Olanzapine for Breakthrough CINV

Olanzapine for Breakthrough CINV

PEP Topic 
Chemotherapy-Induced Nausea and Vomiting
Description 

Olanzapine is an antipsychotic used in the treatment of schizophrenia and bipolar disorder. Olanzapine has been evaluated as an adjunctive medication for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer. Olanzapine can be used as needed for breakthrough nausea and vomiting associated with chemotherapy.

 

 

Likely to Be Effective

Systematic Review/Meta-Analysis

Hocking, C.M., & Kichenadasse, G. (2014). Olanzapine for chemotherapy-induced nausea and vomiting: A systematic review. Supportive Care in Cancer, 22(4), 1143–1151. 

doi: 10.1007/s00520-014-2138-y
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Purpose:

STUDY PURPOSE: To assess the efficacy of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) and treating breakthrough CINV with a secondary purpose of evaluating the side effects associated with olanzapine
 
TYPE OF STUDY: Systematic review

Search Strategy:

DATABASES USED: MEDLINE, Embase, and the Cochrane Database of Systematic Reviews
 
KEYWORDS: Nausea and chemotherapy, vomiting and chemotherapy, and olanzapine
 
INCLUSION CRITERIA: Trials of adult patients receiving moderately or highly emetogenic chemotherapy where olanzapine was used as an intervention; only randomized controlled trials were evaluated.
 
EXCLUSION CRITERIA: Exclusion criteria were not delineated.

Literature Evaluated:

TOTAL REFERENCES RETRIEVED: 217 studies were identified (23 from Medline, 203 from Embase, and four from Cochrane). 196 studies excluded because of non-randomized trials and non-focused on CINV. 21 texts underwent second screening and again, 15 studies were excluded for being non-randomized and non-focused on CINV.  
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: The Jadad scale was used to evaluate the final six trials. A higher score (range 0–5) indicates greater methodological rigor in terms of randomization, blinding, and accountability. For trials looking at prevention, two scored 4 out of 5 with the other study at 3 out of 5. With breakthrough trials, one scored 5 on the Jadad scale with the other two, which where unpublished reports, scoring 2 out of 5.   

Sample Characteristics:

FINAL NUMBER STUDIES INCLUDED = 6 (3 prophylaxis of CINV, 3 breakthrough CINV) 
 
TOTAL PATIENTS INCLUDED IN REVIEW = 488 (prophylaxis of CINV), 323 (breakthrough CINV) 
 
KEY SAMPLE CHARACTERISTICS: Group characteristics were broken down to two groups. One is prophylaxis of CINV and the other is breakthrough CINV. Among the 488 patients in the prophylaxis group, age range was 18–81 years, and the group included 267 females and 221 males. Primary cancer sites were not identifiable in one trial of 18 patients. Of the other 470 patients, 38% had breast cancer, 29% had non-small cell lung cancer, and 9% had lymphoma. Highly emetogenic chemotherapy consisted of cisplatin at > 70 mg/m2 in 56.5%, doxorubicin and cyclophosphamide in 42.9%, and dacarbazine in less than 1%. The breakthrough group included 323 patients. Age range was 37–85 years and included 154 females and 169 males. A breakdown of cancer diagnoses and regimens was not described in two trials totaling 215 patients. In the remaining trial of 108 patients, 50% were patients with breast cancer, 34% were patients with non-small cell lung cancer, 9% were patients with lymphoma, and 6% were patients with bladder cancer. Cisplatin at > 70 mg/m2 was used in 41% of patients, while doxorubicin and cyclophosphamide were used in 59% of patients.   

Phase of Care and Clinical Applications:

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Palliative care 

Results:

In the prophylaxis group, complete response was the primary endpoint evaluated in the acute and delayed phases without any statistical significance. One trial reported more sleepiness with olanzapine than the controls, but another trial reported no differences between olanzapine and aprepitant. In one trial, there were significant differences between olanzapine and aprepitant with secondary endpoints of delayed nausea (69% versus 38%; p < 0.01) and no overall nausea (69% versus 38%; p < 0.01). In another large trial, olanzapine was added to a 5-HT3 antagonist and dexamethasone and compared to controls. There was statistical significance in delayed and overall complete response rates in highly (overall CR = 79% versus 57%; p < 0.05) and moderately (overall CR = 89% versus 76%; p < 0.05) emetogenic chemotherapy. One small study of aprepitant compared with olanzapine showed no statistical significance.  
 
