Olanzapine for Breakthrough CINV

STUDY PURPOSE: To evaluate the effectiveness of olanzapine compared to other antiemetic regimens for preventative and breakthrough chemotherapy-induced nausea and vomiting (CINV). A secondary objective is to evaluate the effectiveness of 5 mg compared to 10 mg olanzapine for the prevention of CINV.

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 13 total studies, 10 for prevention and 3 for breakthrough CINV
• TOTAL PATIENTS INCLUDED IN REVIEW = 1,082 patients for prevention and 308 patients for breakthrough
• SAMPLE RANGE ACROSS STUDIES: Prevention studies: 19–241 patients; breakthrough studies: 106–109 patients
• KEY SAMPLE CHARACTERISTICS: Prevention studies: Six studies included patients with HEC, four with both HEC and MEC, and no studies with only MEC. Breakthrough studies: Two studies included patients with MEC, and one study included HEC.

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Elder care

Efficacy of Acute Phase: Olanzapine was statistically superior to non-olanzapine regimens for emesis (RR = 1.10, 95% CI [1.03, 1.17]) but not nausea. The 10 mg olanzapine was statistically superior to a non-olanzapine regimen for emesis and nausea.

Efficacy of Delayed Phase: Olanzapine was statistically superior to standard antiemetic regimens for emesis (RR = 1.31, 95% CI [1.14, 1.52]) and for nausea (RR = 1.50, 95% CI [1.15, 1.97]). The 10 mg olanzapine was statistically superior to a non-olanzapine regimen for emesis (RR = 1.31, 95% CI [1.11, 1.54]) and nausea (RR = 1.50, 95% CI [1.15, 1.97]).

Efficacy Overall: Olanzapine was statistically superior to standard anti-emetic regimens for emesis (RR = 1.41, 95% CI [1.18, 1.68]) and for nausea (RR 1.53, 95% CI [1.18, 1.97]). Olanzapine 5 mg and 10 mg were both statistically superior for emesis, and 10 mg strength was superior for nausea. No studies were available for nausea with 5 mg.

Efficacy of Breakthrough: Only emesis (not nausea) was available for analysis, and olanzapine showed superiority (RR = 2.09, 95% CI [1.63, 2.68]) to non-olanzapine regimens.

Olanzapine is effective in treating emesis at all time points and is effective in treating nausea in the delayed phase. More studies are needed to determine the most effective dosing.

• Limited number of studies included
• Low sample sizes
• A secondary objective was to evaluate the effectiveness of 5 mg compared to 10 mg, but no results were found to answer this objective (5 mg and 10 mg were compared only to non-olanzapine regimens).

Olanzapine should be used as an adjunct medication for the treatment of acute chemotherapy related vomiting, breakthrough vomiting, and delayed CINV.

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Palliative care

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.

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.

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.

To evaluate the safety and efficacy of olanzapine for breakthrough emesis in addition to standard antiemetic regimen in patients with cancer receiving highly emetogenic chemotherapy

All patients were treated with the institutional standard for HEC: ondansetron 24 mg IV BID and dexamethasone 10 mg IV BID on day 1. Oral metoclopramide 10 mg TID plus dexamethasone 10 mg po BID were given on days 2 and 3. Oral olanzapine 5 mg was given after the first vomiting episode. Twelve hours later, the second dose was given concurrently with the standard prevention regimen. 

• N = 46  
• AGE: 89.1% younger than 50 years, 10.9% were 50 years or older
• MEDIAN AGE = 33.5 years 
• MALES: 69.5%, FEMALES: 30.5% 
• KEY DISEASE CHARACTERISTICS: Patients with solid tumors to receive at least one cycle of chemotherapy. No nausea or vomiting reported for at least 12 hours prior to chemotherapy 

• SITE: Single site    
• SETTING TYPE: Not specified    
• LOCATION: Khon Kaen, Thailand

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics, elder care 

• Phase II prospective open-labeled clinical trial

• CINV measured by the Index of Nausea, Vomiting, and Retching (INVR tool) every 12 hours. Adverse drug reactions were evaluated by using the Naranjo’s algorithm to estimate the occurrence probability. CTCAE V. 4.03 was used.

Complete response of breakthrough emesis was 60.9%, retching was 71.7%, and nausea was 50.0%. Adverse events were mild, including dizziness, fatigue, and dyspepsia. 

The study demonstrated the effectiveness and safety of olanzapine in the treatment of nausea and vomiting in HEC patients. Olanzapine could be considered for treatment of patients at high risk for breakthrough emesis despite standard prevention. Olanzapine 5 mg every 12 hours for at least 24 hours could be recommended per the study.

• Small sample (< 100)
• Risk of bias (no control group)
• Other limitations/explanation
  • The “standard antiemetic” is not recommended by NCCN, ONS, MASCC, and ASCO for HEC.   
  • The medications used in the delayed phase were not recommendations by NCCN, MASCC, ONS, and ASCO guidelines.   
  • Olanzapine was only used for 24 hours at 5 mg (2 doses). Other olanzapine studies and guidelines recommend 3 days at 10 mg. 

Olanzapine is a drug that could be extremely helpful in treatment of CINV. Studies have shown olanzapine to be a safe and effective medication in acute and delayed CINV. The reviewed study attempted to show effectiveness in the breakthrough setting but many limitations were reported and are listed above. The researchers should not conduct CINV studies for “breakthrough” if the patient is given suboptimal treatment upfront.

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

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.

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

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

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

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.

• 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.

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)

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.

• 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.

The study was conducted at multiple outpatient sites in Indiana.

All patients were in active antitumor treatment.

This was a randomized, parallel group trial.

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

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.

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

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.

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

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.

• 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%).

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

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

• Retrospective chart review

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.

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.

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.

• 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

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

RESOURCE TYPE: Consensus-based guideline

PROCESS OF DEVELOPMENT: A literature search for papers published between January 1, 2009, and January 6, 2015, related to high-dose chemotherapy, multiple-day chemotherapy regimens, and breakthrough nausea and vomiting

DATABASES USED: PubMed

INCLUSION CRITERIA: Clinical trials, systematic reviews, stem cell transplantations (SCTs), patients with germ cell tumors

EXCLUSION CRITERIA: Other studies

PHASE OF CARE: Active antitumor treatment

Few studies related to the prevention of acute and delayed CINV in patients receiving high-dose and multiple-day chemotherapy regimens and for breakthrough nausea and vomiting. Little evidence related to the control of nausea exists.

Aprepitant should be added to two-drug antiemetic regimens in patients receiving high-dose and multiple-day cisplatin regimens to prevent acute and delayed CINV. Olanzapine is recommended for breakthrough CINV.

RESOURCE TYPE: Evidence-based guideline

PHASE OF CARE: Multiple phases of care

One hundred seventy-one articles were retrieved via aPubMed search. No information was provided regarding which articles were selected as relevant to these guidelines, and no discussion of any method used for rating the quality of included evidence exists.

Limited database used. Recommendations are a combination of evidence- and consensus-based suggestions, and most nonpharmacologic interventions are by consensus.

Provides multiple evidence- and consensus-based recommendations for prophylaxis and the management of nausea and vomiting due to chemotherapy or radiation therapy. Recommendations provide a list of chemotherapy agents, including oral agents and categorization as to emetic potential.

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.

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.

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.