Olanzapine for the prevention and treatment of cancer‐related nausea and vomiting in adults New

Abstract

Abstract 

Background 

Olanzapine as an antiemetic represents a new use of an antipsychotic drug. People with cancer may experience nausea and vomiting whilst receiving chemotherapy or radiotherapy, or whilst in the 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 vomiting related 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2017, as well as ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform for unpublished trials. We checked reference lists, and contacted experts in the field and study authors.

Selection criteria 

We included randomised controlled trials (RCTs) of olanzapine versus any comparator with or without adjunct therapies for the prevention 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 for absence 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 nausea and 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 and vomiting. 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 vomiting during 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. Four reported 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 no treatment 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 olanzapine increases 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 and vomiting (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 or vomiting. 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 of somnolence 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 of 50% 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 overall nausea (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, in addition 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 findings of this review cannot be extrapolated to provide evidence about the efficacy and safety of any injectable form (intravenous, intramuscular or subcutaneous) of olanzapine.

Author(s)

Anna Sutherland, Katrien Naessens, Emma Plugge, Lynda Ware, Karen Head, Martin J Burton, Bee Wee

Abstract

Plain language summary 

Olanzapine for the prevention and treatment of cancer‐related nausea 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 with cancer may commonly experience distressing nausea and vomiting, despite the current medications available, before, during, and after chemotherapy or radiotherapy, and during a palliative phase of illness (when the aim of treatment is symptom relief rather than cure). Some people still experience problematic nausea and vomiting 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 for preventing 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 oral olanzapine 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 compared olanzapine to other antiemetics.

Were participants receiving anticancer treatments? 

Thirteen RCTs included participants receiving chemotherapy. Chemotherapy is graded according to how likely it is to provoke nausea 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 from cancer foundations, endowments, or universities. Nine studies made no declaration regarding funding.

Key results 

Fifty percent of people who received olanzapine as well as standard treatment probably would not be nauseous or vomit during chemotherapy compared to just 25% of those who received standard treatment. 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 risk of 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 standard treatment might have an improved quality of life compared to those who used standard treatment alone, but we were very uncertain of this because we were unable to analyse the data. There was not enough evidence to say whether people prefer to use olanzapine compared 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 in use.

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 and vomiting 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.

Author(s)

Anna Sutherland, Katrien Naessens, Emma Plugge, Lynda Ware, Karen Head, Martin J Burton, Bee Wee

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For adults with cancer‐related nausea and vomiting 

Olanzapine probably reduces the number of people with cancer who experience chemotherapy‐induced nausea and vomiting (CINV), when given by mouth in addition to a standard antisickness treatment, compared to the standard antisickness treatment alone. Olanzapine probably almost doubles the likelihood that there will be no nausea or vomiting during a course of chemotherapy. The evidence we reviewed found that with standard antisickness treatment about 75% of participants experienced some nausea and may have vomited during chemotherapy. When olanzapine was added to standard antisickness treatment this fell to 50%.

Unfortunately, olanzapine probably increases somnolence. This may be more likely with 10 mg a day than 5 mg. The risk of other adverse events may be increased by olanzapine when used with other antisickness treatment compared to using the antisickness treatment alone.

Olanzapine is unlicensed for this indication.

For clinicians 

Oral olanzapine is probably an effective antiemetic when used with a standard antiemetic regimen compared to the standard antiemetic regiment alone in the treatment of people experiencing CINV with solid tumours. Whilst 5 mg may have a similar antiemetic effect to 10 mg, we did not include studies directly comparing doses in this review. There is a lack of randomised controlled trial (RCT), evidence to support the use of 2.5 mg olanzapine as an antiemetic or to support the use of olanzapine administration by any route other than oral. There may be an increase in adverse events with olanzapine, and somnolence is probably more likely and may limit its clinical use, although 5 mg may cause less somnolence than 10 mg. We are less certain about the risk of serious adverse events, particularly hyperglycaemia, agranulocytosis, QTc prolongation and extra‐pyramidal adverse events.

There is limited information regarding the efficacy and safety of olanzapine compared to other antiemetics.

Safety concerns have been raised in the literature that intravenous olanzapine may lead to serious respiratory depression. Cardiovascular and respiratory depression have also been noted when it is administered intramuscularly. The results of this review therefore cannot be extrapolated to support the use of olanzapine via the intravenous, intramuscular or subcutaneous route.

