Journal of Pain and Symptom Management
Volume 39, Issue 4 , Pages 756-767, April 2010

A Systematic Review of the Treatment of Nausea and/or Vomiting in Cancer Unrelated to Chemotherapy or Radiation

This article was presented at the Ohio Hospice and Palliative Care Organization Conference, November 5, 2008, Columbus, OH, USA, and the Toronto Pain and Symptom Management Conference, November 22, 2008, Toronto, Ontario, Canada.

  • Mellar P. Davis, MD, FCCP

      Affiliations

    • The Harry R. Horvitz Center for Palliative Medicine, Division of Solid Tumor, The Taussig Cancer Center, The Cleveland Clinic, Cleveland, Ohio, USA
    • Palliative Medicine & Supportive Oncology Services, Division of Solid Tumor, The Taussig Cancer Center, The Cleveland Clinic, Cleveland, Ohio, USA
    • Corresponding Author InformationAddress correspondence to: Mellar P. Davis, MD, FCCP, Division of Solid Tumor, The Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Center, The Cleveland Clinic, 9500 Euclid Avenue, R35, Cleveland, OH 44195, USA.
    • ,
  • Gretchen Hallerberg, MS, MSLS, AHIP

      Affiliations

    • Library, The Cleveland Clinic, Cleveland, Ohio, USA
    • ,
  • Palliative Medicine Study Group of the Multinational Association of Supportive Care in Cancer

Accepted 4 August 2009.

Article Outline

Abstract 

Context

A systematic review of antiemetics for emesis in cancer unrelated to chemotherapy and radiation is an important step in establishing treatment recommendations and guiding future research. Therefore, a systematic review based on the question “What is the evidence that supports antiemetic choices in advanced cancer?” guided this review.

Objectives

To determine the level of evidence for antiemtrics in the management of nausea and vomiting in advanced cancer unrelated to chemotherapy and radiation, and to discover gaps in the evidence, which would provide important areas for future research.

Methods

Three databases and independent searches using different MeSH terms were performed. Related links were searched and hand searches of related articles were made. Eligible studies included randomized controlled trials (RCTs), prospective single-drug studies, studies that used guidelines based on the etiology of emesis, cohort studies, retrospective studies, and case series or single-patient reports. Studies that involved treatment of chemotherapy, radiation, or postoperation-related emesis were excluded. Studies that involved the treatment of emesis related to bowel obstruction were included. The strength of evidence was graded as follows: 1) RCTs, A; 2) single-drug prospective studies, B1; 3) studies based on multiple drug choices for etiology of emesis, B2; and 4) cohort, case series, retrospective, and single-patient reports, E. Level of evidence was determined by the Oxford Centre for Evidence-Based Medicine Levels of Evidence (May 2001) (A, B, C, D).

Results

Ninety-three articles were found. Fourteen were RCTs, most of them of low quality, based either on lack of blinding, lack of description of the method of randomization, concealment, and/or attrition. Metoclopramide had modest evidence (B) based on RCTs and prospective cohort studies. Octreotide, dexamethasone, and hyoscine butylbromide are effective in reducing symptoms of bowel obstruction, based on prospective studies and/or one RCT. There was no evidence that either multiple antiemetics or antiemetic choices based on the etiology of emesis were any better than a single antiemetic. There is poor evidence for dose response, intraclass or interclass drug switch, or antiemetic combinations in those individuals failing to respond to the initial antiemetic.

Conclusion

There are discrepancies between antiemetic studies and published antiemetic guidelines, which are largely based on expert opinion. Antiemetic recommendations have moderate to weak evidence at best. Prospective randomized trials of single antiemetics are needed to properly establish evidence-based guidelines.

