom Management, vol. 23, pp. 526–532, 2002. [32]W.F.PirlandA.J.Roth,“Remissionofchemotherapy-induced emesis with concurrent olanzapine treatment: a case report,” Psycho-Oncology,vol.9,no.1,pp.84–87,2000. [33] W. C. Jackson and L. Tavernier, “Olanzapine for intractable nausea in palliative care patients,” Journal of Palliative Medicine, vol. 6, no. 2, pp. 251–255, 2003. [34] M. Srivastava, N. Brito-Dellan, M. P. Davis, M. Leach, and R. Lagman, “Olanzapine as an antiemetic in refractory nausea and vomiting in advanced cancer,” Journal of Pain and Symptom Management, vol. 25, no. 6, pp. 578–582, 2003. [35] F.P.Bymaster,D.O.Calligaro,J.F.Falconeetal.,“Radioreceptor binding profile of the atypical antipsychotic olanzapine,” Neu- ropsychopharmacology,vol.14,no.2,pp.87–96,1996. [36] F.P.Bymaster,J.F.Falcone,D.Bauzonetal.,“Potentantagonism of 5-HT3 and 5-HT6 receptors by olanzapine,” European Journal of Pharmacology,vol.430,no.2-3,pp.341–349,2001. [37] J. A. Rudd, M. P. Ngan, M. K. Wai et al., “Anti-emetic activity of ghrelin in ferrets exposed to the cytotoxic anti-cancer agent cisplatin,” Neuroscience Letters,vol.392,no.1-2,pp.79–83,2006. [38] K. Yakabi, C. Sadakane, M. Noguchi et al., “Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia,” Endocrinology,vol.151,no.8,pp.3773–3782,2010. [39] R.M.Navari,L.H.Einhorn,S.D.Passiketal.,“AphaseIItrialof olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study,” Supportive Care in Cancer, vol. 13, no. 7, pp. 529–534, 2005. [40]R.M.Navari,L.H.Einhorn,P.J.LoehrerSr.etal.,“AphaseII trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study,” Supportive Care in Cancer,vol. 15, no. 11, pp. 1285–1291, 2007. [41] N. Mizukami, M. Yamauchi, K. Koike et al., “Olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy: a randomized, double-blind, placebo-controlled study,” Journal of Pain and Symptom Management,vol.47,no.3,pp. 542–550, 2014. Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 495704, 14 pages http://dx.doi.org/10.1155/2015/495704

Review Article Biological and Pharmacological Aspects of the NK1-Receptor

Susana Garcia-Recio1,2 and Pedro Gascón1,2 1 Laboratori d’Oncologia Molecular i Traslacional, FundacioCl´ ´ınic per a la Recerca Biomedica,` 08036 Barcelona, Spain 2Departament de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain

Correspondence should be addressed to Pedro Gascon;´ [email protected]

Received 23 December 2014; Revised 19 April 2015; Accepted 25 April 2015

AcademicEditor:BernardoL.Rapoport

Copyright © 2015 S. Garcia-Recio and P. Gascon.´ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The neurokinin 1 receptor (NK-1R) is the main receptor for the tachykinin family of peptides. Substance P (SP) is themajor mammalian ligand and the one with the highest affinity. SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, and cell survival. It is also considered a mitogen, and it has been associated with tumorigenesis and metastasis. Tachykinins and their receptors are widely expressed in various human systems such as the nervous, cardiovascular, genitourinary, and immune system. Particularly, NK-1R is found in the nervous system and in peripheral tissues and are involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis and to sensory neuronal transmission associated with depression, stress, anxiety, and emesis. NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and the area postrema). This anatomical localization has led to the successful clinical development of antagonists against NK-1R in the treatment of chemotherapy-induced nausea and vomiting (CINV). The first of these antagonists, aprepitant (oral administration) and fosaprepitant (intravenous administration), are prescribed for high and moderate emesis.

1. Tachykinins and Their Receptors Genome Organization (HUGO) Gene Nomenclature Com- mittee (http://www.genenames.org/) also encodes other ta- The tachykinins are one of the largest conserved families chykinins, including NKA, neuropeptide K (NPK). and neu- of peptides involved in neurotransmission and inflamma- ropeptide 𝛾 (NP𝛾). On the other hand, the TAC3 gene only tory processes. The idea that tachykinins act exclusively as codes for NKB (previously known as PPT-B gene). In 2000, neuropeptides is currently being challenged. Substance P Zhang et al. identified a third gene called TAC4 (previously (SP), a small undecapeptide present in both mammalian and named preprotachykinin-C (PPT-C)) and demonstrated its nonmammalian species, was the first member of the family to association with the hematopoietic system and the matura- be discovered (as early as 1931, by von Euler and Gaddum). SP tion of B lymphocytes [7]. This gene encodes hemokinin 1 is associated with multiple processes: hematopoiesis, wound (HK-1) and its shorter derivative hemokinin (4–11) and four healing, microvasculature permeability, neurogenic inflam- other peptides called endokinins (EKS), EKA, EKB, EKC, and mation, leukocyte trafficking, cell survival, and metastatic EKD [6]. dissemination [1–5]. The three classical members of the Tachykinin receptors have been divided into three dif- mammaliantachykininfamilyareSPandneurokininA ferent types according to their affinity ligands (high or (NKA), both encoded by the TAC1 gene, and neurokinin low): TACR1 (NK-1 receptor), TACR2 (NK-2 receptor), and B (NKB), encoded by the TAC3 gene. A third mam- TACR3 (NK-3 receptor) (Table 1), which have preferential malian tachykinin gene (TAC4) codes for hemokinins and (butnotexclusive)affinitiesforSP,NKA,andNKBrespec- endokinins [1, 6, 7]. The TAC1 gene (according to the Human tively [8–10]. The order of potency of these receptors per 2 BioMed Research International

