Keywords
Chemotherapy-induced nausea and vomiting - highly emetogenic chemotherapy - olanzapine
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
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
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?
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.
Table 1
Phase 3 trials comparing olanzapine versus other antiemetic regimen in patients receiving
highly emetogenic chemotherapy
|
Study
|
Olanzapine-based regimen Aprepitant-based regimen
|
Acute (0-24 h) CINV
|
Delayed (25-120 h) CINV
|
|
OPD - Olanzapine, palonosetron, dexamethasone; OAPD - Olanzapine, aprepitant, palonosetron,
dexamethasone; APD - Aprepitant, palonosetron, dexamethasone; AD - Azasetron, dexamethasone;
CR - Complete response; CINV - Chemotherapy-induced nausea and vomiting; OAD - Olanzapine,
azasetron, dexamethasone
|
|
Navari et al.
[17]
|
OPD
|
APD
|
CR (no rescue) 97% versus 81%, P>0.05
|
CR (no rescue) 11% versus 13%, P>0.05
|
|
Navari et al.
[7]
|
OAPD
|
APD
|
CR 85.7% versus 64.6%, odds ratio 0.30, P<0.001
|
CR 66.9% versus 52.4%, odds ratio 0.55, P=0.007
|
|
Tan et al.
[18]
|
OAD
|
AD
|
No difference in acute CINV
|
CR 69% versus 30%, P<0.05
|
Guidelines
The NCCN 2019 antiemetic guidelines recommends OPD regimen for the treatment of HECThe
ASCO 2018 antiemetic guidelines recommends addition of olanzapine to antiemetic regimen
in patients receiving HECThe Multinational Association of Supportive Care in Cancer/European
Society of Medical Oncology 2016 antiemetic guidelines recommends OPD as an effective
antiemetic regimen.
Toxicity
The side effect of olanzapine is sedation (severe in 5%[7]). If patients experience sedation, the dose can be reduced to 5 mg/day.
Olanzapine, Palonosetron, Dexamethasone Failure
Olanzapine, Palonosetron, Dexamethasone Failure
Patients who have breakthrough emesis while on olanzapine can be treated with aprepitant-based
regimen.
Cost-Effectiveness
Olanzapine (6 cycles, Rs. 170/-) is priced 50 times lower as compared to aprepitant
(6 cycles, Rs. 9000/-). A recent study from Southeast Asia showed olanzapine-based
regimen to be very cost-effective.[19]
Conclusion
OPD regimen should be the preferred antiemetic schedule for all patients receiving
HEC as it has similar efficacy with minimal toxicity as compared to APD regimen. The
NCCN 2019 antiemetic guidelines recommends OPD regimen for HEC. Further considering
the low cost of therapy, it is an attractive, cost-effective option in a resource-limited
setting.