Key Words: Nausea, vomiting, systematic review, antiemetic

 

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Introduction 

Evidence from published literature should be integrated into a clinical decision guideline. Such evidence requires adequately designed and completed randomized controlled trials (RCTs). A systematic review using predetermined criteria for selecting, appraising, interpreting, and summarizing data from original studies can clarify the existing evidence base.1, 2 If more than one RCT of acceptable quality and similar design are available, a quantitative meta-analysis may be performed, which then would additionally support the development of treatment guidelines. If RCTs are not available or are of poor quality, other types of studies, including prospective or retrospective observational studies, cohort studies, and single-case reports, must be used to inform treatment decisions.3, 4

Narrative reviews are subject to systematic and random error. Systematic reviews are preferable because of their rigorous approach to evidence review. This includes 1) an established preplanned search design; 2) a comprehensive search of all potentially available articles; 3) reproducible criteria for the selection of articles, so that others may repeat the review and come to the same number of studies; 4) a grading system of study quality; and 5) a synthesis of the results.3

Treatment guidelines based on high-quality RCTs are well established for chemotherapy-related nausea and vomiting.5 The treatment of nausea and vomiting unrelated to chemotherapy or radiation has previously undergone a systematic review, which included 21 studies, the great majority of which were not RCTs.6 Three studies using multiple antiemetics based on the clinically determined mechanism of emesis (etiology-based antiemetic trials or EBAT) have been published.7, 8, 9 In addition, multiple narrative reviews that have attempted to collate studies have been published. We performed a systematic review of treatment trials and narrative or systematic reviews that summarized studies of antiemetics in advanced cancer. The objective of this systematic review was to determine the level of evidence for antiemetics in the management of nausea and vomiting in advanced cancer unrelated to chemotherapy and radiation. The second objective was to discover gaps in the evidence, which would provide important areas for future treatment trials.

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Materials and Methods 

Studies that met the inclusion criteria were those that 1) involved individuals with active cancer; 2) included adults (age ≥18 years); 3) evaluated a treatment for nausea and vomiting clinically determined to be related to the cancer or as a complication from the cancer; and 4) were characterized as RCTs, prospective trials, treatment based on the etiology of nausea and vomiting (EBAT), cohort studies, case series, and single-case reports. Studies that incorporated both cancer patients and individuals without cancer or individuals treated for nausea because of cancer and chemotherapy-induced emesis were included. Most of these were earlier treatment trials. Antiemetic trials for the management of chemotherapy-, radiation-, or postoperation-related nausea and vomiting were excluded. The systematic review was limited to studies published in English or for which English abstracts were available. The period of review was from 1950 to 2008.

The evidence was graded based on the determinants of quality of evidence published by the American Thoracic Society —A: evidence from RCT; B1: evidence from single-drug prospective studies or in which single-drug activity could be determined; B2: evidence from prospective etiologic guideline trials or multiple drug combination studies in which single-drug activity could not be determined; C: evidence from cohort studies, retrospective studies, case series, or single-case reports. The grade of recommendation is based on the Oxford Centre for Evidence-Based Medicine Levels of Evidence (May 21)—A: evidence from a systematic review of RCT or a well-designed and executed RCT; B: evidence from a systematic review of well-designed and executed cohort studies or from a well-designed and executed cohort, case-control study, or low-quality RCT; C: evidence from case series or poor-quality cohort or case-control study; D: expert opinion. The quality of RCTs was determined by the criteria published by Jadad et al.10 Reviews were included if systematic or narrative reviews contained summaries of treatment trials. These were mostly used for hand searches of references. Most narrative reviews pre-dated the development of systematic reviews. Reviews that provided treatment guidelines only and pharmacological reviews of antiemetics were excluded.

The systematic-review protocol included the following elements:

1.An initial computerized search by a physician of the National Library of Medicine Medline database using the PubMed Entrez interface was selected for the initial search. Medical subject heading (MeSH) search terms were “nausea and vomiting and cancer or neoplasm or malignancy and treatment or medications.” An extensive related links and hand search for references was performed. This yielded 58 relevant studies or reviews.

2.A second systematic review by a physician was done using Ovid Med. The search terms were “cancer or neoplasm or malignancy and nausea or vomiting and treatment or drugs or medications.” This search yielded 2,276 abstracts and eight additional studies or reviews not found in the initial PubMed review.