In the breakthrough group, one trial compared olanzapine versus metoclopramide and found statistical significance in the olanzapine-treated patients with emesis (70% versus 31%; p < 0.01) and no nausea (68% versus 23%; p < 0.01). The second trial compared olanzapine with metoclopramide and dexamethasone at 66%, 36%, and 37% complete response rates, respectively. The other trial compared olanzapine and dexamethasone with metoclopramide and prochlorperazine at 66%, 36%, and 20% complete response rates, respectively.

Conclusions:

Per the authors, evidence exists to support olanzapine in highly emetogenic regimens. The Navari (2011) trial was the strongest study to support the use of olanzapine. Toxicity in all included trials demonstrated little side effects. Only one trial described sleepiness during chemotherapy. Olanzapine is a safe and more costly option to use instead of NK-1 antagonists. When used with other antiemetics such as metoclopramide there is a role in prevention, and as a single agent it shows efficacy in delayed CINV as well.

Limitations:

There were only three studies in each group. Only the Shumway trial was double-blinded, but it was a small trial. All the breakthrough trials were by the same investigator and included less than 110 patients.

Nursing Implications:

Olanzapine may have a role in preventing CINV and delayed CINV but there is still limited research. The most recent trial for delayed CINV is a small trial but is double-blinded. Further research is indicated.

Research Evidence Summaries

Navari, R.M., Einhorn, L.H., Loehrer, P.J., Sr., Passik, S.D., Vinson, J., McClean, J., … Johnson, C.S. (2007). A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Supportive Care in Cancer, 15, 1285-1291.

doi: 10.1007/s00520-007-0248-5
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Study Purpose:

To examine the effectiveness of olanzapine in the treatment of chemotherapy-induced nausea and vomiting without the use of dexamethasone after day 1

Intervention Characteristics/Basic Study Process:

A 10-mg oral dose of olanzapine was given every day, four times a day for prevention (rather than breakthrough) nausea and vomiting. On day 1 of chemotherapy, patients received 0.25 mg IV palonosetron and dexamethasone (8 mg for moderately emetogenic chemotherapy [MEC], 20 mg for highly emetogenic chemotherapy [HEC]) as well as 10 mg oral olanzapine. On days 2-4, patients received only 10 mg olanzapine daily. The same antiemetic regimen was continued for as many cycles as the patient completed (1-6 cycles). Patients received no other antiemetics on days 2-4. Patients were permitted to take rescue therapy.

Sample Characteristics:

The sample consisted of 40 patients who were chemotherapy-naive and receiving HEC or MEC.

Study Design:

This was a prospective, nonrandomized trial with no control or comparison group, consisting of descriptive analysis only (percentage of patients with response described).

Measurement Instruments/Methods:

  • The M.D. Anderson Symptom Inventory (MDASI) was used.
  • Patients recorded daily episodes of vomiting and retching.

Results:

Complete response (CR), defined as no emesis and no rescue medications administered and no nausea, was found in 100% of HEC patients and 97% of MEC patients in the acute period (0-24 hours after chemotherapy).

Responses for the delayed period (24-120 hours) decreased. Seventy-five percent of patients reported CR in the delayed and overall periods for emesis and even fewer for control of nausea (50% of HEC patients with CR for nausea and 78% of MEC patients with CR for nausea in the delayed and overall periods). No adverse events to study drugs were noted (no grade 3 or 4 toxicities). Olanzapine was not associated with sedation, weight gain, or hyperglycemia.