Table 1: Genes of human tachykinin receptors. is not removed and the premature stop codon is identified before starting exon 5. Receptor Gen Access number Chromosomal Lai et al. [21] observed that SP specifically increased location intracellular calcium in embryonic kidney cells (HEK293) NK-1 TACR1 NM 001058 2p13.1-p12 stably transfected with the long isoform, while there was NK-2 TACR2 NM 001057 10q11-q21 no effect in those transfected with the truncated isoform. NK-3 TACR3 NM 001059 4q25 Likewise, cells expressing the long isoform activated NF- B and IL-8, while those expressing the truncated one had a lower mRNA expression of IL-8 and were unable to tachykinin is shown as follows [10, 11]. Order of affinity of activate NF-QB. The activation of protein kinase Erk was tachykinin receptor by its agonists is also altered in the same cells: whereas phosphorylation of this protein through the long isoform was fast (1 to (a) Receptor NK-1: SP>NKA>NKB; 2 minutes) and sustained, cells transfected with truncated > > isoform were not able to phosphorylate Erk protein within (b) Receptor NK-2: NKA NKB SP; 20 min after exposure to SP21 [ ]. In addition, other studies (c) Receptor NK-3: NKB>NKA>SP. have demonstrated that SP had a lower relative affinity for the truncated receptor form (up to 10 times less than the NP𝛾 and NPK preferentially bind to the NK-2 receptor. full isoform) [18]. Moreover, the loss of certain C-terminal The affinities of NKA and NKB for the NK-1 receptor are, serine and threonine residues is important for G protein- respectively, 100 and 500 times lower than that of SP [12]. It coupled receptor kinase (GRK) interaction and 𝛽-arrestin has also been reported that SP interacts with fibronectin (FN) recruitment for subsequent receptor internalization [22–24]. and hematopoietic growth factor inducible neurokinin-1 type Therefore, the truncated form should be capable of (HGFIN) [13, 14]. The homology between the NK1 receptor prolonging the responses after ligand binding because its and HGFIN has recently been described. This finding may desensitization and internalization are affected. Besides the be relevant because both the NK-1 receptor and HGFIN have differences between the two isoforms, another important been linked to tumorigenesis, including breast cancer (BC) phenomenon involved in the receptor signaling should be [14]. However, whereas the NK-1 receptor has been described mentioned. Tansky, Leeman, and Pothoulakis showed that as a tumor promoter, HGFIN may act as a suppressor [14]. the amino terminal end had two glycosylated Asn (N-) sites The three tachykinin receptors belong to family 1 and described how these glycosylations can influence the (rhodopsin-like) G protein-coupled receptors (GPCRs) and functional level of the receptors [25]. are encoded by five exons [9, 15]. These are seven- They observed that nonglycosylated receptors showed transmembrane-helix receptors which share the same struc- half the affinity for SP shown by glycosylated receptors, and tural unit: three extracellular (EL1, EL2, and EL3) and three in fact the nonglycosylated NK-1 receptor was internalized intracellular loops (C1, C2, and C3) with the possibility faster than the glycosylated form. This also suggested the pos- of a fourth loop, due to the palmitoylation of cysteine sibility that glycosylation may be a feature in the stabilization (Cys), flanked by seven intermembrane domains (TM 1-VII), of the receptor in the plasma membrane. Several bands of and an amino-terminal extracellular and carboxy-terminal different molecular weights have been identified, probably cytoplasmic domain [9](Figure 1). due to this phenomenon. For example, in lymphocytes, The carboxy-terminal conserved domain of tachykinins certain forms of glycosylated receptor (58 kDa) have been (Phe-X-Gly-Leu-Met-NH2) interacts with tachykinin recep- described [26], while others with bands of 38 and 33 kDa tors, while the amino-terminal sequence is responsible for appear in IM-9 lymphoblasts (26). Furthermore, isoforms the specificity of the receptor16 [ ]. All tachykinins are with bands of 75, 58, 46, and 34 kDa have been identified amidated at the C-terminal and deamidation suppresses in several studies of tumor pancreatic carcinoma cell lines their activity [8]. The second and third loops are involved [27, 28]. in the binding of agonists or antagonists, while the third In the past two decades, other isoforms have been cytoplasmic loop is responsible for binding to protein G. The identified besides the conventional ones, with different SP C-terminus contains serine/threonine residues which, once affinities. For example, in rat salivary glands another appar- phosphorylated, cause desensitization of the receptor when it ently truncated isoform has also been detected in the C- 󸀠 isrepeatedlyactivatedbytheagonist.The5 region of the gene terminal end, with 8 kDa less than the long isoform [29]. Li et hasseveralputativeregulatoryDNAelementssuchasthe al. also demonstrated that the short isoform seems to have an cAMP responsive element, AP-1, AP-2, AP4, NF-QB, OCT-2, SPaffinitysimilartothatofthecompleteisoform.Ithasbeen and a domain Sp-1 [16]. Specifically, the NK-1 receptor has suggestedthatthisisoformcomesfromposttranslational 407 amino acids and a relative molecular mass of 46 kDa modifications [30]. In addition, other studies have shown [17]. NK-2 and NK-3 consist of 398 and 465 amino acids, that some receptor isoforms present different affinities from respectively, NK-3 being the longest of the three receptors. the “classic” forms. This has led to a division of the NK- The most important splicing identified loses the last 96 amino 1 receptor into three different classes: (1) the “classic” NK- acids at the C-terminus and thus has 311 amino acids [18– 1 receptor (which shows greater binding affinity for the SP 20](Figure 1). This shorter or truncated isoform (NK1-Tr) is ligand), (2) the “sensitive to septide” NK-1 receptor (showing generatedwhentheintronlocatedbetweenexons4and5 a very similar affinity for binding to SP and other tachykinins BioMed Research International 3

