Jco 17/9
ASCO SPECIAL ARTICLERecommendations for the Use of Antiemetics: Evidence-Based,
Clinical Practice Guidelines
By Richard J. Gralla, David Osoba, Mark G. Kris, Peter Kirkbride, Paul J. Hesketh, Lawrence W. Chinnery, Rebecca Clark-Snow, David P. Gill, Susan Groshen, Steven Grunberg, James M. Koeller, Gary R. Morrow, Edith A. Perez, Jeffrey H. Silber, and David G. Pfister for the American Society of Clinical Oncology THE GOAL OF ANTIEMETIC therapy is to prevent Good clinical guidelines include considerations of validity,
nausea and vomiting completely. This goal is achieved reliability, reproducibility, clinical applicability, clinical flex- for many patients receiving chemotherapy or radiation ibility, clarity, multidisciplinary process, review of evidence, therapy, and is based on clinical and basic research that has and documentation.4 steadily improved the control of emesis over the last 20 In formulating recommendations for antiemetic usage, years. As therapy has become more effective, it has also ASCO considered these tenets of guideline development, become safer, with few side effects associated with the most emphasizing the review of data from controlled clinical commonly used regimens. These regimens are convenient trials. The level and grade of evidence can differ; such for patients to receive and for health care professionals to evidence is rated according to the criteria outlined in Table 2.
administer. However, despite improvements, a significant It is important to realize that guidelines cannot always number of patients still experience emesis, and efforts to account for individual variation among patients. They are reduce this side effect of treatment must continue.
not intended to supplant physician judgment with respect to As antiemetic usage has grown, the classes of agents available particular patients or special clinical situations. They cannot for antiemetic treatment, the number of agents, and the indica- be considered to be inclusive of all proper methods of care or tions for antiemetics have all increased as well. The prevention of exclusive of other treatments reasonably directed at obtain- delayed emesis and anticipatory emesis is equal in importance to ing the same results.
the need to prevent acute chemotherapy- and radiation-induced It is also important to note that not all relevant questions emesis. Additionally, managing special and difficult emetic regarding emesis in cancer care have been addressed by problems and selecting the proper antiemetic approach necessi- clinical trials. The antiemetic methods listed in this article tate identification of the patient's emetic risk.
have been shown to be beneficial (or not), but additional Although the neuropharmacologic basis of emesis is still research in the prevention of emesis is strongly encouraged.
incompletely understood, the selection of an appropriate In some instances, specific areas of research need are antiemetic regimen is possible and can have an impact on indicated in this article. As ongoing research is completed, several aspects of clinical care. Goals related to the complete helpful results from these trials will be incorporated into control of emesis, ie, no vomiting, include providing care updates of these guidelines.
that is convenient for the patient, treatment that reduces Accordingly, ASCO considers adherence to these guide-
hospitalization and time in the ambulatory setting, and lines to be voluntary. The ultimate determination regard-
therapy that enhances the patient's quality of life. Addition- ing their application is to be made by the physician in
ally, practitioners need to be mindful of reducing costs of light of each patient's individual circumstances. In addi-
treatment while achieving these goals.1-3 tion, these guidelines describe administration of thera-
The American Society of Clinical Oncology (ASCO) pies in clinical practice; they cannot be assumed to apply
appreciates these issues and their applicability to the manage- to interventions performed in the context of clinical
ment of patients with cancer. Accordingly, ASCO convened trials, given that such clinical studies are designed to test
an Expert Panel under the auspices of its Health Services innovative and novel therapies for this symptom in
Research Committee to develop recommendations regardingantiemetic therapy (Table 1). This report describes the aims,methods, and results of this Panel's deliberations.
From the American Society of Clinical Oncology, Alexandria, VA.
Adopted on February 18, 1999, by the American Society of Clinical PRACTICE GUIDELINES Address reprint requests to American Society of Clinical Oncology, Health Services Research, 225 Reinekers Lane, Suite 650, Alexandria, Practice guidelines are systematically developed state- VA 22314; email [email protected]. ments to assist the practitioner and patient decisions about r 1999 by American Society of Clinical Oncology. appropriate health care for specific clinical circumstances.4 Journal of Clinical Oncology, Vol 17, No 9 (September), 1999: pp 2971-2994 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
Table 1. Summary of Guidelines
I. Chemotherapy-Induced Emesis A. Acute Emesis (vomiting occurring 0 to 24 hours after chemotherapy) 1. Antiemetic Agents: Highest Therapeutic Index a. Serotonin Receptor Antagonists i. Agent equivalence At equivalent doses, serotonin receptor antagonists have equivalent safety and efficacy and can be used interchangeably based on convenience,availability, and cost.
Established, proven doses of all agents are recommended.
iii. Drug schedule Single doses of antiemetics are effective and preferred for convenience and cost.
iv. Route of administration At biologically equivalent doses, oral agents are equally effective and are as safe as intravenous antiemetics. In most settings, oral agents are lesscostly and more convenient; for these reasons, they are recommended over intravenous therapy.
b. Corticosteroids i. Agent equivalence and route of administration At equivalent doses, corticosteroids have equivalent safety and efficacy and can be used interchangeably.
ii. Drug dose and schedule Single doses of corticosteroids are recommended.
2. Antiemetic Agents: Lower Therapeutic Index—Dopamine Antagonists, Butyrophenones, Phenothiazines, and Cannabinoids For chemotherapy with a high risk of emesis, selective serotonin antagonists (with dexamethosone) are recommended.
3. Antiemetic Agents: Adjunctive Drugs—Benzodiazepines and Antihistamines Benzodiazepines and antihistamines are useful adjuncts to antiemetic drugs but are not recommended as single agents.
4. Antiemetic Agents: Combinations of Antiemetics It is recommended that serotonin antagonists be given with corticosteroids.
5. Risk Factors for Acute Emesis a. Patient Characteristicsb. Chemotherapeutic Agentsc. Guidelines i(a). High risk: Cisplatin The combination of a 5-HT3 antagonist plus a corticosteroid is recommended before chemotherapy.
i(b). High risk: noncisplatin The combination of a 5-HT3 antagonist plus a corticosteroid is recommended before chemotherapy.
ii. Intermediate risk A corticosteroid is suggested for patients being treated with agents of intermediate emetic risk.
It is suggested that for patients being treated with agents of low emetic risk, no antiemetic be routinely administered before chemotherapy.
iv. Combination chemotherapy It is suggested, that when combination chemotherapy is given, the patient be given antiemetics appropriate for the chemotherapeutic agent ofgreatest emetic risk.
v. Multiple consecutive days of chemotherapy It is suggested that antiemetics appropriate for the risk class of the chemotherapy, as outlined above, be administered for each day of the chemo-therapy.
B. Delayed Emesis (vomiting occurring ⬎24 hours after chemotherapy) 1. Antiemetic Agents i. Corticosteroids ii. Metoclopramide and serotonin receptor antagonists b. Combinations of Agents 2. Risk Factors for Delayed Emesis a. Patient Characteristicsb. Chemotherapeutic Agentsc. Guidelines i(a). High risk: cisplatin For all patients receiving cisplatin, a corticosteroid plus metoclopramide or plus a 5-HT3 antagonist is recommended for the prevention of delayed emesis.
i(b). High risk: noncisplatin A prophylactic corticosteroid as a single agent, a prophylactic corticosteroid plus metoclopramide, and a prophylactic corticosteroid plus a 5-HT3antagonist are regimens suggested for the prevention of delayed emesis.
ii. Intermediate—low risk No regular preventive use of antiemetics for delayed emesis is suggested for patients receiving these chemotherapeutic agents.
Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES Table 1. Summary of Guidelines (Cont'd)
C. Anticipatory Emesis Use of the most active antiemetic regimens appropriate for the chemotherapy being given to prevent acute or delayed emesis is suggested. Such regi-mens must be used with the initial chemotherapy, rather than after assessment of the patient's emetic response to less effective treatment.
If anticipatory emesis occurs, behavioral therapy with systematic desensitization is effective and is suggested.
D. Special Emetic Problems 1. Emesis in Pediatric Oncology The combination of a 5-HT3 antagonist plus a corticosteroid is suggested before chemotherapy in children receiving chemotherapy of high emetic risk.
2. High-Dose Chemotherapy A 5-HT3 antagonist plus a corticosteroid is suggested.
3. Vomiting and Nausea Despite Optimal Prophylaxis in Current or Prior Cycles It is suggested that clinicians (1) conduct a careful evaluation of risk, antiemetic, chemotherapy, tumor, and concurrent disease and medication factors,(2) ascertain that the best regimen is being given for the emetic setting, (3) consider adding an antianxiety agent to the regimen, and (4) consider substi-tuting a dopamine receptor antagonist, such as high-dose metoclopramide, for the 5-HT3 antagonist (or add the dopamine antagonist to the regimen).
II. Radiation-Induced Emesis A. Risk Factors for Radiation-Induced Emesis a. High Risk: Total Body Irradiation A serotonin receptor antagonist should be given with or without a corticosteroid before each fraction and for at least 24 hours after.
b. Intermediate Risk: Hemibody Irradiation, Upper Abdomen, Abdominal-Pelvic, Mantle, Cranial Radiosurgery, and Craniospinal Radiotherapy A serotonin receptor antagonist or a dopamine receptor antagonist should be given before each fraction.
c. Low Risk: Radiation of the Cranium Only, Breast, Head and Neck, Extremities, Pelvis, and Thorax Treatment should be given on an as-needed basis only. Dopamine or serotonin receptor antagonists are advised. Antiemetics should be continued pro-phylactically for each remaining radiation treatment day.
which better treatment is of paramount importance. In
that guideline development involves a review and synthe-
A methodology similar to that applied in prior ASCO practice sis of the latest literature, practice guidelines also serve
guidelines documentation5 was used and is described in more detail to identify important questions for further research and
those settings in which investigational therapy should be
Expert Panel Composition The Panel was composed of experts in clinical medicine, clinical research, outcomes/health services research, medical decision-making,and health economics, with a focus on expertise in supportive care and Table 2. Levels and Grade of Evidence for Recommendations280,281
in antiemetics. A patient representative was also included on the Panel.
