Abstract

Chemotherapy-induced nausea and vomiting (CINV) is significantly debilitating and worsens the quality of life. Olanzapine, an atypical antipsychotic drug, also has an antiemetic potential. Studies have shown that olanzapine-based regimens have similar efficacy as compared to aprepitant in patients receiving highly emetogenic chemotherapy (HEC). National Comprehensive Cancer Network guidelines also recommends olanzapine-based regimen in HEC. Olanzapine, palonosetron, dexamethasone regimen is a cost-effective option in resource-limited settings in patients receiving HEC.

Introduction

Chemotherapy-induced nausea and vomiting (CINV) is debilitating and worsens the quality of life. Acute CINV occurs within 24 h of chemotherapy, and delayed CINV is predominant during 24–48 h until 5 days. The prevention strategies for highly emetogenic chemotherapy (HEC) include corticosteroids, serotonin (5-HT3) receptor antagonists, and neurokinin 1 receptor antagonists. Olanzapine is an antipsychotic drug of thiobenzodiazepine class that is used in the management of schizophrenia and bipolar disorder. This drug has also shown to have high antiemetic potential.

Mechanism Of Action

Olanzapine acts as an antagonist on multiple receptors including dopaminergic (D1, D2, D3, and D4), serotonergic (5-HT2A, 5-HT2C, 5-HT3, and 5-HT6), adrenergic (alpha 1), histaminic (H1), and muscarinic (M1, M2, M3, and M4) receptors.

Discovery

In 1954, chlorpromazine was shown to be effective in controlling CINV in patients with advanced cancer.[1] Subsequently, in 1960, preclinical studies proved that haloperidol has antiemetic properties.[2] In 1992, Fuller and Snoddy showed that, in rats, olanzapine blocks serotonin and dopamine receptors better than clozapine and could be a potential antipsychotic drug.[3] It was termed novel “atypical” antipsychotic as it has additional anticholinergic properties that have lesser extrapyramidal symptoms.[4] In 1995, olanzapine showed efficacy in patient with schizophrenia with lower incidence of extrapyramidal symptoms.[5] In 2000, a case report highlighting the antiemetic properties of olanzapine was published.[6] This lead to the development of various clinical trials with olanzapine.

Approval

It is United States Food and Drug Act approved in the management of schizophrenia and bipolar disorder. Olanzapine is approved by the Drugs Controller General of India for the treatment of schizophrenia and resistant depression. It is currently not approved for use as antiemetic.

Highly Emetogenic Chemotherapy

The National Comprehensive Cancer Network (NCCN) defined HEC (>90% risk of emesis): cisplatin, carboplatin ≥AUC 4, adriamycin-cyclophosphamide (AC), cyclophosphamide >1500 mg/m2, ifosfamide >2 g/m2 per dose, adriamycin >60 mg/m2, epirubicin >90 mg/m2, and dacarbazine.

Olanzapine Dose

Tablet olanzapine 10 mg D1, D2, D3, and D4.

Olanzapine, Palonosetron, Dexamethasone Regimen

Tablet olanzapine 10 mg D1–D4Injection palonosetron 0.25 mg D1Injection dexamethasone 12 mg intravenous D1.

Why Olanzapine-Based Regimen is Better That Other Regimens?

Navari et al. showed that olanzapine, palonosetron, dexamethasone (OPD) regimen has similar control over nausea and vomiting as compared to aprepitant, palonosetron, dexamethasone (APD) regimen in patients receiving HEC. The second study showed that regimen olanzapine, APD (OAPD) had a superior efficacy as compared to APD regimen.[7] A prospective study also demonstrated that APD regimen was as effective as OPD for patients with breast cancer who received AC chemotherapy.[8] [Table 1] In a recent study, olanzapine proved to be effective in patients who failed aprepitant-based regimen while receiving HEC.[9] Mini OPD regimen (tablet olanzapine 5 mg D1 and D2 along with palonosetron and dexamethasone) has shown to be cost-effective in patients receiving weekly cisplatin for carcinoma cervix.[10] Addition of olanzapine to palonosetron and dexamethasone significantly reduces nausea and the need for rescue medications in patients receiving moderately emetogenic chemotherapy.[11] A meta-analysis revealed that olanzapine is more effective than other antiemetics for controlling CINV in delayed and overall phase and 5 mg is equally as effective as 10 mg dose.[12] A systematic review and meta-analysis from Japan revealed that olanzapine, when substituted instead of aprepitant in the APD regimen, can be hugely cost-effective.[13] Although the newer antiemetics (fosaprepitant,[14] netupitant,[15] and rolapitant [16]) have shown to be effective in HEC, they are less effective in controlling nausea and are more expensive.