3.A third systematic review by a physician used the Evidence-Based Medicine reviews: Cochrane Central Register of Controlled Trials and MeSH terms “nausea, emesis or vomiting and cancer or neoplasm or malignancy and treatment or drugs or medications.” This search yielded 1,834 abstracts. Related links from articles and hand searches were done through studies found in this review. Two reviews and one trial were found in the search. Three additional studies were obtained from hand searches of articles, and six additional articles were obtained from two reviews found through the hand search.

4.An independent PubMed review was done by G.H. using the terms “any anti-emetics or any nausea/drug therapy or any vomiting/drug therapy and advanced neoplasm or advanced cancer.” This yielded 150 abstracts and 27 studies, of which two were not previously found (a case series and narrative review) in the first three searches.

5.A second independent PubMed search by G.H. used “any anti-emetics or any nausea/drug therapy or any vomiting/drug therapy and any intestinal obstruction or peritoneal implants or anxiety or any anxiety disorder or any CNS disorders or any CNS neoplasm/secondary or any opioid analgesic/adverse effects, toxicity, poisoning and any neoplasm.” This review yielded 164 citations, five narrative reviews, and three new case series. Related links and hand searches yielded five additional studies.

6.A review using the ProQuest database for dissertations/theses was performed. This was done because these were mentor reviewed and, hence, would be considered high-quality citations. No relevant citations were found in 82 references.

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Results 

Ninety-three articles were found that met the inclusion criteria (Table 1). Only 14 were RCTs and six were not blinded; the randomized procedure was not explicitly published in most, and the method of concealment was not outlined11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 (Table 2). Attrition rate was not provided in the largest studies and was about 20% in trials for which there was information. The longest duration for any study was 15 days. Because the placebo response for nausea is not established, the confidence interval for the minimally important change on nausea cannot be established by the present studies. Most of the RCTs would be Level II evidence according to the American College of Chest Physicians Anti-thrombotic Consensus Conference Guidelines and Level 2b evidence according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence.25, 26 Trial designs varied, five studies involved bowel obstructions, and one was limited to patients experiencing nausea and vomiting because of morphine. Three studies were carried out by a single group, which involved a similar design and drugs and which may not have been separate studies but staged reports of one or two RCTs. These three studies20, 21, 22 had the greatest number of participants, but they were not blinded, and the methods of randomization and attrition were not described (Table 2). Responses were measured as reductions in the severity of nausea and vomiting episodes or reduction in the duration of nausea.

Table 1. Grade and Number of Studies (n=93)
Study Graden (%)
A14 (16)
B113 (14)
B26 (6)
C46 (49)
Reviews14 (15)
Table 2. Summary of Randomized Controlled Trials
StudyDrugsPT Pop.#Crossover; BlindedMethod of Randomization; ConcealmentToolsOutcomesDurationAttrition Reasonsa—Jadad
1. Bruera et al. (1994)14CR vs. IRAdvanced cancer34+; +−; −VAS-nauseaMet SR>IR—VAS3 days5/34+3
CAT-nauseaMet SR=IR—CAT
CaloriesMet SR=IR—calories
2. Bruera et al. (2000)12CR vs. placeboAdvanced cancer26+; +−; −VAS-nauseaSR>placebo—VAS (17±12mm vs. 12±10mm)5 days13/26+3
Dyspepsia
3. Bruera et al. (2004)13±Advanced cancer51−; + (parallel)−; −NRS+CAT
# vomiting: 24/hour		Met=met+dex8 days8/51+3
4. Corli et al. (1995)15vs. levosulpirideAdvanced cancer30+; +−; −Presence/absence, duration, intensity, vomiting—presence, frequency, overall nausea index
CAT intensity
Levosulpiride>met14 days1/29−3
5. Hardy et al. (2002)17vs. ondansetron vs. placeboAdvanced cancer; on morphine+nausea94−; + (parallel)+; −Complete control of emesis/nausea, antiemetic rescuePlacebo=ondansetron (prematurely stopped because of difficulty with recruitment)24 hours17/94+2
6. Brown et al. (1992)11Acupressure braceletHospice patients6+; −−; −Number of episodes of emesis; duration and severity of nauseaPlacebo band=acupressure band4 days3/6+2
7. Mystakidou et al. (1997)22
Trop