Extracellular glycosylation

N T S MI N P F L D S D M P L V N D M -NH2 S T E S N Q F V Q P W Y V Y Y L K K T N G L F H R S P D W L V M N R I V H P T P Q E1 F V TE E3 Q A P Y N I C W Y Y M I E E E2 E I Q V C T Y V T K Y L F K T A P L W N F S Y H L A A A A V V F H N Y Y C I F L W S M Y T N F G Q V F V L A I T V A F A P I F P L T V F H S M V V M A A L L A I Y L P S T Intracellular T S A C F A L L F L C W M Y V V A E S L A P A I N G N F A Y S I V W L V L F T I P palmitoylation V N L T M V I I V C I Y V V V A F I G Y V V C C I W Y F L V A V V A Y M I L N I N F K T M D C C T K R R P I T D A V C4 C1 R V V V K R F F F L V C2 T K R A Y G A A I T M A L H R S I G protein S G K S K R M A R L F K I I H P L Q P T interactions V A L Q G W E D A C3 H Y S Y E R E I P G D S S D G L M E T S K E H A G V V T S I T T E L R S L V K Y V S S Q T Q L Y R P E E E E G P K Intracellular Ser/Thr residues A T P S S L D L T S N G S S R S N S K T M T E S S F Y S N M L A -CO2H (a)