Limitations:

  • The sample size was small.
  • Investigators stated that combination olanzapine, dexamethasone, and palonosetron was effective in controlling acute and delayed CINV in patients receiving both HEC and MEC; however, no control or comparison group was included in the study.
  • The investigators stated that the results indicated effectiveness compared to studies using triple-drug regimens; however, no head-to head comparison was done in this study. This is especially problematic given that aprepitant was not used and is now recommended per guidelines.
  • Half of the patients in the HEC group still experienced nausea in the delayed and overall study periods (0-120 hours after chemotherapy). In the MEC group, 22% of patients still experienced nausea in the delayed and overall periods.
  • Use of rescue medications was not described, although these were allowed and patients were permitted to continue in the study even if rescue medications were used.

Navari, R.M., Nagy, C.K., & Gray, S.E. (2013). 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 Cancer, 21, 1655-1663.

doi: 10.1007/s00520-012-1710-6
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Study Purpose:

To compare the effectiveness of a regimen using olanzapine versus a regimen using metoclopramide for breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC)

Intervention Characteristics/Basic Study Process:

Patients receiving HEC were randomly assigned to receive either a regimen containing olanzapine or metoclopramide for breakthrough CINV. All patients received prophylactic antiemetics of 12 mg IV dexamethasone, 0.25 mg IV palonosetron, and 150 mg IV fosaprepitant on day 1 prior to chemotherapy. On days 2-4, patients received 4 mg oral dexamethasone, twice per day. The metoclopramide regimen was 10 mg orally every 8 hours for 72 hours. The olanzapine regimen was 10 mg daily for 72 hours. 

Those on olanzapine also received placebo once daily so that the number of pills were the same for both groups, so patients were blinded to the study group. Patients were instructed to begin the breakthrough treatment within 30 minutes after any emesis or nausea level greater than 3 on a visual analog scale (VAS). If the breakthrough treatment was begun, patients were to discontinue the oral dexamethasone, notify the on-call nurse, and begin recording nausea and any emesis. Patients were contacted by phone every 24 hours to remind them to complete information and assess toxicities.

Sample Characteristics:

  • The study consisted of 276 patients; of these, 108 used a breakthrough regimen and were analyzed.
  • Median age was 62 years with a range of 38–79.
  • The study sample was 46.3% male and 53.7% female.
  • Cancer diagnoses were breast, bladder, lung, and lymphoma.
  • All patients were receiving HEC.

Setting:

The study was conducted at multiple outpatient sites in Indiana.

Phase of Care and Clinical Applications:

All patients were in active antitumor treatment.

Study Design:

This was a randomized, parallel group trial.

Measurement Instruments/Methods:

The M.D. Anderson symptom assessment scale was used.

Results:

A total of 39% of patients randomized needed to begin the breakthrough CINV regimen as assigned.  Over the 72 hour observation period, 70% of those on olanzapine had no further emesis, compared to 31% of those on metoclopramide (p < 0.01), and 68% on olanzapine had no further nausea, compared to 23% with no nausea in the metoclopramide group (p < 0.01). The pattern of symptom control showed that the incidence of nausea and vomiting declined each study day.

Conclusions:

A regimen of breakthrough CINV treatment using olanzapine was more effective than metoclopramide for relief of breakthrough nausea and vomiting in patients receiving HEC.

Nursing Implications:

Olanzapine can be more effective than metoclopramide to manage breakthrough CINV. The breakthrough regimen tested here involved the provision of consistent medication, rather than treatment of each breakthrough episode individually, which may not be the usual approach for management. Findings here showed that about 40% of patients required a breakthrough regimen, despite use of aggressive standard antiemetic therapy. Olanzapine was found to be more effective in relieving nausea, which has been more difficult to effectively control than vomiting.  Strong consideration should be given to use of this type of olanzapine regimen and immediate patient-initiated use of such a regimen based on self assessment of CINV severity early in the course of treatment. Most current guidelines provide limited recommendations for breakthrough CINV.