Met

Chl

Dex

Advanced cancer, on opioids120−; −−; −Duration of nausea, episodes of vomitingMet+trop=met+trop+dex>>met+dex15 daysNA/120−1
8. Mystakidou et al. (1998)21
Trop

Met

Chl

Dex

Advanced cancer with emesis on standard antiemetics280−; −−; −Duration of nausea/day
Emesis episodes/day
Trop=trop+met=trop+met+dex=trop+chl+trop+chl+dex>>met+dex=met+chl15 daysNA/280−1
9. Mystakidou et al. (1998)21
Trop

Chl

Dex

Advanced cancer with emesis after control with160−; −−; −Duration of nausea
Episodes of vomiting		Trop=trop+chl=trop+chl+dex>>chl+dex15 daysNA/160−1
10. Laval et al. (2000)18Methylprednisone+antiemeticsAdvanced cancer with bowel obstruction52−; ++; −“Symptom improvement”NG suction+steroids=NG suction
No NGT+steroids>
No NGT		4 days8/52+3
11. Hardy et al. (1998)16
Ond

Met

Advanced cancer with bowel obstruction25+; +−; -Response=
Flatus, Light diet
No vomiting		Placebo=
(8/14)=(13/21) (study stopped—poor accrual)		10 days2/25+3
12. Mercadante et al. (2000)19Octreotide vs. hyoscine butylbromideAdvanced cancer with bowel obstruction18−; −−; −Episodes of emesis
Nausea by CAT		Octreotide>hyoscine butylbromide3 days3/18+2
13. Ripamonti et al. (2000)24Octreotide, hyoscine butylbromideAdvanced cancer with bowel obstruction17−; −−; −CAT-nauseaOctreotide>hyoscine butylbromide in a subset treated at home (10)3 days
0/17

0

1
14. Mystakidou et al. (2002)23Octreotide, hyoscine butylbromide, chlorpromazineAdvanced cancer with bowel obstruction68−; −−; −Diary of nausea/vomiting by CAT-nausea in duration×intensity by CATOctreotide>hyoscine butylbromide6 daysNA/68−2

trop=tropisetron; met=metoclopramide; chl=chlorpromazine; dex=dexamethasone; ond=ondansetron; VAS=visual analog scale; PT pop.=patient population; CAT=categorical scale; NRS=numerical rating scale; #=number of individuals in the study; vs=versus or compared to; CR=continuous release; IR=immediate release; SR=sustained release; NA=not assessed; NGT=nasogastric tube; NG=nasogastric.

Jadad score 1–4 based on randomization, blinding, attrition and reasons for withdrawal, and method of randomization. Researcher concealment from randomization further reduces bias.

aReasons for attrition.

A meta-analysis of the existing data was not possible because of heterogeneous patient populations, different drugs and doses, and varied study designs. Because of the low quality of most of the RCTs, only Level B evidence exists to support any treatment. Guidelines cannot be constructed based on this systematic review of studies, though treatment recommendations may be made, which can be modified once additional RCTs are completed. It is clear that Level Ia and Ib evidence does not exist for any antiemetic, as determined by the Oxford Centre for Evidence-Based Medicine Levels of Evidence.