Clinical experts represented all relevant disciplines, including medical Evidence is obtained from meta-analysis of multiple, well-designed, oncology, oncology nursing, radiation oncology, pediatric oncology, controlled studies. Randomized trials have with low false-positive and and oncologic pharmacy practice. A steering committee under the low false-negative errors (high power).
auspices of the Health Services Research Committee chose Panel Evidence is obtained from at least one well-designed experimental participants for the clinical practice guideline development process.
study. Randomized trials have high false-positive and/or -negativeerrors (low power).
Literature Review and Data Collection Evidence is obtained from well-designed, quasi-experimental studies Pertinent information from the published literature as of July 1998 such as nonrandomized, controlled, single-group, pre-post, cohort, was retrieved and reviewed for the creation of these guidelines.
time, or matched case-control series.
MEDLINE (National Library of Medicine, Bethesda, MD) and other Evidence is from well-designed, nonexperimental studies, such as databases were searched for pertinent articles. The following keywords comparative and correlational descriptive and case studies.
or phrases were used: antiemetics, neoplasms, adverse effects, anticipa- Evidence is from case reports and clinical examples.
tory ⫹ nausea, anticipatory ⫹ vomiting, serotonin antagonists, pheno- Grade Grade for Recommendation thiazines, butyrophenones, cannabinoids, corticosteroids, and metoclo- There is evidence of type I or consistent findings from multiple studies pramide. Directed searches were made of the primary articles.
of types II, III, and IV.
There is evidence of types II, III, and IV, and findings are generally Consensus Development Based on Evidence The Panel identified topics to be addressed by the guidelines, There is evidence of types II, III, and IV, but findings are inconsistent.
developed a strategy for completion of the guidelines, and reviewed the There is little or no systematic empirical evidence.
literature. The Panel emphasized the inclusion of prospective random- Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
assignment studies. Phase II trials and clinical reports that evaluated reliable measure.7-9 The validity of this measure is demon- less-well-studied areas of antiemetic treatment were also reviewed. The strated by the fact that complete control of vomiting recommendations made by the Expert Panel are based on current correlates highly with patients' perception of emesis and methods of emetic treatment and prevention. The guidelines werecirculated in draft form through several iterations, and all members of with patients' satisfaction with their emetic control.
the Panel had opportunities to comment on the recommendations.
In contrast, the mechanisms responsible for mediating The Panel did not attempt to codify established practice. The experts nausea are less well explained.10 Nausea, or the perception reviewed the available evidence and added their best clinical judgment that emesis may occur, can be judged only by the patient.
to make final recommendations, using standardized language to charac- Various questionnaires, using either visual analog or categori- terize the strength of the evidence. In accordance with the ASCO HealthServices Research Policies and Procedures for guidelines, ‘‘recommen- cal scales, are in widespread use.9,11,12 The incidence of dation'' was used when there was level I or II evidence and Panel nausea correlates well with the incidence of vomiting13; consensus. ‘‘Suggestion'' was used when there was level III, IV, or V however, chemotherapy-induced nausea occurs at a greater evidence and Panel consensus. ‘‘No guideline possible'' was used when frequency than vomiting. Many large random-assignment there were no data or the Panel could not reach consensus.
trials have shown that complete control rates for vomiting Guidelines and Conflict of Interest are higher than those for the complete control of nausea.14,15 The concept of total control (no vomiting or nausea) is The content of the guidelines and the manuscript were reviewed and attractive; however, recent large studies have indicated that approved by the Health Services Research Committee and by the ASCOBoard of Directors before dissemination. In addition, several practitio- the total control rate is essentially identical to the complete ners who had not been directly involved in the development of the nausea control rate. It seems that this additional category guidelines were asked to assess the clarity and utility of the document.
does not provide further useful information.14,15 All participants in the guideline development process complied with the Lesser control rates, such as major control (zero to two or ASCO policy on conflict of interest, which requires disclosure of any one to two emetic episodes) or minor control (three to five financial or other interest that might be construed as constituting anactual, potential, or apparent conflict.6 emetic episodes), have been useful in the past and may stillhave some value in particularly difficult emetic situations.
Revision Dates However, the panelists reached consensus in advising the use of At annual intervals, the Panel chairpersons and two Panel members complete control rates for the evaluation of most emetic situa- designated by the chairpersons will determine the need for revisions to tions and for use in the guideline development process.
the guidelines based on an examination of current literature. The entirePanel will be reconvened every 3 years to discuss potential changes, or A. Acute Emesis more frequently if new information suggests that more timely modifica- (Vomiting Occurring 0 to 24 Hours After Chemotherapy) tions may be warranted. Where appropriate, the Panel will recommendthe revised guideline to the Health Services Research Committee and 1. Antiemetic Agents: Highest Therapeutic Index the ASCO Board for review and approval.
Two classes of agents are in this category, the serotonin receptor antagonists and corticosteroids (Table 3).16-37 Both Definition of Terms classes are highly effective, with few significant side effects For cisplatin, high risk is defined as emesis that has been when used appropriately, and can be given safely in documented to occur in more than 99% of patients. For the combination when indicated. These agents have been largely high-risk, noncisplatin group, the incidence of emesis is in the responsible for the ease of use and high effectiveness of 30% to greater than 90% range. Chemotherapeutic agents in the antiemetics in clinical practice.
intermediate-risk category induce emesis in 10% to 30% of a. Serotonin Receptor Antagonists. The issues of agent patients. A less than 10% risk of emesis in patients receiving equivalence, drug dosage, drug schedule, and route of chemotherapeutic drugs was categorized as low risk.
administration are discussed separately below. Specificguidelines for differing acute emetic risk settings are given I. CHEMOTHERAPY-INDUCED EMESIS in a later section.
In discussing evidence for the control of emesis, it is i. Agent equivalence: necessary to outline definitions of control. Emesis, or Guideline: At equivalent doses, serotonin receptor antago- vomiting, is usually measured by counting the number of nists have equivalent safety and efficacy and can be used vomiting episodes and is the most important end point. With interchangeably based on convenience, availability, and cost.
currently available agents, complete control of emesis, ie, no Level of Evidence: I.
vomiting, is achievable in the majority of patients in the first Grade of Recommendation: A.
24 hours and in approximately 45% of patients during the There are currently four agents of this class commercially first 5 to 7 days of chemotherapy. Studies have documented available in many countries: dolasetron, granisetron, ondanse- that the complete control end point is a highly accurate and tron, and tropisetron. Other, similar agents are available in Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES Table 3. Antiemetic Agents, Doses, and Administration Schedule
Schedule (for acute chemotherapy- Antiemetic Agent (trade name) induced emesis, unless otherwise noted) Agents with highest therapeutic index Serotonin receptor antagonists Dolasetron (Anzemet) 100 mg or 1.8 mg/kg IV One time, before chemotherapy Dolasetron (Anzemet) One time, before chemotherapy Granisetron (Kytril) 1 mg or 0.01 mg/kg IV One time, before chemotherapy Granisetron (Kytril) One time, before chemotherapy Ondansetron (Zofran) 8 mg or 0.15 mg/kg IV One time, before chemotherapy Ondansetron (Zofran) Oral doses vary (12-24 mg/d) (8 mg doses usually One time, before chemotherapy (two to three times used in delayed or RT emesis) daily in delayed or RT emesis) Tropisetron (Navoban) One time, before chemotherapy Tropisetron (Navoban) One time, before chemotherapy Dexamethasone (Decadron) One time, before chemotherapy One time, before chemotherapy Agents of lower therapeutic index Dopamine receptor antagonists Metoclopramide (Reglan) 2 mg/kg to 3 mg/kg IV Before chemotherapy and 2 hours after chemo- Metoclopramide (Reglan) 20 mg to 0.5 mg/kg PO for delayed emesis or RT Two to four times a day for delayed emesis 10 mg to 30 mg IV Every 3 to 4 hours Every 3 to 4 hours individual countries or are under investigation. The majority finding38,40,45,48,61-77; few studies have carefully examined of multiple, randomized, well-controlled studies with suffi- tropisetron dosing. With excellent safety profiles through cient patients to precisely estimate differences in treatment large dosing ranges, toxicity has not been the criterion for have demonstrated that these agents have equivalent anti- determining dosage. It is clear that too low a dose can be emetic activity and safety.38-50 There was unanimity among found for these agents, with attenuated activity observed at the Panel members for this conclusion.
less than optimal doses (listed in Table 3).65,67,73,74,78 Panel These agents exert their activities by the same mecha- members concurred that it is likely that a threshold effect nism, antagonism of the type 3 serotonin (5-hydroxytrypta- exists. Once all relevant receptors are saturated, higher doses mine [5-HT3]) receptor.51-57 They are all highly selective do not enhance any aspect of activity. Two corollaries are with high affinities for this receptor.58-60 All clinically also important: sufficient doses must be given to ensure relevant antiemetic actions are mediated in this way by these maximum efficacy. Most Panel members agreed that the agents. These agents also share the same low side-effect dose will be the same in all antiemetic settings in which a pattern, with mild headache, transient asymptomatic trans- serotonin receptor antagonist is required. The Panel unani- aminase elevations, and constipation being among the most mously concluded that the lowest fully effective dose for commonly reported adverse events.17,18,20,23 each of the agents should be used.