Vig, S., Seibert, L., & Green, M.R. (2014). Olanzapine is effective for refractory chemotherapy-induced nausea and vomiting irrespective of chemotherapy emetogenicity. Journal of Cancer Research and Clinical Oncology, 140(1), 77–82.

doi: 10.1007/s00432-013-1540-z
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Study Purpose:

To retrospectively evaluate the efficacy of the addition of olanzapine in adults experiencing refractory chemotherapy-induced nausea and vomiting (CINV) stratified by chemotherapy emetogenicity

Intervention Characteristics/Basic Study Process:

This was a retrospective chart review of adults receiving chemotherapy between January 2008 and January 2012. Inclusion criteria required that patients received one or more daily doses of olanzapine 10 mg per dose for the indication of refractory CINV during the same admission. Each patient must have received antiemetic prophylaxis and first-line rescue antiemetics appropriate for the emetogenicity level of the chemotherapy regimen according to National Comprehensive Cancer Network guidelines at the time of chemotherapy administration. Patients were excluded if olanzapine was used for anything other than refractory CINV.

Sample Characteristics:

  • N = 33
  • MEDIAN AGE = 49 years (range = 19–77 years)
  • MALES: 20, FEMALES: 13
  • KEY DISEASE CHARACTERISTICS: The most common oncologic diagnoses were advanced melanoma (36%) and Hodgkin lymphoma (34%).
  • OTHER KEY SAMPLE CHARACTERISTICS: Most subjects were Caucasian (58%) or Hispanic (24%).

Setting:

  • SITE: Single site  
  • SETTING TYPE: Inpatient  
  • LOCATION: Southwest United States

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment
  • APPLICATIONS: Elder care, palliative care 

Study Design:

  • Retrospective chart review

Measurement Instruments/Methods:

Researchers measured the number of rescue antiemetics received following the first dose of olanzapine. Patients were stratified by chemotherapy emetogenicity level, age, gender, and number of prophylactic antiemetics received.

Results:

Thirteen women and 10 men were included in this study, the majority of whom were Caucasian (58%) and were most frequently being treated for advanced melanoma (36%) and non-Hodgkin lymphoma (24%). The addition of olanzapine was successful for 65% of patients receiving regimens with low to moderate emetogenicity (n = 23) and 70% of patients receiving regimens with high emetogenicity (n = 10). For these cohorts, olanzapine 5–10 mg was administered for one to eight days (median four days). More women (85%) than men (55%) were successfully treated with the addition of olanzapine. For patients receiving a serotonin antagonist, glucocorticoid, and aprepitant as prophylaxis, the addition of olanzapine was successful for controlling breakthrough nausea 68% of the time. Patients who received a prophylactic serotonin antagonist alone were treated successfully 63% of the time for breakthrough nausea with olanzapine. Cohorts 18 to 50 years old (n = 12) and over 50 years (n = 15) received relief with the addition of olanzapine 67% of the time.

Conclusions:

Adding olanzapine contributed to the success of CINV management, particularly for women more often than men. Findings suggest that the addition of olanzapine for refractory to prophylactic and breakthrough antiemetic regimens in all levels of emetogenicity may be beneficial.

Limitations:

  • Small sample (< 100)
  • Risk of bias (no random assignment)
  • Risk of bias (no appropriate attentional control condition)
  • Unintended interventions or applicable interventions not described that would influence results
  • Findings not generalizable
  • Retrospective design

Nursing Implications:

Nurses who assess and administer chemotherapy with low to moderate or high levels of emetogenicity should consider the addition of olanzapine for refractory CINV.

Guideline/Expert Opinion

Roila, F., Herrstedt, J., Aapro, M., Gralla, R.J., Einhorn, L.H., Ballatori, E., … ESMO/MASCC Guidelines Working Group. (2010). Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: Results of the Perugia consensus conference. Annals of Oncology, 21(Suppl. 5), v232–v243.

doi: 10.1093/annonc/mdq194
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Type of Resource/Evidence-Based Process:

This Perugia consensus panel was composed of 10 committees that reported findings to a 23-member expert panel from 10 different countries. The panel determined level of evidence and made changes in 2004 guidelines if evidence supported a greater than 10% increase in benefit. Updates were approved by the European Society of Medical Oncology (ESMO) Guidelines Working Group. All author relationships were reported. The panel used MEDLINE and other databases, which were not specified.

