Abstract
Background
Olanzapine as an antiemetic represents a new use of an antipsychotic drug. People with cancer may experience nausea andvomiting whilst receiving chemotherapy or radiotherapy, or whilst inthe palliative phase of illness.
Objectives
To assess the efficacy and safety of olanzapine when used as an antiemetic in the prevention and treatment of nausea and vomitingrelated to cancer in adults.
Search methods
We searched CENTRAL, MEDLINE and Embase for published data on 20th September 2017, as well as ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform forunpublished trials. We checked reference lists, and contacted experts in the field and study authors.
Selection criteria
We included randomised controlled trials (RCTs) of olanzapineversus any comparator with or without adjunct therapies for theprevention or treatment, or both, of nausea or vomiting in people with cancer aged 18 years or older, in any setting, of any duration, with at least 10 participants per treatment arm.
Data collection and analysis
We used standard Cochrane methodology. We used GRADE to assess quality of evidence for each main outcome. We extracted data forabsence of nausea or vomiting and frequency of serious adverse events as primary outcomes. We extracted data for patient perception of treatment, other adverse events, somnolence and fatigue, attrition, nausea or vomiting severity, breakthrough nauseaand vomiting, rescue antiemetic use, and nausea and vomiting as secondary outcomes at specified time points.
Main results
We included 14 RCTs (1917 participants) from high‐, middle‐ and low‐income countries, representing over 24 different cancers. Thirteen studies were in chemotherapy‐induced nausea andvomiting. Oral olanzapine was administered during highly emetogenic (HEC) or moderately emetogenic (MEC) chemotherapy (12 studies); chemoradiotherapy (one study); or palliation (one study). Eight studies await classification and 13 are ongoing.
The main comparison was olanzapine versus placebo/no treatment. Other comparisons were olanzapine versus NK1 antagonist, prokinetic, 5‐HT3 antagonist or dexamethasone.
We assessed all but one study as having one or more domains that were at high risk of bias. Eight RCTs with fewer than 50 participants per treatment arm, and 10 RCTs with issues related to blinding, were at high risk of bias. We downgraded GRADE assessments due to imprecision, inconsistency and study limitations.
Olanzapine versus placebo/no treatment
Primary outcomes
Olanzapine probably doubles the likelihood of no nausea or vomitingduring chemotherapy from 25% to 50% (risk ratio (RR) 1.98, 95% confidence interval (CI) 1.59 to 2.47; 561 participants; 3 studies; solid tumours; HEC or MEC therapy; moderate‐quality evidence) when added to standard therapy. Number needed to treat for additional beneficial outcome (NNTB) was 5 (95% CI 3.3 ‐ 6.6).
It is uncertain if olanzapine increases the risk of serious adverse events (absolute risk difference 0.7% more, 95% CI 0.2 to 5.2) (RR 2.46, 95% CI 0.48 to 12.55; 7 studies, 889 participants, low‐quality evidence).
Secondary outcomes
Four studies reported patient perception of treatment. One study (48 participants) reported no difference in patient preference. Fourreported quality of life but data were insufficient for meta‐analysis.
Olanzapine may increase other adverse events (RR 1.71, 95% CI 0.99 to 2.96; 332 participants; 4 studies; low‐quality evidence) and probably increases somnolence and fatigue compared to notreatment or placebo (RR 2.33, 95% CI 1.30 to 4.18; anticipated absolute risk 8.2% more, 95% CI 1.9 to 18.8; 464 participants; 5 studies; moderate‐quality evidence). Olanzapine probably does not affect all‐cause attrition (RR 0.99, 95% CI 0.57 to 1.73; 943 participants; 8 studies; I² = 0%). We are uncertain if olanzapineincreases attrition due to adverse events (RR 3.00, 95% CI 0.13 to 70.16; 422 participants; 6 studies). No participants withdrew due to lack of efficacy.
We are uncertain if olanzapine reduces breakthrough nausea andvomiting (RR 0.38, 95% CI 0.10 to 1.47; 501 participants; 2 studies; I² = 54%) compared to placebo or no treatment. No studies reported 50% reduction in severity of nausea or vomiting, use of rescue antiemetics, or attrition.
We are uncertain of olanzapine‘s efficacy in reducing acute nausea orvomiting. Olanzapine probably reduces delayed nausea (RR 1.71, 95% CI 1.40 to 2.09; 585 participants; 3 studies) and vomiting (RR 1.28, 95% CI 1.14 to 1.42; 702 participants; 5 studies).
Subgroup analysis: 5 mg versus 10 mg
Planned subgroup analyses found that it is unclear if 5 mg is as effective an antiemetic as 10 mg. There is insufficient evidence to exclude the possibility that 5 mg may confer a lower risk ofsomnolence and fatigue than 10 mg.
Other comparisons
One study (20 participants) compared olanzapine versus NK1 antagonists. We observed no difference in any reported outcomes.
