Abstract

Background: Chemotherapy induced nausea and vomiting is a debilitating effect of the chemotherapy drugs 
administered to patients with malignancy and deteriorates the quality of life of the patients. The antiemetic drugs 
that are commonly prescribed for controlling CINV are 5-HT3 RA, NK1RA, Dexamethasone, Olanzapine and 
Metoclopramide. These drugs are used either in combinations or alone for treating CINV.
Objective: The purpose of this review is to analyze the various treatment modalities for CINV and to identify the 
suitable antiemetic agents for nausea and emesis caused by various chemotherapy agents.
Methods: We systematically reviewed randomized controlled trials (RCTs) in adult patients undergoing 
chemotherapy treatment and are at risk of CINV, extracting and synthesizing data from eligible articles on study 
design, randomization, withdrawal, blinding, type of analysis, duration, and names and doses of drugs. The primary 
outcome measure was complete response (no emesis and no administration of rescue medication) in preventing 
CINV in acute and delayed phases and secondary outcome was incidence of TRAEs.
Findings: This review included seventeen RCTs among which eleven were blinded and six were open label studies. 
Four studies evaluated the effectiveness of olanzapine in preventing CINV in which one of the study compared 
efficacy of olanzapine and metoclopramide for the treatment of breakthrough emesis. One of the study compared 
the efficacy of granisetron as transdermal delivery system with ondansetron in preventing CINV and concluded that 
granisetron transdermal system was non inferior to ondansetron in controlling CINV. Three studies investigated the 
change in the prevention of CINV on single day administration of dexamethasone with multiple day administration 
of dexamethasone. All the three studies reported that single day administration of dexamethasone was similar 
in efficacy to multiple day dosing. Two studies investigated the efficacy of rolapitant in which one of the study 
concluded that addition of rolapitant to antiemetic treatment regimen consisting of granisetron and dexamethasone 
significantly improved CINV compared with treatment regimen without rolapitant. Three studies evaluated the 
efficacy of NEPA which is a combination of Netupitant (NK1 RA) and Palonosetron (5HT3 RA)among which one 
study concluded that NEPA was superior to Palonosetron and in another NEPA was compared with palonosetron 
and aprepitant and concluded that NEPA was similar to them in controlling CINV. One study evaluated the efficacy 
of fosaprepitant, a prodrug of aprepitant compared to aprepitant and concluded that single dose fosaprepitant was 
non inferior to multiple day administration of aprepitant. Two studies evaluated fosnetupitant in which one study 
compared the efficacy of fosnetupitant at the dose of 81 mg and 235 mg and concluded that dose of 235 mg was 
superior to 81 mg of fosnetupitant. The other study compared the safety profile of fosnetupitant to fosaprepitant 
How to cite this article:
John Stephen Raj, S Monisha, MG Rajanandh, et. al./ A Systematic Review of the Management of Chemotherapy-Induced Nausea 
and Vomiting/Indian J Canc Educ Res 2022;10(2):65-79.
and concluded that both were similar.
Conclusion: Antiemetic triplet treatment 
regimen for CINV consisting of 5HT3 RA, NK1 RA 
and dexamethasone was found to be effective in 
this review but the quality of some of the evidence 
of the studies included in this review contains high 
risk of bias and is not completely reliable. Hence 
we recommend that future trials be conducted 
with minimum risk of bias to ensure high quality 
of evidence.