Extracellular glycosylation

N T S MI N P F L D S D M P L V N D M S T -NH2 E S N Q F V Q P W Y V Y Y L K K T N G L F H R S P D W L V M N R I V H P T P Q E1 F V TE E3 Q A P Y N I C W Y Y M I E E E2 E I Q V C T Y V T K Y L F K T A P L W N F S Y H L A A A A V V F H N Y Y C I F L W S M Y T N F G Q V F V L A I T V A F A P I F P L T V F H S M V V M A A L L A I Y L P S T T S A C F A L L F L C W M Y V V A E S L A P A I N G N F A Y S I V W L V L F T I P V N L T M V I I V C I Y V V V A F I G Y V V C C I W Y F L V A V V A Y M I L N I N F K T M D I T D T V K R -CO2H A V V L C1 V R C2 T V K R K A Y G A T M A H R S I S K M A L G protein R I I H P L Q P R T interactions V L Q W E A C3 H S Y R E I P G D S S D (b) Figure 1: Schematic model of the NK-1 receptor. (a) Complete isoform or long isoform-full length (NK1-FL) with 407 amino acids. It contains an extracellular N-terminus, seven transmembrane domains, three extracellular loops (E1, E2, and E3) and three intracellular loops (C1, C2, and C3), a possible C4 because of a Cys palmitoylation residue and an intracellular C-terminus. Asn14 and Asn18 are given as putative glycosylation sites. (b) Depiction of the truncated isoform with 311 amino acids, showing that this isoform has lost a part of the C-terminal end, and also the intracellular Ser/Thr residues responsible for internalization. Modified from [149]. 4 BioMed Research International as NKA, NPK, NP𝛾, NKB, and even other synthetic peptides Gs-related pathway is activated (by contrast, AC inhi- such as septide fragment 6–11 SP, which gives the receptor its bition is conducted by the Pertussis toxin-sensitive name) [10, 31],and(3)the“newNK-1sensitive”receptor[32]. Gi-protein(PTX)inratsubmandibularcells)[48]. Thissubtypehasahigheraffinityforlongertachykininsand Other studies have reported that the Gs subunit is does not bind to septide or SP (6–11). However, more studies the substrate of cholera toxin (CTX), produced by are needed to identify the real differences in the signaling Vibrio cholerae, which catalyzes its ADP ribosylation pathways of each NK-1R isoform and the preferred sites of and inhibits its intrinsic GTPase activity [42]. It has expression of the different isoforms or glycosylated forms. been widely reported that increased cAMP levels lead to activation of protein kinase A (PKA). Activation 1.1. Signaling Pathways Modulated by Tachykinins and Their of PKA, then, phosphorylates the transcription factor NK-1R. The physiological processes mediated by SP or other CREB (cAMP-responsive element-binding protein tachykinins occur via the NK-1 receptor, which belongs to CRE). CREB binds to the cAMP response element the large family of G-protein-coupled receptors (GPCRs). (CRE) of a target gene and negatively affects the Via second messengers, G proteins activate transduction activation of NF-QB[49]. However, despite the Gs pathways within the cell. Which pathways are activated by action, the power to generate cAMP accumulation by G proteins depends on the nature of the proteins belonging NK-1R agonists is lower than the ability to induce IP3 to this large family: for example, the activation of NF-𝜅B and intracellular calcium of Gq/11 [50]. mediated by SP,interleukins, or growth factors (IL-1, IL-6, IL- (iii) Gi:theroleofthisclassmemberistomediate 𝛼 8, TNF- , and IFNy) and the activation of MAPKs pathway the inhibition of different types of AC. Functional or PI3K/Akt among others [33–35]. studies have been conducted with PTX, produced by Bordetella pertussis. Unlike CTX, PTX decouples the 1.1.1. GPCR-Mediated Signal Transduction: Classification and G protein from its receptor and remains inactive and Function of G Proteins. GPCRs mediate their signaling bound to GDP [51]. through heterotrimeric G proteins transmitting signals from a variety of surface cell receptors to enzymes and ion chan- (iv) G12/13: this subunit is expressed ubiquitously in mam- nels. This complex is composed by three distinct subunits: mals and is composed by two proteins, G𝛼12 and the G𝛼 subunit that binds to GDP/GTP and the G𝛽 and G𝛾 G𝛼13 which are also toxin resistant [42]. Meshki et subunits that form the G𝛽𝛾 complex (which present strong al. reported that the G12/13 subunit could regulate bindings between them) [36, 37]. After binding SP to the changes in cytoskeletal rearrangement when the cell specificNK-1receptor,achangeoccursintheG𝛼 subunit, was preparing to migrate. These changes depend on allowing it to exchange GTP for GDP and permitting the the activation of Rho/Rock which directly modulates dissociation of the G𝛽𝛾 dimer. These subunits𝛼 (G and G𝛽𝛾) the myosin regulatory light chain. Phosphorylation of begin their own signaling cascade separately and positively this protein is associated with the formation of small or negatively regulate the activity of enzyme effectors and ion spherical outgrowths arising from the membrane channels that are cell type- or GPCR-specific [38, 39]. known as bubbles or blebs, in a process known as blebbing.Thisprocessisnotalwaysassociatedwith The GTP hydrolysis returns the G𝛼 subunit to its inactive apoptosis but may be associated with the cytoplasmic state, allowing again the trimeric formation with the G𝛽𝛾 subunit [40]. G𝛽𝛾 in contrast to the G𝛽𝛾 subunit, the broad disorganization at the time of cell migration and range of the 𝛼 subunit is limited because all 𝛼 subunits, except Meshki et al.’s study showed how the NK-1 receptor G𝛼t, have a palmitic acid posttranslational modification in had the ability to interact with the G12/13 protein the amino-terminal portion, which keeps them adhered to throughout this process [52]. 𝛼 the plasma membrane [41]. The subunit itself has intrinsic (v) Go: this subunit is one of the most abundant G GTPase capacity and may modulate its own inactivation. In proteins in neuronal and neuroendocrine tissues [53]. anycase,thisGTPhydrolysisisrelativelylowcomparedwith Nishimura et al. provided the first evidence of NK-1R’s other accessory proteins called cytoplasmic regulators of G potential to activate Go in Sf9 cells [54]. This subunit protein signaling (RGS) [42](Figure 2). signals downstream of frizzled (Fz) GPCRs. Go is crucial for the activation of Wnt-𝛽-catenin signaling (i) Gq/11: the receptor interaction by the agonists regu- pathways [42]. While Go is abundant in nervous lates the activation of Gq/11 protein and the subse- quentactivationofphospholipaseC𝛽 (PLC𝛽), which tissues, its deficiency causes lesions that appear to be degrades the phosphatidylinositol 4, 5-bisphosphate mediated mainly by this subunit [42, 55]. (PIP2) to produce two compounds: diacylglycerol The G𝛽𝛾 subunit has been less studied than G𝛼.The𝛽𝛾 (DAG) and inositol 1,4,5-triphosphate (IP3), respon- complex can be formed by five different 𝛽 subunits and 12 sible for increasing intracellular calcium [43–47]. 𝛾 subunits [42].Atfirst,itwasthoughtthatitsrolewas (ii) Gs: this subunit is responsible for the activation of merelypassivebutlateritwasfoundthatitmayplayarole the second messenger adenylate cyclase (AC), which in the activation of effectors such as PLC𝛽, adenylyl cyclases, + catalyzes the conversion of cytoplasmic ATP into PI3K, K ion channels, and Src. All these associations cyclic adenosine monophosphate (cAMP) when the between trimeric G proteins and second messengers lead BioMed Research International 5