The overall conclusion is based on the excellent evidence As mentioned above, the question of ideal dose has been available for granisetron, ondansetron, and, more recently, best studied with dolasetron, granisetron, and ondansetron.
dolasetron. The studies with tropisetron are less rigorous(level of evidence: II; grade of recommendation: B), but the A lesser degree of evidence is found for tropisetron,79,80 but Panel found that they are sufficient to allow the confidence the conclusion reached was the same.
in the above-stated conclusion.
iii. Drug schedule: ii. Drug dosage: Guideline: Single doses of antiemetics are effective and Guideline: Established, proven doses of all agents are are preferred for convenience and cost.
Level of Evidence: I.
Level of Evidence: I.
Grade of Recommendation: A.
Grade of Recommendation: A.
Several recent studies have examined the issue of multiple Many studies have addressed the question of establishing antiemetic doses compared with a single administration. The the ideal doses for these agents. Dolasetron, granisetron, and latter approach, if equally effective, enhances convenience ondansetron are the best-studied agents in terms of dose- and adherence. A single-dose regimen using the lowest fully Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
effective dose can provide economic benefit and the poten- Panel reached consensus that oral and intravenous routes are tial for the fewest side effects. Large, randomized studies similar in efficacy, especially when given in combination with granisetron,80 dolasetron,81 and ondansetron66,67,82 have with corticosteroids,33 but the level of evidence is somewhat indicated the equivalence of single-dose schedules of these less for this conclusion than it is for those reported above.
agents when compared with multiple-dose regimens of the Corticosteroids also have a high same agents. Dolasetron has been largely explored as a therapeutic index when used for acute chemotherapy- single-dose agent; however, with the exception of one induced emesis. They are among the most frequently used study,47 its single-dose activity is equivalent to single doses antiemetics, with single-agent use being appropriate in of ondansetron,45,46,48 confirming the utility of this schedule low-risk settings. They are especially valuable when given for all three agents. The Panel was unanimous in concluding in combination with serotonin receptor antagonists in pa- that single-dose regimens are as active as multiple-dose tients receiving highly emetogenic chemotherapy20,33,35,96- 105 (this is covered in more detail in a later section). Issues of Tropisetron has generally been used in single-dose sched- equivalence and route of administration, as well as drug dose ules, with few formal dosing comparisons.44,49,79,83,84 The and schedule, are discussed together.
level of evidence is less regarding this agent, but the Panel's i. Agent equivalence and route of administration: conclusion was the same.
Guideline: At equivalent doses, corticosteroids have iv. Route of administration: equivalent safety and efficacy and can be used interchange- Guideline: At biologically equivalent doses, oral agents are equally effective and are as safe as intravenous antiemet- Level of Evidence: IV and Expert Consensus.
ics. In most settings, oral agents are less costly and more Grade of Recommendation: C.
convenient; for those reasons, they are recommended over The corticosteroids most frequently studied for use as antiemetics have been dexamethasone106-111 and methylpred- Level of Evidence: I.
nisolone.112-118 Some reports have used prednisone.119 Al- Grade of Recommendation: A.
though efficacy has been reported with these agents, there Intravenous and oral routes have been studied with these have been no comparison trials. Dexamethasone has the agents. Most of the conclusions concerning drug equiva- advantages of being available in many dosage formulations lence, dosage, and schedules are based on intravenous and accessible in generic forms in many countries.
administration. An emerging body of formal trials is now There are no formal trials comparing oral with parenteral becoming available concerning the oral route compared with corticosteroids. Knowledge of acceptable bioavailability the intravenous in the administration of various serotoninreceptor antagonists. All of these agents have undergone and corticosteroid utility in many indications for these pharmacologic testing. Excellent absorption is found with agents has encouraged their use in the oral form.
all agents: reports indicate 50% to 80% bioavailability with In the absence of comparison studies, most panelists these drugs.85 Because 5-HT recommended dexamethasone or methylprednisolone be- 3 receptors are found in the enterochromaffin cells in the gut, with vagal afferent fibers in cause of the published experience with these agents.
this area,86 it has been suggested that oral administration ii. Drug dose and schedule: may be particularly appropriate for these agents.
Guideline: Single doses of corticosteroids are recom- Large, randomized studies have shown that, in the settings of both highly emetogenic chemotherapy and chemotherapy Level of Evidence: II.
of intermediate emetogenicity, a single dose of oral granis- Grade of Recommendation: B.
etron demonstrates similar efficacy when compared with a Some comparison trials have explored these issues.107 single intravenous dose of ondansetron.14,15 Only extremely Until recently, these trials have typically been consecutive small differences were found; these differences were even dose-level investigations rather than randomized studies.
smaller when both agents were combined with corticoste- Findings suggest that single doses are as effective as roids. Oral dolasetron was tested in patients receiving multiple-dose schedules. Although few studies have ad- chemotherapy of intermediate emetogenicity25,47,87,88 and dressed this issue, there is no benefit to starting the cisplatin,89 and in comparison with intravenous ondansetron, corticosteroid the day before chemotherapy.120 To date, there in a large randomized study.47 Again, similar efficacy was is no evidence that doses of dexamethasone greater than 20 reported. Both ondansetron90-95 and tropisetron79 are known mg are more effective.120 A recent randomized study demon- to be active when given orally; however, studies have not strated improved efficacy and equivalent adverse effects been as formalized with the oral form of these drugs. The with dexamethasone given at 20 mg (with serotonin antago- Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES nists) compared with dexamethasone at lower doses.121 Side logic advantage for either agent or route; however, there was effects of single corticosteroid doses are rare, although a modest patient preference for the oral dronabinol in this elevations of serum glucose levels and sleep disturbances cross-over, blinded trial. These agents cause frequent dizzi- occur.122 The Panel achieved consensus that single-dose ness, sedation, hypotension, and dysphoria, especially in regimens are most appropriate.
older adults.156,157 The Panel was unanimous in finding that in acute chemotherapy-induced emesis, especially in the high-risk 2. Antiemetic Agents: Lower Therapeutic Index—Dopamine setting, there is no group of patients for whom agents of Antagonists, Butyrophenones, Phenothiazines, and lower therapeutic index (metoclopramides, phenothiazines, butyrophenones, and cannabinoids) are appropriate as first- Guideline: For chemotherapy with a high risk of emesis, choice antiemetic drugs. These agents should be reserved for selective serotonin antagonists (with dexrazoxane) are rec- patients intolerant of or refractory to serotonin receptor antagonists and corticosteroids.
Level of Evidence: I.
Grade of Recommendation: A.
3. Antiemetic Agents: Adjunctive Drugs—Benzodiazepines There are several classes of agents with antiemetic activity that are less efficacious than the serotonin receptor Guideline: Benzodiazepines and antihistamines are useful antagonists or corticosteroids. These other agents generally adjuncts to antiemetic drugs, but are not recommended as have more side effects because they are less selective than single agents.
the serotonin receptor antagonists.
Level of Evidence: II.
Several of these agents are antagonists of dopamine type 2 Grade of Recommendation: B.
receptors. Foremost in this group is the substituted benza- Benzodiazepines, most commonly lorazepam, have been mide, metoclopramide. At higher doses, however, metoclop- widely given, both in combination and as single agents.158-166 ramide acts primarily as a serotonin receptor antagonist Trials, including randomized, blinded studies with loraz- (Table 3).123 Antiemetic efficacy with metoclopramide is epam in combination regimens, have indicated limited slightly less than that seen with the selective serotonin antiemetic activity for this agent.160 However, because of its receptor antagonists.120,124-132 Side effects include acute potent antianxiety effects, lorazepam was believed to be a dystonic reactions, akathisia, and sedation.17,18,20,133,134 useful addition to the active antiemetics given in the Butyrophenones (such as haloperidol and droperidol)135- combination. In general, lorazepam and similar drugs should 138 and phenothiazines (prochlorperazine and thiethylpera- be viewed as adjunctive agents rather than as useful zine)126,139,140 have antiemetic activity mediated by their antidopaminergic actions. Efficacy is generally lower than Antihistamines have been administered both as antiemet- with metoclopramide.136 Side effects include dystonic reac- ics and as adjunctive agents to prevent dystonic reactions tions, akathisia, sedation, and postural hypotension (espe- with dopamine antagonists.120,160 Drugs such as diphenhydra- cially with intravenous phenothiazines).141,142 mine, hydroxyzine, and benztropine have been the most Cannabinoids, both as plant extracts (dronabinol) and as commonly used agents. Studies have not shown antiemetic semisynthetic agents (nabilone and levonantradol), have activity for these drugs.120 Diphenhydramine can prevent been found to have antiemetic activity when used alone143- extrapyramidal reactions120; however, because dopamine 150 or in combination with other agents.151,152 The activity of receptor antagonist agents are no longer first-choice drugs, dronabinol (given in oral doses varying from 2.5 mg per the role for antihistamines is limited.
dose to 10 mg/m2) has been shown to be significantly lessthan that of metoclopramide in a randomized, double-blinded trial with patients receiving cisplatin.153 Activity 4. Antiemetic Agents: Combinations of Antiemetics reported for dronabinol in patients receiving methotrexate Guideline: It is recommended that serotonin antagonists was not seen by the same investigator testing the agent in be given with corticosteroids.
patients receiving cyclophosphamide and doxorubicin.154 Level of Evidence: I.