One study (112 participants) compared olanzapine versus a prokinetic (metoclopramide), reporting that olanzapine may increase freedom from overall nausea (RR 2.95, 95% CI 1.73 to 5.02) and overall vomiting (RR 3.03, 95% CI 1.78 to 5.14).
One study (62 participants) examined olanzapine versus 5‐HT3 antagonists, reporting olanzapine may increase the likelihood of50% or greater reduction in nausea or vomiting at 48 hours (RR 1.82, 95% CI 1.11 to 2.97) and 24 hours (RR 1.36, 95% CI 0.80 to 2.34).
One study (229 participants) compared olanzapine versus dexamethasone, reporting that olanzapine may reduce overallnausea (RR 1.73, 95% CI 1.37 to 2.18), overall vomiting (RR 1.27, 95% CI 1.10 to 1.48), delayed nausea (RR 1.66, 95% CI 1.33 to 2.08) and delayed vomiting (RR 1.25, 95% CI 1.07 to 1.45).
Authors’ conclusions
There is moderate‐quality evidence that oral olanzapine probably increases the likelihood of not being nauseous or vomiting during chemotherapy from 25% to 50% in adults with solid tumours, inaddition to standard therapy, compared to placebo or no treatment. There is uncertainty whether it increases serious adverse events. It may increase the likelihood of other adverse events, probably increasing somnolence and fatigue. There is uncertainty about relative benefits and harms of 5 mg versus 10 mg.
We identified only RCTs describing oral administration. The findingsof this review cannot be extrapolated to provide evidence about theefficacy and safety of any injectable form (intravenous, intramuscular or subcutaneous) of olanzapine.
Plain language summary
Olanzapine for the prevention and treatment of cancer‐relatednausea and vomiting in adults
Background
Olanzapine has been studied to see if it might work as an antisickness (antiemetic) medication and if it is safe. People withcancer may commonly experience distressing nausea and vomiting, despite the current medications available, before, during, and after chemotherapy or radiotherapy, and during a palliative phase ofillness (when the aim of treatment is symptom relief rather than cure). Some people still experience problematic nausea andvomiting with chemotherapy even when they are given standard antisickness medication.
Recently research studies have focused on preventing and treating chemotherapy‐induced nausea and vomiting.
Review question
We investigated the benefits and harms of using olanzapine forpreventing and treating nausea and vomiting in adults with cancer.
Search date
We searched for studies in September 2017.
Study characteristics
We included 14 randomised controlled trials (RCTs) because they provide the most reliable evidence, with 1917 participants in total, from all around the world that investigated the use of oralolanzapine in treating or preventing nausea and vomiting.
All the included studies used olanzapine in combination with other medications, usually antiemetics (antisickness medications). Nine studies compared olanzapine to placebo (a substance with no therapeutic effect) or no treatment. Other studies comparedolanzapine to other antiemetics.
Were participants receiving anticancer treatments?
Thirteen RCTs included participants receiving chemotherapy. Chemotherapy is graded according to how likely it is to provokenausea and vomiting (i.e. how emetogenic it is). In six RCTs participants received highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). In six RCTs participants only received HEC. One RCT did not state whether participants received HEC or MEC.
No RCTs included participants receiving radiotherapy alone. One trial included participants who were receiving both chemotherapy and radiotherapy treatment for their cancer. One trial included participants who were not receiving either chemotherapy or radiotherapy.
Study funding sources
No included RCTs reported receiving funds from pharmaceutical companies. Five studies stated that they had received funding fromcancer foundations, endowments, or universities. Nine studies made no declaration regarding funding.
Key results
Fifty percent of people who received olanzapine as well as standardtreatment probably would not be nauseous or vomit during chemotherapy compared to just 25% of those who received standardtreatment. Olanzapine probably makes unwanted sleepiness more likely. We are uncertain if using 5 mg olanzapine a day instead of 10 mg olanzapine a day reduces the likelihood of being sleepy without reducing the antisickness benefit. We are not certain about the riskof experiencing other side effects or serious side effects, so it is important to be aware that these might happen. There was some suggestion that people who take olanzapine with standardtreatment might have an improved quality of life compared to those who used standard treatment alone, but we were very uncertain ofthis because we were unable to analyse the data. There was not enough evidence to say whether people prefer to use olanzapinecompared to not taking it.
There is not enough evidence to say whether olanzapine is as good as, worse or better than other antisickness medications currently inuse.
Quality of the evidence
We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. ‘Very low‐quality evidence’ means that we are very uncertain about the results. ‘High‐quality evidence’ means that we are very confident in the results. We found moderate‐quality evidence that olanzapine reduces overall nausea andvomiting but that it also increases unwanted sleepiness when compared to placebo or no treatment. There was moderate‐quality evidence for patient preference and low‐quality evidence for adverse events. The remaining evidence was of low‐ or very‐low quality.
Implications of the review
Olanzapine is probably an effective antisickness medication. We are unsure which dose is best to use, 5 mg or 10 mg, or if 2.5 mg might work just as well. However, this review only found information about giving olanzapine by mouth and did not find any about injecting it. More research is needed to inform practice.