γ β Effectors GDP α γ β GDP GTP α GTP GDP α γ β

GTP −Pi α Effectors RGS

Figure 2: Heterotrimeric G protein activation by GTP and consequent separation of subunits. Heterotrimeric G proteins have been grouped into four distinct families based on the G𝛼 amino acid homologous sequence: Gs,Gi,Gq,andG12/13. There are two major signaling pathways associated with G𝛼s and G𝛼q subunits and are mainly how NK-1 receptor signals [48, 50, 59]. The different signaling pathways activated by each subunit will be explained below. This figure was made using Servier Medical Art collectionhttp://creativecommons.org/licenses/by/3.0 ( ). to a cascade of intracellular events that cause a particular and induce DNA synthesis and cell proliferation (Figure 3). response, depending on cell type. Another protein kinase activated by NK-1 receptor is PKC𝛿. GPCRs constitute a large family of cell surface receptors Earlier studies by Della Rocca et al. [77]foundthatPLC which regulate many cellular functions, including cell prolif- activation dependent on both Gq/11 (𝛼1B adrenergic receptor) eration, survival and motility, the sense of smell, emesis, and and G𝛽𝛾 subunits (Gi dissociated from 𝛼2A adrenergic depression. They have recently emerged as key receptors in receptor protein) increased cytoplasmic IP3 levels, resulting 2+ tumor growth, angiogenesis, and metastasis. in an increase in cytoplasmic Ca . High concentrations Specifically, interactions involving the Gq/11 protein occur of intracellular calcium, probably through calmodulin, lead in several systems and endocrine secretion, vasodilatation, to kinase activation, called proline-rich tyrosine kinase 2 neuromodulation, and activation of monocytes as well as (Pyk2, English protein tyrosine kinase 2) associated with in cell proliferation [56–60]. Therefore, experimental evi- focal adhesion kinase (FAK). In turn, this Pyk2 activity dence from several recent studies supports the view that (now known as PTK2B) regulates kinase protein Src. Src- alterations in the endocrine system regulated by NK-1R dependent tyrosine phosphorylation of adaptor proteins such and SP contribute to the development of pathologies such as Shc recruits Grb2-SOS complex to the plasma membrane as depression, neural degeneration, alcohol addiction, pain, andinitiatesthephosphorylationcascadeleadingtheErk1/2 migraine, inflammatory bowel disease, pruritus, viral infec- activation that triggers cell proliferation pathways [77]. tion, bacterial infection, cancer, and emesis [27, 35, 61–65]. According to some studies, MAPK activation depends not only on G proteins and their canonical or classical 1.1.2. Signaling Pathways of NK-1R and SP. The NK-1 receptor pathway signaling, but also on the scaffold for the assembly signals through different pathways depending on the nature of multiprotein complexes for NK-1R internalization or other of the G proteins. For example, in glioblastoma cell lines GPCRs. In some models such as G𝛼q-coupled proteinase- and in many other tumor types, the SP binding causes activated receptor 2 (PAR2), the interaction of this receptor the accumulation of DAG, which in turn activates PKC. with 𝛽-arrestin internalization proteins causes a retention of This protein phosphorylates other proteins such as c-Raf- Raf-1 and phosphorylated Erk1/2 proteins in the cytoplasm 1 and MEK, which phosphorylate tyrosine protein kinase and these proteins cannot be transferred to the nucleus [78]. Erk1/Erk2 (also known as p-42/44) of the MAPK protein fam- However, others such as the 𝛽2-adrenergic receptor (𝛽2- ily [27, 65–69]. The mechanism by which PKC activates ERK AR) are internalized through the complex formed by 𝛽- is not entirely understood. Discordant results are found in the arrestin, Src, and Erk [79]. In this case, 𝛽2-AR receptor activa- literature, in which different molecules have been implicated tion causes Erk1/2 phosphorylation and induces a different set in MAPK activation via GPCRs. These disparities may be of cellular responses to those produced by PAR2, since Erk1/2 explained by differences in the cell culture methods used or is not retained in the cytoplasm. These differences may be thenatureofthesamplesanalyzed[70–76]. Subsequently, due to the different scaffolding protein complexes responsible transcription factors such as c-fos or c-myc are activated for the distinct subcellular localization of activated kinases 6 BioMed Research International