There were 15 Level B1 studies found. Seven were published in or before 1990.27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 All of the trials involved phenothiazines (chlorpromazine, methotrimeprazine, olanzapine, prochlorperazine, or thiethylperazine) or metoclopramide. Doses of phenothiazines were generally higher in early studies32 than those used in a recent RCT.22, 23 Subjective responses were assessed in most of the studies, though responses were determined by different criteria among the studies. Phenothiazine switches were attempted to reduce emesis and nausea in those individuals not initially responding. Some studies indicated that patients responded in narrative form. Three studies that involved individuals with malignant bowel obstruction found benefits to corticosteroids or octreotide in the management of bowel obstruction.24, 35, 36, 42

A dose-response relationship to antiemetics cannot be obtained from RCT studies and could not be established by prospective studies.20, 21, 22, 29, 32 Results from B1 studies are summarized in Table 3.7, 8, 9, 43, 44

Table 3. Level B1 Evidence
ItemsOutcomes from Studies
1Chlorpromazine is an effective antiemetic32, 55
2Metoclopramide continuously infused or given in high doses is an effective antiemetic29
3Levomepromazine is an effective antiemetic30, 34
4Olanzapine is an effective antiemetic37
5Prochlorperazine is an effective antiemetic31, 33
6Thiethylperazine is an effective antiemetic27
7Octreotide is effective in the management of bowel obstruction35, 36, 40
8Corticosteroids reduce nausea and vomiting in bowel obstruction38

Five studies had Level B2 evidence. Three studies used EBAT. Treatment by EBAT was successful in reducing nausea and vomiting in most of the participants. However, only 100 individuals were treated in these three trials. Two prospective studies found that hyoscine butylbromide, haloperidol, and morphine reduced symptoms of bowel obstruction.43, 44 Results from prospective B2 studies are summarized in Table 4.

Table 4. Level B2 Evidence
ItemsOutcomes from Studies
1Etiology-based treatment guidelines for nausea and vomiting are effective in greater than 50% of treated individuals7, 8, 9
2A combination of an anticholinergic medication, haloperidol, and an opioid relieves symptoms from a bowel obstruction44, 51

Forty-four studies were found with Level C evidence, which accounts for most of the studies.42, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 These studies add some weak evidence for antiemetics to RCT or prospective single-drug trials (chlorpromazine, olanzapine, metoclopramide, octreotide, levomepromazine, and corticosteroids in the case of bowel obstruction) and provide some published experience with other medications (cannabinoids, ondansetron, mirtazapine, perphenazine, propofol, risperidone, or in the case of nausea associated with leptomeningeal carcinomatosis, carbamazepine) or provide weak evidence for combination therapy. One study was a retrospective audit of antiemetic practices in the hospital.49 Two studies used a mixture of antiemetics as initial treatment of emesis, one of which had tolerance only as the outcome.59, 84 Others involved individuals with bowel obstruction.53, 54, 55, 65, 68, 69 Results of Level C studies are listed in Table 5.

Table 5. Level C Evidence
ItemsOutcomes from Studies
1Chlorpromazine is an effective antiemetic46, 55, 60, 64, 71, 72
2Levomepromazine is an effective antiemetic41, 45
3Metoclopramide is an effective antiemetic and responses improve with dose47, 48, 73
4Perphenazine is an effective antiemetic56, 82
5Thiethylperazine is an effective antiemetic86
6Olanzapine is an effective antiemetic40, 57, 78
7Risperidone is an effective antiemetic74
8Mirtazapine is an effective antiemetic58, 75, 81
9Thioperazine is an effective antiemetic85
10Diphenhydramine is an effective antiemetic67
11Ondansetron alone or the combination of ondansetron and haloperidol effectively relieves nausea and vomiting unresponsive to initial treatment50, 76
12Cannabinoids are effective antiemetics62
13Propofol reduces refractory nausea at the end of life61
14Carbamazepine reduces nausea associated with meningeal carcinomatosis80
15Patients frequently require more than one antiemetic combinations83
16A combination of lorazepam, diphenhydramine, metoclopramide, and haloperidol is tolerable84
17A cocktail of antiemetics is effective when used as first-line therapy (metoclopramide, diphenhydramine, dexamethasone)59
18Glycopyrrolate is effective in the management of nausea and vomiting in bowel obstruction51
19The combination of hyoscine butylbromide and octreotide is effective in symptoms unresponsive to standard therapy for bowel obstruction43
20Corticosteroids reduce nausea and vomiting associated with bowel obstruction54, 90
21Sustained-release octreotide is effective in bowel obstruction35, 65
22Chlorpheniramine can be substituted for cyclizine as an antiemetic70
23Chlorprophenpyridamine is an effective antiemetic42
24Octreotide is an effective antiemetic for bowel obstruction36, 69
25Substituting one phenothiazine for another will reduce nausea and vomiting in those not responding to the first antiemetic52, 55
26Antiemetic cocktails control nausea and are tolerable59, 84

