Abstract
Introduction
Nausea and vomiting occur in 40%–70% of people with cancer, and are also common in other chronic conditions such as hepatitis C and inflammatory bowel disease. Nausea and vomiting become more common as disease progresses.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for nausea and vomiting occurring as a result of either the disease or its treatment in adults with cancer? What are the effects of treatments for nausea and vomiting occurring as a result of either the disease or its treatment in adults with chronic diseases other than cancer? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found nine systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: 5HT3 antagonists, antihistamines, antimuscarinics, atypical antipsychotics, benzodiazepines, butyrophenones, cannabinoids, corticosteroids, haloperidol, metoclopramide, NK1 antagonists, phenothiazines, prokinetics, 5HT3 antagonists plus corticosteroids, and venting gastrostomy.
Key Points
Nausea and vomiting occur in 40%–70% of people with cancer, and are also common in other chronic conditions such as hepatitis C and inflammatory bowel disease. Nausea and vomiting become more common as disease progresses.
Nausea and vomiting may occur as a result of the disease or its treatment.
The evidence base for treatment-related causes of nausea and vomiting (chemotherapy and radiotherapy) is much greater and more robust than for disease-related causes.
Metoclopramide is likely to be effective for reducing episodes of vomiting in people having chemotherapy.
Dexamethasone, in combination with other antiemetics, reduces acute and delayed emesis compared with placebo in people receiving emetogenic chemotherapy, and it may be more effective than metoclopramide in this population.
5HT3 antagonists also reduce acute vomiting in people having chemotherapy compared with metoclopramide-based regimens, and this benefit is enhanced by the addition of dexamethasone.
There is consensus that haloperidol, phenothiazines, and venting gastrostomy are effective for controlling nausea and vomiting in people with cancer.
Cannabinoids are effective for nausea and vomiting in people receiving chemotherapy, but may be associated with a high and often unacceptable burden of adverse effects.
We don't know whether antihistamines, antimuscarinics, antipsychotics, benzodiazepines, or NK1 antagonists are effective in people with cancer-related nausea and vomiting.
We don't know whether 5HT3 antagonists alone reduce nausea and vomiting in people having radiotherapy. However, adding dexamethasone to 5HT3 antagonists seems more effective than 5HT3 antagonists alone.
Despite the lack of robust RCT evidence, there is a consensus based on clinical experience that antihistamines have a place in the management of nausea and vomiting, especially that related to motion sickness, mechanical bowel obstruction, and raised intracranial pressure.
We don't know whether any other interventions are effective for controlling nausea and vomiting in people with chronic conditions other than cancer.
Clinical context
About this condition
Definition
Nausea and vomiting (emesis) are common in people with cancer and other chronic diseases. They may occur because of several factors, most easily categorised as disease-related and treatment-related. The evidence base for treatment-related causes of nausea and vomiting (chemotherapy and radiotherapy) is much greater and more robust than for disease-related causes. This review focuses on the management of nausea and vomiting in people with cancer or other chronic conditions, and does not include people with postoperative nausea and vomiting. For the purposes of this review, we have used the NICE definition of supportive care as follows: supportive care "helps the patient and their family to cope with cancer and treatment of it — from pre-diagnosis, through the process of diagnosis and treatment, to cure, continuing illness or death and into bereavement. It helps the patient to maximise the benefits of treatment and to live as well as possible with the effects of the disease. It is given equal priority alongside diagnosis and treatment." This definition was written in relation to people with cancer but is applicable to all people with chronic or terminal illness: for example, heart failure or lung disease. We have used the WHO definition of palliative care as follows: "Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual." Although this definition of palliative care does not specify incurable or terminal illness, there is consensus that palliative care applies to people approaching the end of life: that is, people with a prognosis of less than 1 year. Thus, both supportive and palliative care embrace the same priorities of maximising quality of life; but supportive care aims to do this in people who may live longer, become cured, or who are living in remission from their disease.
Incidence/ Prevalence
Nausea and vomiting occur in 40%–70% of people with cancer and are also common in other chronic conditions such as hepatitis C and inflammatory bowel disease. Nausea and vomiting become more common as disease progresses.
Aetiology/ Risk factors
Nausea and vomiting are complex neurological and physical phenomena involving a range of areas of the central nervous system and gastrointestinal tract. In palliative and supportive care, nausea may be due to chemotherapy, especially platinum-based chemotherapy, other drugs (opiates, antibiotics), or radiotherapy. It may also have disease-related causes: for example, metabolic (hypercalcaemia, uraemia), cranial (raised intracranial pressure, VIIIth nerve tumours), gastrointestinal (gastric outflow obstruction, hepatomegaly constipation, bowel obstruction, or ileus), or psychogenic (anticipatory nausea and vomiting, anxiety, or fear).