Inhalant marijuana has been compared with dronabinol in Grade of Recommendation: A.
only one randomized, double-blind trial with patients receiv- Extensive research has shown that combinations of anti- ing chemotherapy of intermediate emetic risk.155 The inhal- emetics are significantly more effective than single agents ant and the oral cannabinoids were not effective in either arm when used with chemotherapy that is likely to induce of the study. There was no efficacy, side effect, or pharmaco- emesis. Among the antiemetic agents listed in the highest Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
therapeutic index category, corticosteroids given in combina- useful, but they do not provide precise differentiation among tion with a serotonin receptor antagonist yield the greatest chemotherapy drugs.7,91,93,183-187 A recent publication has antiemetic protection in repeated, multicenter, randomized endeavored to establish categories based on data.188 It has studies designed with sufficient numbers of patients to tried to place both single agents and chemotherapy combina- precisely estimate treatment effects.20,33,62,97-100,104,105,167-169 tions in a classification scheme based on the actual incidence Side effects are usually low with these combinations. For of emesis. Although this approach was encouraged by the patients receiving cisplatin or noncisplatin chemotherapy of Panel, consensus could not be reached because there is no high emetic risk (as discussed below in Risk Factors for clear evidence of the emetic potential for the majority of Acute Emesis under High-Risk Cisplatin), these combina- chemotherapeutic agents and combinations.
tions are the regimens of choice. The Panel was unanimous c. Guidelines. To formulate guidelines, a classification in its recommendation that in these emetic situations, when a based on antiemetic recommendations is needed. Outlined serotonin antagonist is indicated, a corticosteroid should below is the rationale for such a classification by emetic risk also be given unless the use of the latter agent is strongly of the chemotherapy agent (Table 4, A, B, and C). Table 4 is adapted from other reviews, such as that listed in the Perugia Older, well-conducted, randomized trials131,160 have also Consensus Conference,189 and ranks the drugs from highest demonstrated that corticosteroids given in combination with to lowest risk within each category. It was possible to reach agents in the lower therapeutic index category, such as agreement for these treatment-related categories. It was metoclopramide, also give superior efficacy when compared difficult to place in the proper category those agents that with the single agent in high-risk emetic situations. In these seem to be at the borderline between risk categories. These situations, however, a large random-assignment trial showed categories are outlined, as follows: that a serotonin receptor antagonist added to a corticosteroidwas superior to a high-dose metoclopramide added to a i(a). High risk – cisplatin: corticosteroid.170 The benefit was in terms of both efficacy Guideline: The combination of a 5-HT3 antagonist plus a and fewer side effects.
corticosteroid is recommended before chemotherapy.
Level of Evidence: I.
5. Risk Factors for Acute Emesis Grade of Recommendation: A.
The literature clearly documents the incidence of emesis Two major categories predicting risk of acute emesis with cisplatin.126,187,190 These data are valuable in antiemetic (emesis occurring in the first 24 hours) or of differences in studies for several reasons: (1) the usefulness of cisplatin in antiemetic control can be identified. These factors involve oncology; (2) cisplatin causes emesis in all patients (⬎ 99% patient characteristics and the chemotherapeutic agents.
risk without active antiemetics); and (3) cisplatin provides a a. Patient Characteristics. Several patient factors, some model for antiemetic testing. Trials to date show that if an confirmed by multivariate analysis, have been shown to antiemetic is useful in cisplatin-induced emesis, it will be at predict poor antiemetic control.18,171-180 These factors in- least as effective with other chemotherapy drugs.191 clude poor control with prior chemotherapy, female sex, a The risk of emesis with cisplatin (ⱖ 50 mg/m2) is low chronic alcohol intake or history, and younger age. The universal, but other factors can alter the risk. As the dose of last factor, age, is a less consistent finding in trials. However,the majority of the panelists indicated that this is a factor to cisplatin increases, the ability to prevent acute and delayed be considered. Chronic alcohol intake can include a prior, emesis decreases. This observation has placed cisplatin at rather than a current, history of high alcohol use (frequently the top of any classification scheme and often in a category defined as the use of more than 100 g of alcohol per day for a of its own. The treatment guideline for cisplatin is indepen- period of several years). In general, the higher the alcohol dent of dose or infusion time of the agent.
intake history, the lower the emetic risk with chemotherapy.
Because of the careful documentation of cisplatin- Pre-existing nausea and certain health-related quality-of-life induced emesis with numerous well-conducted trials, the variables, eg, low social functioning and high fatigue scores, Panel was unanimous in its recommendation for treatment.
may also be predictive factors.181,182 Large, multicenter, randomized trials have shown the rate of b. Chemotherapeutic Agents. Agents should be classified complete control of acute emesis (occurring in the first 24 by emetogenic potential, to aid in selection of the appropri- hours) to be approximately 75% (range, 58% to 96%), after ate antiemetic. Prospective documentation of the potential of high-dose cisplatin using the recommended regimen.191 a chemotherapeutic drug to cause emesis has been rigor- i(b). High risk – noncisplatin: ously established for only a few agents. General categories Guideline: Use of a combination of a 5-HT3 antagonist based on experience rather than on specific data have been plus a corticosteroid before chemotherapy is recommended.
Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES Level of Evidence: I, II, III, and Expert Consensus.
Level of Evidence: V and Expert Consensus.
Grade of Recommendation: A-B.
Grade of Recommendation: D.
Documentation of risk for some of the chemotherapy Few antiemetic studies were found that used these chemo- agents in this category (Table 4A), such as cyclophospha- therapeutic agents, which are listed in Table 4C. With a low mide,93 is well established. Overall, the risk of emesis in this perception of risk (much less than 10% for most agents), it is category is greater than 30% and less than that seen with understandable that trials were not conducted. Because the cisplatin. If the classification were based on the incidence of agents in this category are older agents (all of the agents emesis, rather than on treatment recommendations, a case have been in use for at least 20 years), enumeration of the could be made to place some of these drugs in a separate, emetic incidence was not often given as part of the higher-risk group (dacarbazine, nitrogen mustard, extremely drug-testing process. Although most hormonal agents are high doses of cyclophosphamide) in which the risk of acute not included in Table 4C, an exception is made for tamoxi- emesis is greater than 90%.188 fen, which is so commonly given and is of low risk for Other commonly used agents in this category are the inducing emesis. Some of the agents listed at the top of this anthracyclines, the nitrosoureas, and cytarabine. For these category would be placed in the intermediate-risk category agents, especially when given in higher doses, it is expected by some panelists. The Panel reached the following consen- that the majority of patients would have emesis if not given sus for treatment of this group.
effective antiemetics. The Panel was unanimous in its As in all the categories, individual patients, especially treatment recommendation for the agents in this category.
those with poor emetic control and prior drug administra- The type and level of evidence varied according to the tion, may require alteration of their antiemetic regimen.
agent. As mentioned above, there are level I data for Panelists agreed that antiemetic control should exceed 95% cyclophosphamide, the anthracyclines, and combinations of in this group. Occasional use of a single dose of a these agents. In these instances, several large, randomized, corticosteroid, or as-needed prescribing of oral metoclopra- multicenter trials have documented 85% to 90% complete mide or a phenothiazine, is common.
control of acute emesis, using the recommended regimen.191 iv. Combination chemotherapy: A lower level of evidence has been demonstrated for agents Guideline: The Panel suggests that when combination such as dacarbazine.
chemotherapy is given, the patient should be given antiemet- ii. Intermediate risk: ics appropriate for the chemotherapeutic agent of greatest Guideline: A corticosteroid is suggested for patients emetic risk.
treated with agents of intermediate emetic risk.
Level of Evidence: IV.
Level of Evidence: III, IV, and Expert Consensus.
Grade of Recommendation: D.
Grade of Recommendation: B, D.
When combination chemotherapy is given, the patient Table 4B lists several commonly used chemotherapy should be treated for the agent in the combination with the agents in this category. Without treatment, many patients, highest emetic risk.188 For example, if low-risk agents are but not the majority, would have emesis. The risk of emesis added to cisplatin therapy, the patient should be given is in the 10% to 30% range for agents in this group. The antiemetics appropriate for cisplatin. If low-risk chemother- emesis induced by these agents is also easier to control than apy is added to an anthracycline regimen, the patient should that found in the greater-risk categories. The first few agents be given antiemetics recommended for noncisplatin high- in this list were considered by some Panel members to be on risk agents (the anthracycline category). The Panel was the border of the upper category; the lower few were listed in unanimous in this recommendation.
the low-risk group by some panelists. Evidence for emetic The Panel could not reach consensus concerning added risk is often found as part of phase I and II chemotherapeutic emetic risk if patients are given combinations of chemothera- trials for the newer agents in this category, rather than as part peutic agents in which all the drugs are in the low emetic risk of comparative antiemetic studies.
categories. It has been suggested that these combinations The Panel agreed that the complete control rate should may raise the emetic risk one category higher, but there is no exceed 90% with the use of a single dose of a corticosteroid.
definitive evidence at this time. In the absence of firm evidence, There is no formal documentation of efficacy with anti- the panelists nonetheless believed that oncologists should be emetic treatments for these lower-risk chemotherapy agents.
aware of this issue and should carefully evaluate the emetic iii. Low risk: experience of patients given these chemotherapy combinations.
Guideline: It is suggested that for patients treated with Most experts would continue to treat patients given these agents of low emetic risk, no antiemetic be routinely chemotherapy combinations with the antiemetics appropriate for administered before chemotherapy.
the chemotherapeutic agent of the greatest emetic risk.
Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
v. Multiple consecutive days of chemotherapy: Most trials have given the agents twice daily. Dexametha- Guideline: It is suggested that antiemetics appropriate for sone has been the agent tested most frequently, often at the the risk class of the chemotherapy, as outlined above, be dose of 8 mg for 2 to 3 days, occasionally tapering to 4 mg administered for each day of the chemotherapy.
for 1 or 2 additional days. Most panelists recommended oral Level of Evidence: II and III.
use of the agent. There are reports of dexamethasone given Grade of Recommendation: B.
intramuscularly, but there is no clear advantage to this route.