NK-1R NK-1R NK-1R NK-1R

PIP2 𝛼 𝛼i PLC PKC 𝛼 𝛼 s 𝛽 𝛾 γ 3 q 12/13 β β γ β γ 1 2 β-arrestin 4 Src AC IP3 DAG Kinase Src protein Rho 2+ Ca Shc ↑ AMPc

Transactivation IP3 2+ Ca mechanisms of TKRs 2+ PI3K p38 Ca Ras Calcium PKA 2+ 2+ mobilization Ca Ca Rock

Raf NF-𝜅B Akt

MEK- Endoplasmic pMLC reticulum NF-𝜅B ? Erk1/2

Cytoskeletal reorganization DNA synthesis Antiapoptotic effects Cell proliferation IL-6 synthesis Anti-inflammatory Cell proliferation effects Synthesis of proinflammatory cytokines: IL-1, IL8 Migration

Figure 3: Some of the proposed signaling pathways activated by NK-R. (1) G𝛼s activation of AC catalyzes ATP to cyclic AMP (cAMP), which in turn binds to the regulatory subunits of the cAMP-dependent PKA. Usually PKA phosphorylates the CREB transcription factor. CREB binds to the cAMP response element (CRE) of a target gene and negatively affects the activation of NF-QB[49]. (2) Inhibition of the AC is performed by Pertussis toxin sensitive Gi protein [48]. Furthermore, Gi and 𝛽𝛾 subunits enhance Erk1/2 activation after EGFR- mediated transactivation by Src protein [150]. (3) The SP binding to its receptor triggers a GTP-for-GDP exchange on𝛼 G subunits, thus dissociating G𝛼qfromG𝛽𝛾 and subsequently activating downstream effectors such as PLC. This enzyme catalyzes the conversion of PIP2 in the second messenger IP3 and DAG, stimulating calcium mobilization and PKC activation, respectively [151]. Via nonreceptor protein kinasessuchasSrcorPyk2,PKCmayactivatetheMAPKpathwaybutmayalsoactivatetheRafproteindirectly[77]. Another parallel mechanism that regulates MAPK may be developed during NK-1R internalization and its protein recruitment by 𝛽-arrestins [22, 78]. Although the mechanism is unknown, the Erk1/2 protein is also involved in NF-QBactivation[84]. This𝛼 G qsubunitalsomediatesIL-6 production by activation of p38 MAPK [152]. (4) The𝛼 G 12/13 subunit is responsible for the activation of Rho/Rock which directly regulates the phosphorylation of the myosin light chain (MLC) [52]. Phosphorylation of this protein is associated with cytoskeletal reorganization and cell migration. The 𝛽𝛾 dimer activates proteins such as Src, PI3K, and PLC [85]. This figure was made using Servier Medical Art collection (http://creativecommons.org/licenses/by/3.0).