Prognosis
In many cases, nausea will respond to treatment of the underlying cause: for example, nausea resulting from metabolic disturbance such as hypercalcaemia. Nausea resulting from emetogenic drugs such as opioids may resolve if the opioid is switched.
Aims of intervention
To reduce nausea and vomiting and improve quality of life, with minimal adverse effects of treatment.
Outcomes
Vomiting: number of episodes of nausea, retching, or vomiting, vomitus volume; ability to remove nasogastric tube; quality of life; adverse effects of treatment.
Methods
Clinical Evidence search and appraisal April 2008. The following databases were used to identify studies for this systematic review: Medline 1986 to April 2008, Embase 1986 to April 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2008, Issue 1. An additional search was carried out of the NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single-blinded, and containing more than 20 individuals of whom more than 80% were followed up. We also searched for comparative cohort studies — both prospective and retrospective. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. We have searched for treatments for nausea and vomiting in people with advanced cancer or other chronic conditions being treated in the palliative-care setting and have included all RCTs of sufficient quality. We only evaluated interventions currently in common use (excluding, for example, triethylperazine and cisapride). To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Nausea and vomiting in people with cancer and other chronic diseases.
| Important outcomes | Ability to remove nasogastric tube, Adverse effects, Quality of life, Vomiting | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments for nausea and vomiting occurring as a result of either the disease or its treatment in adults with cancer? | |||||||||
| 41 (7891) | Vomiting | Dexamethasone versus placebo or no treatment in people receiving chemotherapy | 4 | 0 | 0 | –1 | +1 | High | Effect-size point added for OR >2. Directness point deducted for inclusion of other antiemetics |
| 3 (189) | Vomiting | Dexamethasone versus metoclopramide in people receiving chemotherapy | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for sparse data. Consistency point deducted for heterogeneity between RCTs. Directness point deducted for inclusion of 5HT3 antagonist in one study |
| 1 (51) | Vomiting | Dexamethasone plus metoclopromide versus metoclopramide alone in people with nausea owing to disease, chemotherapy, or radiotherapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (51) | Quality of life | Dexamethasone plus metoclopromide versus metoclopramide alone in people with nausea owing to disease, chemotherapy, or radiotherapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 11 (2119) | Vomiting | Dexamethasone plus 5HT3 antagonists versus 5HT3 antagonists alone in people receiving chemotherapy | 4 | 0 | 0 | 0 | 1 | High | Effect-size point added for OR of 0.42 |
| 15 (2634) | Vomiting | 5HT3 antagonists versus metoclopramide-based regimens in people receiving chemotherapy | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (41) | Vomiting | Metoclopramide versus placebo or versus prochlorperazine (a phenothiazine) in people receiving chemotherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for unusually high dose of metoclopramide used in the RCT |
| 4 (231) | Vomiting | Cannabinoids versus placebo in people receiving chemotherapy | 4 | 0 | 0 | 0 | 0 | High | |
| at least 19 (at least 2012) | Adverse effects | Cannabinoids versus placebo in people receiving chemotherapy | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of both placebo and antiemetics in control group in analysis |
| 7 (422) | Vomiting | Cannabinoids versus other antiemetics in people receiving chemotherapy | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for range of antiemetics included in the comparison |
| 1 (53) | Vomiting | Lorazepam versus placebo in people receiving chemotherapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (989) | Vomiting | Aprepitant versus placebo in people receiving a standard antiemetic regimen for chemotherapy-related nausea | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for narrowness of population in RCT |
| 1 (105) | Vomiting | 5HT3 antagonists versus metoclopramide in people receiving radiotherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (191) | Vomiting | Adding corticosteroids versus adding placebo in people receiving 5HT3 antagonists | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Karnofsky score
Is a measure of performance status based on physical ability (scale 0–100). 100: normal, no complaints or evidence of disease; 90: able to perform normal activity, minor signs and symptoms of disease; 80: able to perform normal activity with effort, some signs and symptoms of disease; 70: cares for self, unable to perform normal activity or to do active work; 60: requires occasional assistance but is able to care for most of own needs; 50: requires considerable assistance and frequent medical care; 40: requires special care and assistance, disabled; 30: hospital admission indicated, although death not imminent, severely disabled; 20: hospital admission necessary, active supportive treatment required, very sick; 10: fatal processes progressing rapidly, moribund; 0: death.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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