1.  Homburger F, Smithy G. Chlorpromazine in patients with nausea and vomiting due to advanced cancer. N Engl J Med 1954; 251: 820-2
2.  Janssen PA, Niemegeers CJ, Schellekens KH. Chemistry and pharmacology of compounds related to 4-(4-hydroxy-4-phenyl-piperidino)-butyrophenone. III. Duration of antiemetic action and oral effectiveness of haloperidol (R 1625) and of chlorpromazine in dogs. Arzneimittelforschung 1960; 10: 955
3.  Fuller RW, Snoddy HD. Neuroendocrine evidence for antagonism of serotonin and dopamine receptors by olanzapine (LY170053), an antipsychotic drug candidate. Res Commun Chem Pathol Pharmacol 1992; 77: 87-93
4.  Moore NA, Tye NC, Axton MS, Risius FC. The behavioral pharmacology of olanzapine, a novel “atypical” antipsychotic agent. J Pharmacol Exp Ther 1992; 262: 545-51
5.  Baldwin DS, Montgomery SA. First clinical experience with olanzapine (LY 170053): Results of an open-label safety and dose-ranging study in patients with schizophrenia. Int Clin Psychopharmacol 1995; 10: 239-44
6.  Pirl WF, Roth AJ. Remission of chemotherapy-induced emesis with concurrent olanzapine treatment: A case report. Psychooncology 2000; 9: 84-7
7.  Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M. et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med 2016; 375: 134-42
8.  Shivaprakash G, Udupa KS, Sarayu V, Thomas J, Gupta V, Pallavi LC. et al. Olanzapine versus aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving doxorubicin-cyclophosphamide regimen: A prospective, nonrandomized, open-label study. Indian J Pharmacol 2017; 49: 451-7
9.  Mehra N, Ganesan P, Ganesan TS, Veeriah S, Boopathy A, Radhakrishnan V. et al. Effectiveness of olanzapine in patients who fail therapy with aprepitant while receiving highly emetogenic chemotherapy. Med Oncol 2017; 35: 12
10.  Mehra N, Ganesan P, Dhanushkodi M, Ganesan TS, Radhakrishnan V, Jayachandran PK. et al. An effective anti-emetic regimen for less than $2 USD: A prospective observational study. J Clin Oncol 2018; 36: e22194-4
11.  Jeon SY, Han HS, Bae WK, Park MR, Shim H, Lee SC. et al. A randomized, double-blind, placebo-controlled study of the safety and efficacy of olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy: Results of the Korean South West Oncology Group (KSWOG) study. Cancer Res Treat 2019; 51: 90-7
12.  Yang T, Liu Q, Lu M, Ma L, Zhou Y, Cui Y. et al. Efficacy of olanzapine for the prophylaxis of chemotherapy-induced nausea and vomiting: A meta-analysis. Br J Clin Pharmacol 2017; 83: 1369-79
13.  Yokoe T, Hayashida T, Nagayama A, Nakashoji A, Maeda H, Seki T. et al. Effectiveness of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: A systematic review and network meta-analysis. Oncologist 2019; 24: e347-57
14.  Ruhlmann CH, Christensen TB, Dohn LH, Paludan M, Rønnengart E, Halekoh U. et al. Efficacy and safety of fosaprepitant for the prevention of nausea and emesis during 5 weeks of chemoradiotherapy for cervical cancer (the GAND-emesis study): A multinational, randomised, placebo-controlled, double-blind, phase 3 trial. Lancet Oncol 2016; 17: 509-18
15.  Aapro M, Rugo H, Rossi G, Rizzi G, Borroni ME, Bondarenko I. et al. 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. Ann Oncol 2014; 25: 1328-33
16.  Navari RM, Rapoport BL, Powers D, Arora S, Clark-Snow R. Rolapitant for the prevention of nausea in patients receiving highly or moderately emetogenic chemotherapy. Cancer Med 2018; 7: 2943-2950
17.  Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A randomized phase III trial. J Support Oncol 2011; 9: 188-95
18.  Tan L, Liu J, Liu X, Chen J, Yan Z, Yang H. et al. Clinical research of olanzapine for prevention of chemotherapy-induced nausea and vomiting. J Exp Clin Cancer Res 2009; 28: 131
19.  Chanthawong S, Lim YH, Subongkot S, Chan A, Andalusia R, Bustamam RS. et al. Cost-effectiveness analysis of olanzapine-containing antiemetic therapy for managing highly emetogenic chemotherapy in Southeast Asia: A multinational study. Support Care Cancer 2019; 27: 1109-19