Guidelines & Recommendations:

Emetogenicity of agents:

  • As new agents are developed, often limited recording of common toxicities is provided in order to accurately reflect emetogenic potential.
  • Increased use of oral agents and chronic oral administration creates issues regarding whether emetogenicity is defined by a single dose or a full course, and chronic use has blurred the lines between acute and delayed chemotherapy-induced nausea and vomiting (CINV).
  • The authors provided an updated list of chemotherapy agents and levels of emetogenicity. Classification of oral agents was provided on the basis of a full course of treatment.

 

Prevention of acute CINV:

  • Minimal risk: No routine prophylaxis
  • Low risk: Day 1—dexamethasone or 5-HT3 receptor antagonists or dopamine receptor antagonist
  • Moderate emetogenic chemotherapy (MEC)
    • With anthracycline: Day 1—5-HT3 receptor antagonist + dexamethasone + aprepitant or fosaprepitant; days 2 and 3—aprepitant
    • Without anthracycline: Day 1—palonosetron + dexamethasone; days 2 and 3—dexamethasone
  • Highly emetogenic chemotherapy (HEC): Day 1—5-HT3 receptor antagonist + dexamethasone + aprepitant or fosaprepitant; days 2 and 3—dexamethasone + aprepitant; day 4—dexamethasone
  • Although studies have shown effectiveness of casopitant, the producer discontinued regulatory filings, so this was not recommended for use.
  • All 5-HT3 receptor antagonists were found to show the same efficacy. More studies are needed to determine if palonosetron is more effective with cisplatin-based therapies.

 

Prevention of delayed CINV:

  • Aprepitant should be used to prevent delayed CINV.
  • Whether dexamethasone is as effective or if the combination of dexamethasone and aprepitant would be more effective is not known. The optimal dose and duration of dexamethasone is not defined.
  • Prevention with multiple-day cisplatin was not clear. Aprepitant + dexamethasone for acute and dexamethasone for delayed CINV was recommended. The possible role of ​neurokinin 1 (NK1) was not clear.

 

Refractory CINV and rescue:

  • Maximally effective prophylaxis should be used.
  • The addition of cannabinoids, olanzapine, and nonpharmacologic interventions could be considered.

 

Prevention of anticipatory CINV:

  • The best way to prevent this learned response is maximum effective control of acute and delayed CINV.
  • Anticipatory CINV is difficult to control with medication.
  • Benzodiazepines are the only drugs identified as effective, but efficacy tends to decrease as chemotherapy continues.

 

Prevention of CINV with high-dose chemotherapy:

  • Complete protection is currently only achieved in a minority of patients.
  • Current standard is dexamethasone + 5-HT3 receptor antagonists.
  • Evaluation of the addition of aprepitant is needed.

 

Radiation-induced nausea and vomiting:

  • Risk level and antiemetic guidelines are provided.
  • Generally, prophylaxis with 5-HT3 receptor antagonists + dexamethasone and rescue with 5-HT3 receptor antagonists are recommended.

 

Antiemetics in children:

  • All pediatric patients receiving MEC or HEC should receive prophylaxis with 5-HT3 and dexamethasone. Optimal dosing requires further study.
  • No studies have evaluated approaches for prevention of anticipatory CINV.
  • Metoclopramide, phenothiazines, and cannabinoids have shown only moderate efficacy.

Nursing Implications:

The guidelines provide a clear set of recommendations and review of the relevant evidence strength assessed for various cancer treatment scenarios.

A complete listing of databases used for evidence retrieval was not provided.

Control of emesis has markedly improved in recent years; however, nausea remains a challenge and future research should shift attention to this aspect. Current trials generally define complete response end points that exclude consideration of the experience of nausea rather than vomiting. Trials suggest that some agents are more effective for acute vomiting, others are more effective for delayed vomiting, and some may be more effective for nausea. Identification of these differences and incorporation into the rationale for treatment needs to continue.

Further research is needed in the areas of prevention with high-dose chemotherapy and stem cell support, combined chemotherapy and radiation therapy, and anticipatory nausea and antiemetic use in children. Practitioners need to be aware of the impact of oral therapy and chronic oral chemotherapy treatment on current approaches to antiemetic treatment, timing, and definitions of acute and delayed CINV. Practitioners also need to be aware that current chemotherapy risk determination does not apply to combined radiotherapy and chemotherapy.


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