for internalization, because they may be responsible for the formation of different protein scaffold complexes [22]. governing the mitogenic potential of each particular signal. Therefore, better studies are needed to identify the GPCR C- The requirement for 𝛽-arrestin-dependent endocytosis terminal end responsible for the internalization process, since differs between receptor types. This variation also appears this cytoplasmic tail is the key for binding proteins. Feng et al. to be cell type-independent, as the two receptors (NK-1R [23] observed that stimulation of the NK-1 receptor (overex- and PAR2) expressed in the same cell line (KNRK) induce pressed in KNRK cells or naturally expressed in endothelial BioMed Research International 7 cells) by SP, activated Erk1/2 via a 𝛽-arrestin-dependent 2. Distribution of Tachykinin Receptors in mechanism. SP induced the formation of a multiprotein the Body complex near the plasma membrane containing 𝛽-arrestins, Src, and Erk1/2. Once activated, Erk1/2 translocates into the As previously mentioned, tachykinins and their receptors nucleus to induce proliferation and antiapoptotic effects22 [ ]. are widely expressed in various human systems such as the NK-IR internalization and recycling seems to modulate nervous [19, 87–89], cardiovascular [90–93], genitourinary [94], immune systems, gastrointestinal tract [28, 95–102]and cellular responses to SP binding, and although SP is degraded, in some tissues such as salivary gland [103], skin, and muscle the receptor recovery towards the plasma membrane does not (Figure 4). Tachykinin receptors are not evenly distributed. seem to be dependent on new protein synthesis [80]. The NK-1 and NK-3 receptors are found in the nervous In addition to its mitogenic activity, SP is also capable of system and in peripheral tissues, whereas the NK-2 receptor stimulating cytokine release from normal cells and immune is found only in the peripheral tissues (kidney [104], lung, cells from the tumor microenvironment in order to promote placenta [105]andskeletalmuscle)[57, 106, 107]. Specifically, tumor progression. Moreover, the NF-QB-mediatedGprotein like its higher affinity ligand SP, the NK-1 receptor is involved is involved in several cell types. It has been shown that in cellular responses such as pain transmission, endocrine tachykinins activate NF-QB and stimulate the production of and paracrine secretion, vasodilation and modulation of cell proinflammatory cytokines in several cell types: colon epithe- proliferation. It also acts as a neuromodulator contributing lial cells [34], macrophages [81], mast cells [82], T cells [83], tobrainhomeostasisbutalsothesensoryneuronaltransmis- and astrocytoma cells [84]andinalungadenocarcinoma sion associated with depression, stress, anxiety and emesis. epithelial cell (A549) [56]. However, not all the mechanisms Additionally, the NK-1 receptor is responsible for modulating by which this activation occurs are totally known. NF-QB the immune system’s inflammatory response. Expression activation by SP is calcium-dependent in astrocytoma cells, of the NK-1 receptor has been identified in lymphocytes, but not in colon epithelial cells [34, 81]. monocytes, macrophages, NK cells and microglia. NK-1R Another downstream effector of the various signaling is also expressed in bone marrow cells (cells of lymphoid pathways activated by NK-1R is the serine/threonine protein and myeloid lineage) and is considered an hematopoietic kinase Akt, also known as kinase B (PKB) protein. Phospho- regulator [58, 108–112]. Both in normal tissue and during inositol 3-kinase or PI3K is responsible for activating Akt. hematopoiesis, NK-1R mediates stimulation effects and NK- PI3Kcanbeactivatedbyreceptortyrosinekinases(RTKs) 2 exerts suppressor functions (when NK-1R is expressed in or by integrins transactivation or GPCRs [85]. It is unclear normal cells, there is a down-regulation of NK-2R) [113, 114]. how G proteins activate PI3K, but it is known that PIP2 is converted to PIP3 (capable of activating Akt) by PI3K, 3. NK-1R as a Therapeutic Target whereas PTEN opposes this reaction by dephosphorylating PIP3.TheroleofG𝛽𝛾 subunitinPI3Kactivationhasalsobeen SP, through the NK-1 receptor signal, has been implicated reported, because it is known that there is a direct activation in the regulation of many physiological and pathophysio- of kinase by the 𝛽𝛾 dimer [85](Figure 3). Gonzalez´ Moles and logical functions such as neuronal survival, regulation of colleagues [86] reported that stimulation of the bradykinin cell movement, pain, inflammation, salivation, depression, receptor (a receptor of the same family as NK-1) by G𝛼qand stress responses, emotions, reward, neurogenesis, vigilance, cancer progression, and emesis [63, 115–123]. Moreover, the 𝛽1𝛾2 subunits increased Akt phosphorylation due to PI3K and this was responsible for NF-QB activation in HeLa transfected tachykinergic system can regulate motility in several cells cells. These results suggested that if bradykinin receptor [52], stimulates platelet aggregation [124], and is present phosphorylation leads to IKK2 activation, then activation of in many human body fluids such as breast milk, blood, G𝛼q, 𝛽1𝛾2, PI3K and Akt is required (Figure 3). However, saliva, and cerebrospinal fluid [122]. The ubiquity of the these authors reported that inhibition of PI3K and Akt only SP/NK-1 receptor system in many biological functions and partially inhibited the activation of downstream proteins, its upregulation under pathological conditions makes this so their study does not exclude other parallel signaling system an important target for several diseases (depres- pathways such as those mentioned above, including the sion, neural degeneration, alcohol addiction, pain, migraine, MAPK pathway. inflammatory bowel disease, pruritus, viral infection, bacterial infection, cancer, and emesis [27, 35, 61–65]). Among all Finally, other intracellular signaling mechanisms by these conditions, the NK-1R antagonist has only been subject which NK-1R is responsible for SP-induced cell shape changes to clinical development in the treatment of chemotherapy- have also been described. These changes depend on the induced nausea and vomiting (CINV) and in depression. activation of Rho/Rock which directly modulates the myosin These clinical trials led to the registration of aprepitant by regulatory light chain. Meshki and collaborators reported the regulatory agencies EMA and FDA as the first NK-1 that NK1R has the ability to interact with proteins from the receptor antagonist to treat chemotherapy-induced nausea G12/13 family [52]. and vomiting. Therefore, all these studies have identified key molecules involved in NK-1R signaling, in various cell types, such as 3.1. Emesis. NK-1R and SP are present in brain regions p42/44 protein (MAPK), p38 MAPK, NFQB, PI3K, Akt, Src, involved in the vomiting reflex (the nucleus tractus solitarius EGFR, Rho/Rock, 𝛽-arrestin, and Pyk2 depicted in Figure 3. and area postrema) [125]. Aprepitant (MK-869, brand name 8 BioMed Research International

Nervous system [19, 87, 88, 89] Salivary glands [103] Bronchia and lungs [17, 59, 143]

Heart Circulatory system [90, 91, 92, 93]

Liver [102] Stomach

Breast [115] Small intestine [95, 96, 97, 98, 99, 100] Large intestine

Kidney [104] Pancreas [28, 101] Bladder [94] Bone marrow [7, 89, 108, 109] Placenta [105]

Figure 4: NK-1 receptor distributed in the human body. NK-1R distribution across human tissues. This figure was made using Servier Medical Art collection (http://creativecommons.org/licenses/by/3.0).