Few studies have assessed vomiting control for specific Panelists agreed unanimously that corticosteroids should be chemotherapy combinations. There is, however, some evi- part of any regimen for delayed emesis, unless there is a dence that dexamethasone combined with metoclopramide strong contraindication to their usage.
is useful for patients receiving oral cyclophosphamide, There are some reports of the use of adrenocorticotropic methotrexate, and fluorouracil.30 If the chemotherapy can be hormone in delayed emesis,216 but formal trials are few and given as effectively and safely on day 1 of a multiple-day panelists did not see any advantage for this agent over more cycle, the likelihood of controlling emesis will be improved.
readily available and easily administered corticosteroids.
When chemotherapy likely to induce emesis is given on ii. Metoclopramide and serotonin receptor antagonists: several consecutive days with antiemetics (best demon- Several trials have reported efficacy for oral metoclopramide strated with cisplatin and with dacarbazine), control of given in combination with corticosteroids.168,205,206,209,210,217 emesis decreases. The explanation for this has not been Doses typically vary between 20 mg and 40 mg (or elucidated; however, it may be that problems of both delayed 0.5 mg/kg) given two to four times per day for 3 to 4 days.
and anticipatory emesis are added to the difficulty of This agent is generally well-tolerated, with few acute controlling acute chemotherapy-induced emesis. 5-HT3 an- dystonic reactions in the adult population (the group for tagonists plus dexamethasone are especially indicated inhigh-risk settings,192-197 because the risk of dystonic reac- which dystonic reactions are significantly less frequent).
tions with dopamine antagonists increases with consecutive- Akathisia (restlessness) may occur in some patients. This day therapy (particularly in younger patients). If appropriate side effect may be related to dopamine receptor antagonism.
for the chemotherapy administered, antiemetics for delayed Initial reports indicated some efficacy for oral prochlorpera- emesis should be given after the completion of the chemo- zine209,210 with corticosteroids. There are no formal reports, Studies have yielded conflicting results concerning the use of serotonin antagonists for delayed emesis. Ondanse- B. Delayed Emesis tron and granisetron have been given either sin- (Vomiting Occurring ⬎ 24 Hours After Chemotherapy) gly17,18,65,82,176,198,199,212 or in combination with corticoste- The neuropharmacologic mechanism of delayed emesis is roids,30,47,168,211,213,214,217 but trial results have varied in not well understood.9,18,198-203 Prevention of this problem has regard to whether or not these agents are effective against been based on empiric results.24,29,30,47,82,89,92,128,160,168,176,186,204-215 delayed emesis. One randomized study indicates efficacy of Fewer agents have been tested or are commonly used for this a serotonin antagonist for delayed emesis in patients receiv- indication than for acute emesis.
ing chemotherapy of intermediate emetogenicity.82 Thedoses and schedules of these drugs have not been formally 1. Antiemetic Agents determined. Usually, these agents have been given orally a. Single Agents. i. Corticosteroids: twice a day, with ondansetron administered at 8 mg per dose These agents are the most consistently useful drugs for the and granisetron at 1 mg or 2 mg per dose. Side effects have prevention of delayed emesis.47,205-207,211 As shown repeat- been few and are similar to those reported for the use of edly in clinical trials, their widespread availability in oral these agents in acute chemotherapy-induced emesis.
form, low cost, and benefit make corticosteroids the single There is little evidence for the use of other classes of most appropriate agents for this indication. Side effects are agents for the prevention of delayed chemotherapy-induced of some concern because corticosteroids are typically used for 2 to 4 days. Adrenal insufficiency after corticosteroid b. Combinations of Agents. In delayed emesis, as with usage is not a problem for this relatively brief period; acute vomiting, combination regimens seem to be the most however, hyperglycemia in susceptible patients requires effective. In a random-assignment trial with patients receiv- attention. As with corticosteroids in many other settings, ing cisplatin, the oral combination of metoclopramide plus including for acute chemotherapy-induced emesis, the doses dexamethasone was significantly more effective than dexa- and schedules have not been determined by formal testing.
methasone alone.205 There are conflicting results with regard Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES to serotonin receptor antagonist use with corticosteroids. In single doses and multiple daily doses of cisplatin. The Panel one comparison study, granisetron did not add to the efficacy recommended that antiemetics be given to prevent delayed of the corticosteroid211; however, in another large compari- emesis in patients receiving cisplatin. Most panelists recom- son trial, the combination of ondansetron plus dexametha- mended a combination of antiemetics that includes a cortico- sone was equivalent to the combination of metoclopramide steroid, as outlined in Table 4A.
plus dexamethasone.217 The majority of the panelists fa- Trials indicate that the above regimen can give rates of vored the use of combination antiemetics in high-risk complete control of delayed emesis in the range of 50% to settings for delayed emesis.
more than 70%, compared with only 11% to 30% control Few reports address the incidence and treatment of without antiemetics.204,205 A large, multicenter, randomized delayed emesis in children receiving cancer chemother- trial217 obtained equivalent rates of control with corticoste- apy.133 Dopamine antagonists, especially when given over roids plus either metoclopramide or ondansetron, showing several consecutive days, cause a high incidence of dystonic that either regimen could be given. The low side-effect rates reactions and are not a good choice for general multiple-day in the adult population with both regimens do not indicate a use in the pediatric population.133,134 clear choice for either combination. The markedly lowercost of the metoclopramide regimen and similar efficacy are 2. Risk Factors for Delayed Emesis strong points in favor of this combination.
Risk factors for delayed emesis include patient character- i(b). High risk: non-cisplatin: istics and the chemotherapy being administered, as is the Guideline: A prophylactic corticosteroid as a single agent, case for acute chemotherapy-induced emesis. Oncologists a prophylactic corticosteroid plus metoclopramide, and a must be aware of these factors to identify patients who need prophylactic corticosteroid plus a 5-HT3 antagonist are preventive treatment on a routine basis and individuals who regimens suggested for the prevention of delayed emesis.
may be at greater risk.
Level of Evidence: III-V.
a. Patient Characteristics. The most important patient Grade of Recommendation: B-D.
characteristic predicting for greater risk for delayed emesis Only recently has prospectively gathered information is poor control of acute chemotherapy-induced eme- become available concerning the incidence of delayed sis.9,206,214 Patients who experience acute emesis with chemo- emesis in patients receiving chemotherapy in this cat- therapy are significantly more likely to have delayed emesis.
egory.47,82,207,213 In particular, among patients receiving Thus, any patient characteristic that predicts a greater risk cyclophosphamide, anthracyclines, carboplatin, or combina- for acute emesis (such as female sex, emesis with prior tions of these agents, the incidence of delayed emesis varied cycles of chemotherapy, and low prior alcohol intake from 20% to 30% in patients not given prophylactic history) should be considered as a predictive factor for antiemetics for delayed emesis. Use of a corticosteroid as delayed emesis as well.
part of the acute emesis regimen was associated with a lower b. Chemotherapeutic Agents. Delayed emesis was ini- incidence of delayed emesis. The majority of panelists tially described in patients receiving cisplatin.204,206,214 Only recommended that a delayed emesis regimen be given with recently has the problem been formally outlined in patients this degree of risk, but data are lacking concerning efficacy given other chemotherapy.82,186,207 The risk of delayedemesis in patients receiving many chemotherapy drugs has and specific regimen choices.
not been studied. The recommendations listed in Table 5 are Formal trials are needed to determine the length of tempered by a lack of formal data in many settings.
treatment for delayed emesis regimens in this category. Most c. Guidelines. i(a). High risk: cisplatin: panelists recommended using the same dosages as given for Guideline: In all patients receiving cisplatin, a corticoste- cisplatin-induced emesis, although it is possible that fewer roid plus metoclopramide or a 5-HT days of antiemetic treatment (ie, 2 days) may be needed for 3 antagonist is recom- mended for the prevention of delayed emesis.
these chemotherapy agents.
Level of Evidence: I.
ii. Intermediate-low risk: Grade of Recommendation: A.
Guideline: No regular preventive use of antiemetics for Trials have indicated that the majority of patients receiv- delayed emesis is suggested for patients receiving these ing cisplatin will experience delayed emesis if not given preventative antiemetics, with reports indicating an inci- Level of Evidence: V and Expert Consensus.
dence of 60% to nearly 90%.17,18,128,168,176,198,199,204- Grade of Recommendation: D.
206,211,212,217 The rate seems to increase with higher total Few studies have addressed the issues of either the doses of cisplatin, and delayed emesis occurs with both incidence or prevention of delayed emesis in patients Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
Table 4A. High Emetic Risk: Chemotherapeutic Agents and Guidelines for Acute and Delayed Emesis
Evidence (type and grade) Chemotherapy Agent Guideline for Delayed Emesis Cisplatin (Platinol, Bristol-Myers Oncology, Pretreatment: 5-HT3 Oral corticosteroid plus oral Antagonist plus a metoclopramide (or plus an oral 5-HT3 antagonist) Dexamethasone 8 mg twice daily for 3 to 4 days, Metoclopramide 30-40 mg, two to four times per day for 2-4days, 5-HT3 antagonists at doses in High: noncisplatin Dacarbazine (DTIC-Dome, Bayer, Table 3, for 2-3 days (guideline for all agents in this actinomycin-D (Cosmegen, Merck, White- class, except cisplatin) house Station, NJ) Dexamethasone 8 mg twice mechlorethamine (Mustargen, Merck) daily for 2-3 days, streptozotocin (Zanosar, Pharmacia & Upjohn, Metoclopramide 30-40 mg, two hexamethylmelamine (Hexalen, US Bioscience, to four times per day for 2-3 Westconshohocken, PA) carboplatin (Paraplatin, Bristol-Myers 5-HT3 antagonists at doses in cyclophosphamide (Cytoxan, Bristol-Myers Table 3, for 2-3 days lomustine (CeeNU, Bristol-Myers Oncology)carmustine (BiCNU, Bristol-Myers Oncology)daunorubicin (DaunoXome, NeXstar Pharma- ceuticals, San Dimas, CA) doxorubicin (Adriamycin, Pharmacia & epirubicin (Pharmorubicin, Pharmacia & idarubicin (Idamycin, Pharmacia & Upjohn)cytarabine (Cytosar, Pharmacia & Upjohn)ifosfamide (Ifex, Bristol-Myers Oncology) *See Table 3 for dosing.