1.  Homburger F, Smithy G. Chlorpromazine in patients with nausea and vomiting due to advanced cancer. N Engl J Med 1954; 251: 820-2
2.  Janssen PA, Niemegeers CJ, Schellekens KH. Chemistry and pharmacology of compounds related to 4-(4-hydroxy-4-phenyl-piperidino)-butyrophenone. III. Duration of antiemetic action and oral effectiveness of haloperidol (R 1625) and of chlorpromazine in dogs. Arzneimittelforschung 1960; 10: 955
3.  Fuller RW, Snoddy HD. Neuroendocrine evidence for antagonism of serotonin and dopamine receptors by olanzapine (LY170053), an antipsychotic drug candidate. Res Commun Chem Pathol Pharmacol 1992; 77: 87-93
4.  Moore NA, Tye NC, Axton MS, Risius FC. The behavioral pharmacology of olanzapine, a novel “atypical” antipsychotic agent. J Pharmacol Exp Ther 1992; 262: 545-51
5.  Baldwin DS, Montgomery SA. First clinical experience with olanzapine (LY 170053): Results of an open-label safety and dose-ranging study in patients with schizophrenia. Int Clin Psychopharmacol 1995; 10: 239-44
6.  Pirl WF, Roth AJ. Remission of chemotherapy-induced emesis with concurrent olanzapine treatment: A case report. Psychooncology 2000; 9: 84-7
7.  Navari RM, Qin R, Ruddy KJ, Liu H, Powell SF, Bajaj M. et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med 2016; 375: 134-42
8.  Shivaprakash G, Udupa KS, Sarayu V, Thomas J, Gupta V, Pallavi LC. et al. Olanzapine versus aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving doxorubicin-cyclophosphamide regimen: A prospective, nonrandomized, open-label study. Indian J Pharmacol 2017; 49: 451-7
9.  Mehra N, Ganesan P, Ganesan TS, Veeriah S, Boopathy A, Radhakrishnan V. et al. Effectiveness of olanzapine in patients who fail therapy with aprepitant while receiving highly emetogenic chemotherapy. Med Oncol 2017; 35: 12
10.  Mehra N, Ganesan P, Dhanushkodi M, Ganesan TS, Radhakrishnan V, Jayachandran PK. et al. An effective anti-emetic regimen for less than $2 USD: A prospective observational study. J Clin Oncol 2018; 36: e22194-4
11.  Jeon SY, Han HS, Bae WK, Park MR, Shim H, Lee SC. et al. A randomized, double-blind, placebo-controlled study of the safety and efficacy of olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy: Results of the Korean South West Oncology Group (KSWOG) study. Cancer Res Treat 2019; 51: 90-7
12.  Yang T, Liu Q, Lu M, Ma L, Zhou Y, Cui Y. et al. Efficacy of olanzapine for the prophylaxis of chemotherapy-induced nausea and vomiting: A meta-analysis. Br J Clin Pharmacol 2017; 83: 1369-79
13.  Yokoe T, Hayashida T, Nagayama A, Nakashoji A, Maeda H, Seki T. et al. Effectiveness of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: A systematic review and network meta-analysis. Oncologist 2019; 24: e347-57
14.  Ruhlmann CH, Christensen TB, Dohn LH, Paludan M, Rønnengart E, Halekoh U. et al. Efficacy and safety of fosaprepitant for the prevention of nausea and emesis during 5 weeks of chemoradiotherapy for cervical cancer (the GAND-emesis study): A multinational, randomised, placebo-controlled, double-blind, phase 3 trial. Lancet Oncol 2016; 17: 509-18
15.  Aapro M, Rugo H, Rossi G, Rizzi G, Borroni ME, Bondarenko I. et al. 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. Ann Oncol 2014; 25: 1328-33
16.  Navari RM, Rapoport BL, Powers D, Arora S, Clark-Snow R. Rolapitant for the prevention of nausea in patients receiving highly or moderately emetogenic chemotherapy. Cancer Med 2018; 7: 2943-2950
17.  Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A randomized phase III trial. J Support Oncol 2011; 9: 188-95
18.  Tan L, Liu J, Liu X, Chen J, Yan Z, Yang H. et al. Clinical research of olanzapine for prevention of chemotherapy-induced nausea and vomiting. J Exp Clin Cancer Res 2009; 28: 131
19.  Chanthawong S, Lim YH, Subongkot S, Chan A, Andalusia R, Bustamam RS. et al. Cost-effectiveness analysis of olanzapine-containing antiemetic therapy for managing highly emetogenic chemotherapy in Southeast Asia: A multinational study. Support Care Cancer 2019; 27: 1109-19