EMEND) is the first the neurokinin-1 receptor antagonist to 3.2. Depression. The NK-1R antagonist was tested as a novel be commercialized. When added to a standard regimen of antidepressant mechanism in an exploratory phase II clinical a 5-HT3 receptor antagonist and dexamethasone in cancer trial also using aprepitant [121]. patients receiving highly emetogenic chemotherapy, aprepi- In situations of stress and anxiety, neuropeptides such as tant improves the complete response (CR) rate in acute SParereleasedatarateproportionaltotheintensityand CINV. It also improves the CR in delayed CINV when frequency of stimulation [129]. In fact some studies show used in combination with dexamethasone compared with that the SP/NK-1R interaction plays an important role in dexamethasone alone [126]. The use of aprepitant in patients the regulation of emotional behavior [129]. There is evidence receivingmoderatelyemetogenicchemotherapywasrecently that psychosocial help reduces depression, anxiety, and pain approved after phase III clinical trials had demonstrated its andmayprolongsurvivalinsomecancerpatients.Indeed, efficacy127 [ ]. Aprepitant is a substrate, a moderate inhibitor, various forms of stress have been associated with mammary and an inducer of cytochrome P450 (CYP3A4) and CYP2C9. tumorigenesis [130, 131]. Specifically, the NK-1 receptor and Drug interactions should be monitored when aprepitant is SP are involved in emotional responses to stress, suggesting given together with agents affected by CYP3A4 and CYP2C9 that an alteration in the tachykinergic system may be the key isoenzymes. to triggering pathogenesis such as depression (SP expression Aprepitant is the only antagonist with high affinity for has been shown to increase during depression [121]whereas the NK-1 receptor approved to date by the US Food and the genetic deletion of its receptor induces an anxiolytic and Drug Administration (FDA). It was approved in 2003 for antidepressant effect [132]). It has even been reported that oral administration. In 2008, its prodrug, fosaprepitant, was psychotropic drugs modify the expression of genes encoding approved for intravenous use. the synthesis of tachykinin in some areas of the rat brain These two drugs are the only available agents in this [133, 134]. Some of these findings suggest that a reduction class for preventing chemotherapy-induced and postoper- in SP levels in certain regions of the brain, with NK-1R ative nausea and vomiting. However, other agents such as antagonists, may have a therapeutic effect as antidepressant netupitant and rolapitant are currently undergoing phase III drug in affective disorders and also in disorders related clinical trials and are expected to be commercialized in the to cancer. In fact, several publications and reviews have near future [128]. More information on NK-1R as a target for reported experiments correlating emotional behavior (the CINV will appear in the following pages of this issue. limbic system) and cancer [35, 135, 136]. BioMed Research International 9

3.3. Cancer. Experimental evidence obtained in recent years Acknowledgments supports the idea that alterations in the neuroendocrine system may contribute significantly to the tumorigenic process. This work has been partially funded by a grant from the The tachykinins act directly on tumor cells, modulating their Fondo de Investigacion´ Sanitaria, Instituto de Salud Carlos responses in terms of proliferation and survival but also III (PI12/01706), by a grant from the Fundacion´ Cellex and contribute indirectly by altering the tumor microenviron- by Redes Tematicas´ de Investigacion´ en Cancer´ (RTICC, ment and processes related to tumor progression. SP and its RD12/0036/0055) (http://www.rticc.org/). This study was supported by grants from the Fondo de Investigacion´ San- receptor are expressed in a wide variety of tumor cell lines itaria (PI08022), Instituto de Salud Carlos III-Subdirecion´ (WERI-Rb-1 and Y-79 from retinoblastoma, U373 MG and General de Evaluacion´ y Fomento de Investigacion,´ Fondo GAMG from glioma, SNK-BE(2), Kelly and IMR-32 from Europeo de Desarrollo Regional, Union´ Europea, Una man- neuroblastoma, CAPAN-1 and PA-TU 8902 from pancreatic era de hacer Europa, the Fundacion´ Cellex, and Redes cancer, Hep-2 from laryngeal cancer, 23132/87 from gastric Tematicas´ de Investigacion´ en Cancer´ (RTICC, RD07/0020/ cancer, and SW-403 from colon cancer) [65, 67, 137]and 2014). tumors such as astrocytomas, gliomas, neuroblastomas, pancreatic cancer, melanomas, and breast cancer [28, 86, 123, 135, 138, 139]. References It has been estimated that the NK-1R antagonist aprepi- [1] C. 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