Table 4B. Intermediate Emetic Risk: Chemotherapeutic Agents and Guidelines for Acute and Delayed Emesis
Evidence (type and grade) Chemotherapy Agent (trade name) Guideline for Acute Emesis Guideline for Delayed Emesis Irinotecan (Camptosar, Pharmacia & Upjohn) Pretreatment: a cortico- No regular preventive use of III-IV, B-D (range mitoxantrone (Novantrone, Immunex, steroid (such as dexa- antiemetics for delayed methasone 4-8 mg by paclitaxel (Taxol, Bristol-Myers Oncology) mouth, given once before docetaxel (Taxotere, Rhone-Poulenc Rorer, Collegeville, PA) mitomycin (Mutamycin, Bristol-Myers topotecan (Hycamtin, SmithKline Beecham, Philadelphia, PA) gemcitabine (Gemzar, Lilly, Indianapolis, IN)etoposide (Vepesid, Bristol-Myers Oncology)teniposide (Vumon, Bristol-Myers Oncology) NOTE: Individual patients may require treatment similar to that recommended for high emetic risk agents. Combinations of agents in this class are not well studied, but they may occasionally cause more emesis for some patients, requiring treatment similar to that recommended for high-emetic-risk agents.
Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES Table 4C. Low Emetic Risk: Chemotherapeutic Agents and Guidelines for Acute and Delayed Emesis
Evidence (type and grade) Chemotherapy Agent (trade name) Guideline for Acute Emesis Guideline for Delayed Emesis Vinorelbine (Navelbine, Glaxo Wellcome, No routine pretreatment anti- No regular preventive use of Research Triangle Park, NC) antiemetics for delayed fluorouracil (Efudex, Hoffman-LaRoche, Nutley, methotrexate (Rheumatrex, Lederle)thioguanine (Lanvis, Glaxo Wellcome)mercaptopurine (Purinethol, Glaxo Wellcome)bleomycin (Blenoxane, Bristol-Myers Oncology)1-asparaginase (Elspar, Merck)vindesine (Eldisine, Lilly)vinblastine (Velban, Lilly)vincristine (Oncovin, Lilly)busulphan (Myleran, Glaxo Wellcome)chlorambucil (Leukeran, Glaxo Wellcome)melphalan (Alkeran, Glaxo Wellcome)hydroxyurea (Hydrea, Bristol-Myers Oncology)fludarabine (Fludara, Berlex, Wayne, NJ)2-chlorodeoxyadenosine (Leustatin, Ortho Biotech, Raritan, NJ) tamoxifen (Nolvadex, Zeneca, Wilmington, DE) NOTE: Individual patients may require treatment similar to that recommended for intermediate-emetic-risk agents. Combinations of agents in this class are not well studied, but they may occasionally cause more emesis for some patients, requiring treatment similar to that recommended for intermediate-emetic-risk agents.
receiving these chemotherapy agents. The opinion of the C. Anticipatory Emesis panelists is that the risk is quite low for most patients; groups Anticipatory or conditioned emesis may occur in of patients receiving these drugs who are at greater risk have patients who have had poor control of either acute or delayed not been identified.
emesis with prior chemotherapy.218-228 Some factors that Although no prophylactic use of antiemetics is recom- predispose patients to anticipatory emesis have been mended, it may be reasonable for patients to have a small identified,229-234 including a history of motion sick- supply of oral dexamethasone, dopamine receptor antago- nists, or metoclopramide for use if needed.
1. Prevention Table 5. Radiation-Induced Emesis: Radiation Emetic Risk Categories
Prevention of chemotherapy-induced emesis is seen as the best strategy for preventing anticipatory emesis. Consensus was reached concerning prevention and treatment of antici- patory emesis, as outlined below.
Before each fraction: Guideline: Use of the most active antiemetic regimens appropriate for the chemotherapy being given to prevent Hemibody irradiation Before each fraction: acute or delayed emesis is suggested. Such regimens must be 5-HT3 antagonist or used with the initial chemotherapy, rather than after assess- dopamine receptor ing the patient's emetic response with less effective treat- Cranium (radiosurgery) Level of Evidence: III.
Grade of Recommendation: D.
dopamine receptor or5-HT3 antagonist 2. Treatment Guideline: If anticipatory emesis occurs, behavioral therapy with systematic desensitization is effective and is Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
Level of Evidence: III.
Second, it is often given on consecutive days. Third, the patient Grade of Recommendation: B.
may also be receiving radiation therapy, including total-bodyirradiation. Fourth, the patient may also have other medicalproblems or may be receiving other supportive care medi- d. Special Emetic Problems cines likely to cause emesis. Fifth, the majority of patients 1. Emesis in Pediatric Oncology have experienced emesis with prior chemotherapy or irradia- Guideline: The combination of a 5-HT tion. These are not only problems in emetic control, but they 3 antagonist plus a corticosteroid is suggested before chemotherapy in children are confounding factors that make clinical research in this receiving chemotherapy of high emetic risk.
area and comparison between different studies difficult.
Level of Evidence: III.
Some investigators have suggested that higher doses of Grade of Recommendation: B.
serotonin receptor antagonists are more effective in thissetting.255 If so, this is the only situation in which such dose Studies in children receiving chemotherapeutic agents escalation would be beneficial. It is difficult to understand have documented the efficacy of several antiemetics. The this argument based on the concept of the threshold dose most commonly used and best demonstrated antiemetics in saturating all relevant receptors.
children are the serotonin receptor antagonists, which are Few randomized trials have been done in the setting of often given with corticosteroids.245-248 Although the activity high-dose chemotherapy.253,256-259 Recommendations are based of such agents is well-documented, dosing studies have not on phase II studies performed in patients with a variety of clearly established the best doses or special dosing consider- different risk factors.260,261 ations by age, weight, or square meter of body surface area.
Typically used doses follow the adult regimens (eg, ondanse-tron 0.15 mg/kg and granisetron 0.01 mg/kg). The absence of 3. Vomiting and Nausea Despite Optimal Prophylaxis dystonic reactions and the low side-effect profile in general have in Current or Prior Cycles made these agents excellent choices for use in pediatrics.
Guideline: The Panel suggests that clinicians (1) conduct a Predisposition to acute dystonic reactions with dopamine antago- careful evaluation of risk, antiemetic, chemotherapy, tumor, and nists and metoclopramide have been well documented, espe- concurrent disease and medication factors, (2) ascertain that the cially with consecutive daily use of these antiemetics.
best regimen is being given for the emetic setting, (3) consider Although studies have not systematically outlined emetic adding an antianxiety agent to the regimen, and (4) consider risk factors in children, it seems that the chemotherapy selected substituting a dopamine receptor antagonist such as high-dose (with similar classifications as for adults) and prior emetic metoclopramide for the 5-HT experience with chemotherapy are important predictors of risk.249 3 antagonist (or add the dopamine antagonist to the regimen).
As is the case with dose-finding trials, few comparative Level of Evidence: V and Panel Consensus.
antiemetic studies have been conducted in children. Until Grade of Recommendation: D and Panel Consensus.
such studies are conducted, the Panel, led by the pediatric Approaching the patient who has not had good control consultant, agreed that the antiemetic recommendations for with the initial use of antiemetics for chemotherapy-induced adults (with doses adjusted for the pediatric population) arereasonable at this time. The major exception is that dopamine emesis presents several problems. The patient is predisposed receptor antagonists (as outlined in Delayed Emesis) are not to anticipatory emesis, and if the most effective antiemetics considered good choices for children receiving chemotherapy.
were given with the prior cycle of chemotherapy, good Behavioral intervention for reduction of nausea and vomiting control is not likely with the next treatment. When presented may also have some value.250-252 with such a patient, the physician should review severalfactors. These factors include antiemetic agent, chemother- 2. High-Dose Chemotherapy apy, and tumor status.