There is significant publication bias, because the non-RCTs were uniformly positive, and negative results were reported only in RCTs. Negative studies included 1) ondansetron and metoclopramide for morphine-associated emesis in cancer; 2) P6 acupressure bracelet for cancer-associated nausea and emesis; and 3) the addition of corticosteroids to metoclopramide or chlorpromazine for cancer-associated nausea and emesis.11, 13, 17, 20, 21, 22

Fifteen reviews have been published, in which attempts have been made to summarize published studies.6, 38, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 Most reviews pre-date the development of the systematic review methodology. Reviews consist of single antiemetic trials, studies that involve antiemetics for opioid-induced emesis, and trials of medications for nausea and vomiting associated with bowel obstruction.39, 89, 90, 91, 94, 99 One systematic review involved complementary therapies as symptom management, which included nausea and vomiting.96 These narrative summaries of studies were helpful in finding references that were missed with the MeSH term search.3, 101 This was particularly true for antiemetic studies published before 1960.71, 86 A second set of narrative reviews provided additional references in the management of nausea associated with intestinal obstruction. Only one was a formal systematic review.6 Systematic reviews for the individual antiemetics droperidol and haloperidol are in progress, as is a systematic review for antiemetics for opioid-related emesis.94, 97, 98

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Discussion 

This systematic review confirms many of the findings from a previous systematic review,6 which included 21 studies. RCTs made up only 16% of the studies and were not of high quality. The RCTs had lower response rates than single-arm studies.6 Antiemetic doses in RCTs were lower than those in earlier cohort studies, which may be the reason for differences in response, particularly when comparing prospective trials of chlorpromazine.20, 21, 32, 102 In earlier studies, doses of chlorpromazine were started at 25mg four times daily and were titrated; these studies suggested positive responses in 70% of the individuals treated.32, 46, 70, 95, 96, 101 Doses of chlorpromazine in recent RCTs were much lower (25mg/day).20, 21, 22

There is moderate evidence for the use of metoclopramide as a first-line antiemetic (B) and for octreotide in bowel obstruction (B). There is no evidence for using multiple antiemetics as the initial treatment. Treatment based on EBAT cannot be shown to be better than that using a single emetic at effective doses.6, 7, 8, 9, 32, 48 There is moderate evidence that dexamethasone does not add to the antiemetic efficacy of phenothiazines or metoclopramide (B).13, 20, 21, 22 Ondansetron or metoclopramide does not reduce emesis from opioids (B).17 The addition of antiemetics with complementary approaches (such as adding Serotonin (5HT3) receptor blockers to dopamine (D2) receptor blockers) in those whose emesis is unresponsive to D2 receptor blockers has rationale behind the recommendation but lacks evidence regarding efficacy (C). In addition, switching antiemetics is often done, but there is little evidence to guide this practice.20, 21, 22 The best evidence for an antiemetic drug exists for metoclopramide, based on the number and quality of studies.