Olanzapine is currently listed as an antipsychotic, however, it is not licensed for the prevention or treatment of nausea and vomiting in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA), or in the USA by the Food and Drug Administration (FDA). Its use as an antiemetic is therefore currently an off‐licence use in the UK and USA.

For policy makers 

Oral olanzapine is probably an effective antiemetic when added to standard treatment regimens for adults with CINV. Olanzapine is a low‐cost, once‐daily antiemetic that is available as an oral dispersible wafer, with infrequent adverse events. Olanzapine is currently listed as an antipsychotic, however, it is not licensed for the prevention or treatment of nausea and vomiting in the UK by the MHRA, or in the USA by the FDA. Its use as an antiemetic is therefore currently an off‐licence use in the UK and USA.

Additionally, there remains limited evidence for use of olanzapine instead of other antiemetics. In particular there is insufficient evidence to support its use in preference to NK1 antagonists for the treatment of chemotherapy related nausea and vomiting.

For funders 

There is moderate‐quality evidence that oral olanzapine is an effective antiemetic in CINV. Further research is urgently needed to assess the optimal dose regimen. Additionally, further research is needed to assess the relative efficacies of olanzapine and NK1 antagonists, as olanzapine may be a more cost‐effective option. Studies are also needed to look at which settings it is most effective in, particularly in patients receiving radiotherapy or no active anticancer treatment, to address the current paucity of evidence in these groups.

Future trials should be adequately powered to detect a difference and should have an explicit method for reporting adverse effects, including serious adverse events and somnolence.

Implications for research 

General implications 

Large, high‐quality RCTs, with patient‐centred outcomes are needed in order to establish the optimal effective dose regimen of olanzapine that achieves the greatest antiemetic effect with the least incidence of adverse events, particularly somnolence. We await the outcomes of the 13 ongoing studies, and the 8 studies awaiting classification, with interest.

One published abstract (Hashimoto 2016), one unpublished study (Yanai 2015), and two ongoing studies (Mukhopadhyay 2017a; Nagashima et al 2015), address 10 mg olanzapine compared to 5 mg. The review authors are not aware of any studies exploring the efficacy of 2.5 mg olanzapine as an antiemetic.

Design 

In future RCTs, investigators should ensure that the dosing regimen of the standard therapy is the same in both arms so that any observed effect is attributable to the intervention of interest, olanzapine, rather than its combined effect with the variation in the standard therapy administered. In particular, the dose of dexamethasone, which is known to be an effect modifier, should be the same in the intervention and comparator arms. However, it is also important that the regimen of NK1 antagonist or 5‐HT3 antagonist are identical in each comparison arm.

RCTs with a longer intervention and follow‐up period are needed to establish olanzapine's efficacy and safety when used for more than five days.

The parenteral administration of olanzapine is yet to be studied in an RCT. This is of clinical importance as inherent in vomiting is the risk of failure to ingest and absorb it when the oral route is used, although counterbalanced by the known serious respiratory and cardiovascular adverse events associated with the intravenous and intramuscular routes.

Further research is needed to establish its non‐inferiority or otherwise when compared to other antiemetics currently used, including NK1 antagonists, 5‐HT3 antagonists, prokinetics, steroids, and when compared directly to current standard care. We await the full published results of Nguyen 2017, an RCT comparing olanzapine and omeprazole directly to standard care and omeprazole without any other standard therapy. The published abstract states that olanzapine 10 mg oral and omeprazole 20 mg, once daily for three days is "simple, cheap cost, safe, and effective in preventing vomiting, reducing nausea, and preserving QoL [quality of life)" when compared to dexamethasone 4 mg twice daily, omeprazole 20 mg twice daily and metoclopramide 20 mg three times daily, all for five days.

Measurement 

We encourage investigators to use the 'hard' outcome of 'no nausea, no vomiting' rather than the surrogate outcome 'no vomiting, no breakthrough medication' when reporting primary outcomes. When reporting serious adverse events it is important that the nature of these are fully defined. Additionally, if consensus were reached in the future to enable one quality‐of‐life measure to be universally adopted this would allow comparison of data across studies more easily, and therefore aid the applicability of this data in the clinical setting.

Other 

Studies are urgently needed to explore impact of the different anticancer treatment on the efficacy and safety of olanzapine during different phases of illness, particularly in radiotherapy, chemoradiotherapy or no active cancer treatment. We are aware of two ongoing studies (JPRN‐UMIN000010317 and NCT03137121), addressing the use of olanzapine in participants with advanced cancer who are not receiving any active anticancer therapy. In JPRN‐UMIN000010317 participants have malignant bowel obstruction.

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