It is important to evaluate whether appropriate antiemetics Guideline: A 5-HT3 antagonist combined with a corticoste- for the patient's chemotherapy and risk factors were given roid is suggested.
previously, and if they were given at the proper dose and Level of Evidence: II and III.
schedule. If not, corrections in the antiemetic regimen could Grade of Recommendation: C.
be helpful. If the patient were receiving chemotherapy High-dose chemotherapy, often given as part of a bone marrow transplant or autologous stem-cell transplantation with lower emetic risk, then adjustment of the regimen to program, presents many concurrent problems in the control that typically used for a higher-risk group should be tried.
of emesis.253,254 First, the chemotherapy is generally catego- Because all serotonin antagonists share the same mechanism rized as high or intermediate risk as part of a combination.
of action, it is unlikely that substitution of one for another Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES would be superior to using the original agent, but well- emetic risk. More difficult to define, but also important designed studies investigating this have not been performed.
considerations for risk, are the dose of radiotherapy adminis- If the patient received an oral regimen, the physician could tered per fraction and the pattern of fractionation. Using consider giving agents intravenously, although there is no available data and clinical experience, the Panel reached demonstration that this will improve efficacy. If the patient is consensus on definitions of radiotherapy-induced emesis likely to have increased anxiety before the subsequent risk groups (Table 5).
chemotherapy, the possibility of anticipatory emesis war-rants attention. How poor was the control? One or twoepisodes of emesis with cisplatin is not an ideal outcome, 1. Guidelines but it still reflects substantial efficacy of the antiemetics, a. High Risk: Total-body irradiation (TBI). Guideline: with not much likelihood that another regimen would be The Panel suggested giving a serotonin receptor antagonist with or without a corticosteroid before each fraction and for Can the chemotherapy be altered to lessen emesis while at least 24 hours after.
still maintaining antitumor efficacy? Alteration could in- Level of Evidence: II and III clude avoiding multiple-day chemotherapy, lengthening Grade of Recommendation: B and C.
infusion time, stopping an agent, or substituting with a Review of the results of trials that used radiation allows chemotherapeutic drug less likely to induce emesis, if for a series of recommendations. The highest-risk group possible and prudent. Clearly, maintaining a good antitumor includes patients treated with TBI. The Panel was unani- response, or maximizing the chance of avoiding recurrence mous in its recommendation.
in the adjuvant setting, is of primary importance; however, Complete control rates with 5-HT3 antagonists for TBI in a palliative setting, consideration of improvement in the vary between 50% and 90%.254,263,272 The role of corticoste- chemotherapy regimen, if unacceptable emesis is occurring, roids in combination with 5-HT3 antagonists has not been should be given.
studied. If this approach adds efficacy, as occurs with Finally, if the patient is having poor control with appropri- chemotherapy, such regimens would be appropriate for this ate antiemetics, early evaluation of the tumor response is group. Some panelists advised giving corticosteroids to reasonable. Is the chemotherapy achieving its goal? Is patients receiving TBI because of the marked risk in this response occurring, or is the patient receiving palliation situation and findings in preliminary reports.273 There are worth the side effects? If the pattern of the occurrence of the reports that serotonin receptor antagonists are more effective emesis is not typical for the chemotherapy, are there other than metoclopramide or phenothiazines.264,274 disease-related factors (such as intestinal obstruction or b. Intermediate Risk: Hemibody irradiation, upper abdo- brain metastases) that may be causing the emesis? Can one men, abdominal-pelvic, mantle, craniospinal irradiation, rule out other medications (pain medicines, bronchodilators) and cranial radiosurgery. Guideline: The Panel suggested or other disease factors (infection, gastritis) that could be giving a serotonin receptor antagonist or a dopamine recep- complicating the treatment and evaluation of emesis? tor antagonist before each fraction.
Level of Evidence: II and III.
Grade of Recommendation: B.
II. RADIATION-INDUCED EMESIS Existing evidence suggests that preventative treatment is A. Risk Factors for Radiation-Induced Emesis better than intervention on an as-needed basis in this group The risk of emesis with radiotherapy varies with the (see Table 5 for group definition) and that serotonin receptor treatment administered.262-271 Only a minority of patients antagonists are more effective than metoclopramide or receive radiation therapy of high emetic potential, and in that phenothiazines.264,274 There may be smaller differences group of patients, the problem can be difficult to prevent or between these agents in intermediate-risk settings than in manage. Controversy, due to a lack of systematic evaluation, higher-risk settings, and therefore dopamine receptor antago- exists concerning definitions of emetic risk groups. As with nists may be more appropriate, particularly in patients chemotherapy-induced emesis, it is the identification of receiving craniospinal or lower-half-body radiotherapy, where these risk groups that indicates whether antiemetic therapy there is somewhat less risk of emesis.275 There is also some should be given routinely on a preventative basis or whether evidence to suggest that in fractionated radiotherapy, the antiemetics should be reserved for treatment as needed by efficacy of 5-HT3 antagonists may decrease after the first individual patients. The radiation oncology literature indi- week of treatment,276 making it difficult to suggest what the cates that treatment field is one of the major determinants of optimal duration of prophylactic treatment should be.
Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
Trials indicate that both serotonin and dopamine receptor Level of Evidence: IV and V.
antagonist agents are effective for patients who require Grade of Recommendation: B-D.
treatment in this group, with most studies indicating better The incidence of emesis in this patient group, as defined control with serotonin receptor antagonists.274,275 In trials, in Table 5, is relatively low (0% to 30%). Treatment should cannabinoids (such as nabilone and levonantradol) have not be reserved for those patients who experience nausea and provided adequate control of emesis and have had a higher vomiting. With a paucity of trials, and because of the rate of side effects than seen with dopamine or serotonin previously mentioned evidence that the difference in effica- receptor antagonists.277 A recent study indicates that dexa- cybetween 5-HT3 antagonists and dopamine antagonists is methasone has efficacy similar to 5-HT smaller in intermediate- and low-risk settings, dopamine 3 antagonists when given to patients receiving radiotherapy to the upper abdo- antagonists are recommended for routine use with 5-HT3 antagonists reserved for rescue.
c. Low Risk: Radiation of the Cranium Only, Breast, Head and Neck, Extremities, Pelvis, and Thorax. Guideline: ThePanel suggested that treatment be given on an as-needed The Expert Panel expresses its gratitude to Drs Douglas W. Blayney, George J. Bosl, Allen B. Bredt, David R. Gandara, Patricia A. Ganz, basis only. Dopamine or serotonin receptor antagonists are John D. Hainsworth, Robert M. Langdon, Jr, Rudolph M. Navari, T.J.
advised. Antiemetics should be continued prophylactically Priestman, and Fausto Roila for their thoughtful reviews of earlier for each remaining radiation treatment day.
versions of the guidelines.
Antiemetic Guideline Expert Panel Richard J. Gralla, MD, Co-Chair Ochsner Cancer Institute, New Orleans, LA Medical Oncology David Osoba, MD, Co-Chair QOL Consulting, Vancouver, British Columbia, Canada Medical Oncology Lawrence W. Chinnery Rockville, MD Patient Representative Rebecca Clark-Snow, RN, BSN, OCN University of Kansas Cancer Center, Kansas City, KS Oncology Nurse David P. Gill, MD Webster, TX Medical Oncology/Hematology Susan Groshen, PhD University of Southern California, Norris Cancer Center, Los Angeles, CA Biostatistician Steven M. Grunberg, MD University of Vermont Medical Center, Burlington, VT Medical Oncology Paul J. Hesketh, MD St Elizabeth's Medical Center, Boston, MA Medical Oncology Peter Kirkbride, MD Princess Margaret Hospital, Toronto, Ontario, Canada Radiation Oncology Memorial Sloan-Kettering Cancer Center, New York, NY Medical Oncology Jim M. Koeller, MS University of Texas at Austin and the Health Science Center, San Antonio, TX Pharmacist Gary R. Morrow, PhD University of Rochester Cancer Center, Rochester, NY Behavioral Medicine Edith A. Perez, MD Mayo Clinic, Jacksonville, FL Medical Oncology/Hematology Jeffrey H. Silber, MD, PhD Children's Hospital of Philadelphia, Philadelphia, PA Pediatric Oncology 1. Plosker GL, Milne RJ: Ondansetron: A pharmacoeconomic and 6. American Society of Clinical Oncology: Disclosure declaration quality-of-life evaluation of its antiemetic activity in patients receiving form. Alexandria, VA, American Society of Clinical Oncology, 1999, cancer chemotherapy. Pharmacoeconomics 2:285-304, 1992 2. Weeks JC: Special issues that arise in applying techniques of 7. Aapro MS: Methodological issues in antiemetic studies. Invest economic analysis to evaluation of cancer therapies. Monogr Natl Inst New Drugs 11:243-253, 1993 8. Gralla RJ, Clark RA, Kris MG, et al: Methodology in anti-emetic 3. Aapro MS: Costs and benefits of antiemetic therapy. Support Care trials. Eur J Cancer 27:S5-S8, 1991 Cancer 2:304-306, 1994 9. Fetting JH, Grochow LB, Folstein MF, et al: The course of nausea 4. Canadian Medical Association: The Canadian task force on the and vomiting after high-dose cyclophosphamide. Cancer Treat Rep periodic health examination. Can Med Assoc J 121:1193-1254, 1979 66:1487-1493, 1982 5. American Society of Clinical Oncology Ad Hoc Colony- 10. Andrews PLR, Davis CJ: The physiology of emesis induced by Stimulating Factor Guideline Expert Panel: American Society of anti-cancer therapy, in Reynolds DJM, Andrews PLR, Davis CJ Clinical Oncology recommendations for the use of hematopoietic (eds): Serotonin and the Scientific Basis of Anti-Emetic Therapy.
colony stimulating factors: Evidence-based, clinical practice guidelines.
Oxford, United Kingdom, Oxford Clinical Communications, 1995, J Clin Oncol 12:2471-2508, 1994 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES 11. Morrow GR: A patient report measure for the quantification of 26. Burris H, Hesketh P, Cohn J, et al: Efficacy and safety of oral chemotherapy induced nausea and emesis: Psychometric properties of granisetron versus oral prochlorperazine in preventing nausea and the Morrow Assessment of Nausea and Emesis (MANE). Br J Cancer emesis in patients receiving moderately emetogenic chemotherapy.