• 1.   Miyoshi T, Miyashita H, Matsuo N, Odawara M, Hori M, Hiraki Y, Kawanaka H. Palonosetron versus Granisetron in Combination with Aprepitant and Dexamethasone for the Prevention of Chemotherapy-Induced Nausea and Vomiting
• 2.   Aapro M, Caprariu Z, Chilingirov P, Chrápavá M, Curca RO, Gales L, Grigorescu AC, Huszno J, Karlínová B, Kellnerová R, Malejčíková M. Assessing the impact of antiemetic guideline compliance on prevention of chemotherapyinduced nausea and vomiting: Results of the nausea/emesis registry in oncology (NERO). European Journal of Cancer. 2022 May 1;166:126- 33.
• 3.   Aapro M, Jordan K, Gralla RJ, Rizzi G, Rossi G, Palmas M, Alyasova AV, Lisyanskaya AS, Bošnjak SM, Hesketh PJ. Safety and efficacy of NEPA, an oral fixed combination of netupitant and palonosetron, in older patients. Journal of geriatric oncology. 2017 Jan 1;8(1):56-63.
• 4.   Di Renzo N, Musso M, Scimè R, Cupri A, Perrone T, De Risi C, Pastore D, Guarini A, Mengarelli A, Benedetti F, Mazza P. Efficacy and safety of netupitant/palonosetron combination (NEPA) in preventing nausea and vomiting in nonHodgkin’s lymphoma patients undergoing to chemomobilization before autologous stem cell transplantation. Supportive Care in Cancer. 2022 Feb;30(2):1521-7.
• 5.   Sun S, Ko YH, Jin JY, Woo IS, Park SY, Eom YA, Kang JH, Kim HK. Efficacy of the granisetron transdermal system for the control of nausea and vomiting induced by highly emetogenic chemotherapy: a multicenter, randomized, controlled trial. The Korean Journal of Internal Medicine. 2022 Mar 11
• 6.   Schmitt T, Goldschmidt H, Neben K, Freiberger A, Hüsing J, Gronkowski M, Thalheimer M, Pelzl LH, Mikus G, Burhenne J, Ho AD. Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: results of a randomized, placebo-controlled phase III trial. Journal of Clinical Oncology. 2014 Oct 20;32(30):3413-20.
• 7.   Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapyinduced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Supportive Care in Cancer. 2013 Jun;21(6):1655-63.
• 8.   Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapyinduced nausea and vomiting: a randomized phase III trial. The journal of supportive oncology. 2011 Oct 31;9(5):188-95.
• 9.   Liu J, Tan L, Zhang H, Li H, Liu X, Yan Z, Chen J, Yang H, Zhang D. QoL evaluation of olanzapine for chemotherapy induced nausea and vomiting comparing with 5HT 3 receptor antagonist. European journal of cancer care. 2015 May;24(3):436-43.
• 10.   Navari RM. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. InManagement of Chemotherapy-Induced Nausea and Vomiting 2016 (pp. 107-120). Adis, Cham.
• 11.   Rapoport, B.L., Chasen, M.R., Gridelli, C., Urban, L., Modiano, M.R., Schnadig, I.D., Poma, A., Arora, S., Kansra, V., Schwartzberg, L.S. and Navari, R.M., 2015. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. The Lancet Oncology, 16(9), pp.1079-1089.
• 12.   Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol— EASE. Journal of Clinical Oncology. 2011 Apr 10;29(11):1495-501.
• 13.   Feinberg B, Gilmore J, Haislip S, Jackson J, Jain G, Balu S, Buchner D. Impact of initiating antiemetic prophylaxis with palonosetron versus ondansetron on risk of uncontrolled chemotherapy-induced nausea and vomiting in patients with lung cancer receiving multi-day chemotherapy. Supportive Care in Cancer. 2012 Mar;20(3):615-23.
• 14.   Gralla RJ, Bosnjak SM, Hontsa A, Balser C, Rizzi G, Rossi G, Borroni ME, Jordan K. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapyinduced nausea and vomiting over repeated cycles of chemotherapy. Annals of Oncology. 2014 Jul 1;25(7):1333-9.
• 15.   Van der Vorst MJ, Toffoli EC, Beusink M, van Linde ME, van Voorthuizen T, Brouwer S, van Zweeden AA, Vrijaldenhoven S, Berends JC, Berkhof J, Verheul HM. Metoclopramide, Dexamethasone, or Palonosetron for Prevention of Delayed Chemotherapy Induced Nausea and Vomiting After Moderately Emetogenic Chemotherapy (MEDEA): A Randomized, Phase III, Noninferiority Trial. The oncologist. 2021 Jan;26(1):e173-81.
• 16.   Matsuura K, Tsurutani J, Inoue K, Tanabe Y, Taira T, Kubota K, Tamura T, Saeki T. A phase 3 safety study of fosnetupitant as an antiemetic in patients receiving anthracycline and cyclophosphamide: Console BC. Cancer. 2022 Jan 19.
• 17.   Sugawara S, Inui N, Kanehara M, Morise M, Yoshimori K, Kumagai T, Fukui T, Minato K, Iwashima A, Takeda Y, Kubota K. Multicenter, placebo controlled, double blind, randomized study of fosnetupitant in combination with palonosetron for the prevention of chemotherapy induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Cancer. 2019 Nov 15;125(22):4076-83.
• 18.   Aapro M, Rugo H, Rossi G, Rizzi G, Borroni ME, Bondarenko I, Sarosiek T, Oprean C, CardonaHuerta S, Lorusso V, Karthaus M. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Annals of oncology. 2014 Jul 1;25(7):1328-33.
• 19.   Celio L, Cortinovis D, Cogoni AA, Cavanna L, Martelli O, Carnio S, Collovà E, Bertolini F, Petrelli F, Cassano A, Chiari R. Dexamethasone-Sparing Regimens with Oral Netupitant and Palonosetron for the Prevention of Emesis Caused by HighDose Cisplatin: A Randomized Noninferiority Study. The oncologist. 2021 Oct;26(10):e1854-61.
• 20.   Schwartzberg, L.S., Modiano, M.R., Rapoport, B.L., Chasen, M.R., Gridelli, C., Urban, L., Poma, A., Arora, S., Navari, R.M. and Schnadig, I.D., 2015. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, doubleblind, phase 3 trial. The Lancet Oncology, 16(9), pp.1071-1078.
• 21.   Suzuki K, Yamanaka T, Hashimoto H, Shimada Y, Arata K, Matsui R, Goto K, Takiguchi T, Ohyanagi F, Kogure Y, Nogami N. Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study. Annals of Oncology. 2016 Aug 1;27(8):1601-6.
• 22.   Komatsu Y, Okita K, Yuki S, Furuhata T, Fukushima H, Masuko H, Kawamoto Y, Isobe H, Miyagishima T, Sasaki K, Nakamura M. Open label, randomized, comparative, phase III study on effects of reducing steroid use in combination with palonosetron. Cancer science. 2015 Jul;106(7):891-5.

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