This systematic review illustrates the poor evidence available to guide antiemetic therapy. Guidelines are largely expert opinions that influences practice.98, 103 Published guidelines have recommended dexamethasone in combination with metoclopramide, or cyclizine with ondansetron for refractory emesis, with no evidence to support this recommendation and, in fact, evidence to the contrary.103 Haloperidol, droperidol, dronabinol, dexamethasone, and lorazepam have been listed as antiemetics within guidelines, with no single-drug evidence to support this recommendation.99 Antiemetics, such as chlorpromazine, levomepromazine, and tropisetron, are not mentioned in expert opinion guidelines; yet, at least low-quality RCTs or multiple prospective studies have demonstrated responses. Cyclizine and haloperidol have been included as antiemetics in EBAT guidelines; yet, there is no single-drug evidence for such a recommendation.8, 9, 88 Diphenhydramine only has weak evidence as an antiemetic; yet, cyclizine, without even a cohort study, is recommended as the broad-spectrum antihistamine of choice in EBAT guidelines.67 It is, therefore, understandable that clinicians will fail to follow what are considered to be guidelines, because there is such a discrepancy between guidelines for antiemetic choices by experts and evidence based on treatment trials.49

Approaches to manage emesis that fails to respond to the initial antiemetic vary. Choices of antiemetics are largely guided by clinical experience and personal choices. One approach mentioned is to switch drugs within the drug class (phenothiazines) or to a closely-related drug class (atypical antipsychotics).34, 48, 57, 74, 77, 78, 87 A second approach is to titrate the antiemetic to response, because there is a presumed dose-response relationship. A third approach is to switch drug classes.20, 34, 71, 72 The fourth approach is to add antiemetics with complementary receptor-binding activity.50, 59, 83 All of these have a very low level of evidence to guide practice (C).

Cohort studies, retrospective reviews, and single-patient reports may provide some direction for future trials. For instance, anticonvulsants may reduce nausea from meningeal metastases.80 Further studies would be important to be carried out in this area, because nausea from leptomeningeal metastases may be relatively refractory to standard antiemetics. Propofol may be an effective antiemetic at the end of life, when palliative sedation is being considered.61 Mirtazapine may be an effective antiemetic and would serve the dual purpose of an antidepressant and an antiemetic.34 Levomepromazine may be an effective antiemetic in those with advanced carcinoid.

Individuals are presently being treated by prescriber-dependent “N of 1” trials based on drug choices from relatively weak evidence. The results of this will reinforce bias, clinical prejudice, and expert opinion.104 Keeley104 places the ethical imperative on doing well-constructed trials in perspective: “One objection to research is the risk that patients will be subjected to untested or ineffective treatment. “Yet this is precisely the care at the moment in large areas of symptom control where decisions are made on the basis of ‘anecdote-based medicine’ or ‘eminence-based medicine’ … the truth is that autonomy can be little respected at present, as there is little evidence on which patients can make clear clinical choices about the treatment they receive for the control of symptoms.”104

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Summary 

Guidelines cannot be established for antiemetics in advanced cancer with the present available level of evidence. Based on a very limited literature, a first-line therapy would be metoclopramide. A phenothiazine, or a 5HT3 antagonist, could be used based on low-quality RCTs or multiple prospective trials. Second-line treatment may involve a phenothiazine switch, an atypical neuroleptic, an interclass drug switch to a 5HT3 receptor antagonist, dose titration, or the addition of an antiemetic with complementary receptor activity. The evidence supporting these recommendations is quite weak. Future prospective and randomized studies will be needed to confirm recommendations.

Bowel obstruction should be managed with butyrophenones or phenothiazines, an anticholinergic and/or octreotide, though the strength of this recommendation is moderate (B). Dexamethasone improves the nausea and vomiting associated with a bowel obstruction, based on RCTs and confirmed by prospective studies. Neither ondansetron nor metoclopramide improve opioid-induced emesis, based on an RCT.

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 The Harry R. Horvitz Center for Palliative Medicine is a World Health Organization Demonstration Project in Palliative Medicine.

PII: S0885-3924(10)00125-9

doi:10.1016/j.jpainsymman.2009.08.010

Journal of Pain and Symptom Management
Volume 39, Issue 4 , Pages 756-767, April 2010

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