19:S72-S74, 1992 (suppl) Cancer J Sci Am 2:85-90, 1996 12. Willan A, Warr D, Pater J, et al: Methodological issues and 27. Warr D, Willan A, Fine S, et al: Superiority of granisetron to antiemetic studies, in Osoba D (ed): Effect of Cancer on Quality of Life.
dexamethasone plus prochlorperazine in the prevention of chemotherapy- Boca Raton, FL, CRC Press, 1991, pp 229-249 induced emesis. J Natl Cancer Inst 83:1169-1173, 1991 13. Clark R, Tyson L, Frisone M: A correlation of objective (OBJ) 28. Marty M: A comparative study of the use of granisetron, a and subjective (SUBJ) parameters in assessing antiemetic regimens selective 5-HT3 antagonist, versus a standard anti-emetic regimen of (AER). Oncol Nurs Forum 12:96, 1985 (suppl) chlorpromazine plus dexamethasone in the treatment of cytostatic- 14. Perez EA, Hesketh P, Sandbach J, et al: Comparison of single- induced emesis. Eur J Cancer 26:S28-S32, 1990 (suppl 1) dose oral granisetron versus intravenous ondansetron in the prevention 29. Jones AL, Hill AS, Soukop M, et al: Comparison of dexametha- of nausea and vomiting induced by moderately emetogenic chemother- sone and ondansetron in the prophylaxis of emesis induced by apy: A multicenter, double-blind, randomized parallel study. J Clin moderately emetogenic chemotherapy. Lancet 338:483-487, 1991 Oncol 16:754-760, 1998 30. Levitt M, Warr D, Yelle L, et al: Ondansetron compared with 15. Gralla R, Navari RM, Hesketh PJ, et al: Single-dose granisetron dexamethasone and metoclopramide as antiemetics in the chemother- has equivalent antiemetic efficacy to intravenous ondansetron for highly apy of breast cancer with cyclophosphamide, methotrexate, and fluoro- emetogenic cisplatin-based chemotherapy. J Clin Oncol 16:1568-1573, uracil. N Engl J Med 328:1081-1084, 1993 31. Warr D, Willan A, Venner P, et al: A randomised, double-blind 16. Addelman M, Erlichman C, Fine S, et al: Phase I/II trial of comparison of granisetron with high-dose metoclopramide, dexametha- granisetron: A novel 5-hydroxytryptamine antagonist for the prevention sone and diphenhydramine for cisplatin-induced emesis. Eur J Cancer of chemotherapy-induced nausea and vomiting. J Clin Oncol 8:337- 32. Chevallier B: Efficacy and safety of granisetron compared with 17. Marty M, Pouillart P, Scholl S, et al: Comparison of the high-dose metoclopramide plus dexamethasone in patients receiving 5-hydroxytryptamine 3 (serotonin) antagonist ondansetron (GR 38032F) high-dose cisplatin in a single-blind study. Eur J Cancer 26:S33-S36, with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 322:816-821, 1990 33. Heron JF, Goedhals L, Jordaan JP, et al: Oral granisetron alone 18. De Mulder PHM, Seynaeve C, Vermorken JB, et al: Ondansetron and in combination with dexamethasone: A double-blind randomized compared with high-dose metoclopramide in prophylaxis of acute and comparison against high-dose metoclopramide plus dexamethasone in delayed cisplatin-induced nausea and vomiting. Ann Intern Med prevention of cisplatin-induced emesis. Ann Oncol 5:579-584, 1994 113:834-840, 1990 34. Sorbe B, Berglind AM: Tropisetron, a new 5-HT 19. Hainsworth J, Harvey W, Pendergrass K, et al: A single-blind antagonist, in the prevention of radiation-induced nausea, vomiting and comparison of intravenous ondansetron, a selective serotonin antago- diarrhoea. Drugs 43:33-39, 1992 (suppl 3) nist, with intravenous metoclopramide in the prevention of nausea and 35. Sorbe B, Hogberg T, Himmelmann A, et al: Efficacy and vomiting associated with high-dose cisplatin chemotherapy. J Clin tolerability of tropisetron in comparison with a combination of tropise- Oncol 9:721-728, 1991 tron and dexamethasone in the control of nausea and vomiting in- 20. Soukop M, McQuade B, Hunter E, et al: Ondansetron compared duced by cisplatin-containing chemotherapy. Eur J Cancer 30A:629- with metoclopramide in the control of emesis and quality of life during repeated chemotherapy for breast cancer. Oncology 49:295-304, 1992 36. Rusthoven J, O'Brien BJ, Rocchi A: Ondansetron versus meto- 21. Tsavaris N, Charalambidis G, Ganas N, et al: Ondansetron versus metoclopramide as antiemetic treatment during cisplatin-based chemo- clopramide in the prevention of chemotherapy-induced nausea and therapy. Acta Oncol 34:243-246, 1995 vomiting: A meta-analysis. Int J Oncol 1:443-450, 1992 22. Chevallier B, Cappelaere P, Splinter T, et al: A double-blind, 37. Bruntsch U, Drechsler S, Hiller E, et al: Prevention of chemother- multicentre comparison of intravenous dolasetron mesylate and metoclo- apy-induced nausea and emesis in patients responding poorly to pramide in the prevention of nausea and vomiting in cancer patients previous antiemetic therapy comparing tropisetron with optimised receiving high-dose cisplatin chemotherapy. Support Care Cancer standard antiemetic therapy. Drugs 43:23-26, 1992 (suppl 3) 38. Ruff P, Paska W, Goedhals L, et al: Ondansetron compared with 23. Bonneterre J, Chevallier B, Metz R, et al: A randomized granisetron in the prophylaxis of cisplatin-induced acute emesis: A double-blind comparison of ondansetron and metoclopramide in the multi-centre double-blind, randomised, parallel-group study. Oncology prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy. J Clin Oncol 8:1063-1069, 39. Gebbia V, Cannata G, Testa A, et al: Ondansetron versus granisetron in the prevention of chemotherapy-induced nausea and 24. Kaasa S, Kvaly S, Dicato MA, et al: A comparison of ondanse- vomiting. Cancer 74:1945-1952, 1994 tron with metoclopramide in the prophylaxis of chemotherapy-induced 40. Navari R, Gandara D, Hesketh P, et al: Comparative clinical trial nausea and vomiting: A randomized, double-blind study—International of granisetron and ondansetron in the prophylaxis of cisplatin-induced Emesis Study Group. Eur J Cancer 26:311-314, 1990 emesis. J Clin Oncol 13:1242-1248, 1995 25. Fauser AA, Bleiberg H, Chevallier B, et al: A double-blind, 41. Martoni A, Angelelli B, Guaraldi M, et al: An open randomised randomized, parallel study of IV dolasetron mesylate versus IV cross-over study on granisetron versus ondansetron in the prevention of metoclopramide in patients receiving moderately emetogenic chemother- acute emesis induced by moderate dose cisplatin-containing regimens.
apy. Cancer J 9:196-202, 1996 Eur J Cancer 32A:82-85, 1996 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
42. Bonneterre J, Hecquet B: Granisetron (IV) compared with 59. Freeman A, Cunningham K, Tyers M: Selectivity of 5HT3 ondansetron (IV plus oral) in the prevention of nausea and vomiting receptor antagonists and antiemetic mechanisms of action. Anticancer induced by moderately-emetogenic chemotherapy: A cross-over study.
Drugs 3:79-85, 1992 Bull Cancer 82:1038-1043, 1995 60. Marr H, Dancy P, Bartlett A: Emerging differences between 43. Stewart A, McQuade B, Cronje JD, et al: Ondansetron compared 5-HT3 receptor antagonists. Anticancer Drugs 2:513-518, 1991 with granisetron in the prophylaxis of cyclophosphamide-induced 61. Grunberg SM: Phase I and other dose-ranging studies of emesis in outpatients: A multicentre, double-blind, double-dummy, ondansetron. Semin Oncol 19:16-22, 1992 randomized, parallel group study. Oncology 52:202-210, 1995 62. The Italian Group for Antiemetic Research: Dexamethasone, 44. Jantunen IT, Muhonen TT, Kataja V, et al: 5-HT3 receptor granisetron, or both for the prevention of nausea and vomiting during antagonists in the prophylaxis of acute vomiting induced by moderately chemotherapy for cancer. N Engl J Med 332:1-5, 1995 63. Kris MG, Gralla RJ, Clark RA, et al: Phase II trials of the emetogenic chemotherapy: A randomised study. Eur J Cancer 29A:1669- serotonin antagonist GR38032F for the control of vomiting caused by cisplatin. J Natl Cancer Inst 81:42-46, 1989 45. Hesketh P, Navari R, Grote T, et al: Double-blind, randomized 64. Grunberg SM, Stevenson LL, Russell CA, et al: Dose ranging comparison of the antiemetic efficacy of intravenous dolasetron me- phase I study of the serotonin antagonist GR38032F for prevention of sylate and intravenous ondansetron in the prevention of acute cisplatin- cisplatin-induced nausea and vomiting. J Clin Oncol 7:1137-1141, 1989 induced emesis in patients with cancer. J Clin Oncol 14:2242-2249, 65. Grunberg SM, Lane M, Lester EP: Randomized double-blind comparison of three dose levels of intravenous ondansetron in the 46. Fauser AA, Duclos B, Chemaissani A, et al: Therapeutic prevention of cisplatin-induced emesis. Cancer Chemother Pharmacol equivalence of single oral doses of dolasetron mesylate and multiple doses of ondansetron for the prevention of emesis after moderately 66. Seynaeve C, Schuller J, Buser K, et al: Comparison of the emetogenic chemotherapy. Eur J Cancer 32A:1523-1529, 1996 anti-emetic efficacy of different doses of ondansetron, given as either a 47. Lofters WS, Pater JL, Zee B, et al: Phase III double-blind continuous infusion or a single intravenous dose, in acute cisplatin- comparison of dolasetron mesylate and ondansetron and an evaluation induced emesis: A multicentre, double-blind, randomised, parallel of the additive role of dexamethasone in the prevention of acute and group study. Br J Cancer 66:192-197, 1992 delayed nausea and vomiting due to moderately emetogenic chemother- 67. Beck TM, Hesketh PJ, Madajewicz S, et al: Stratified, random- apy. J Clin Oncol 15:2966-2973, 1997 ized, double-blind comparison of intravenous ondansetron administered 48. Audhuy B, Cappelaere P, Martin M, et al: A double-blind, as a multiple-dose regimen versus two single-dose regimens in the randomised comparison of the anti-emetic efficacy of two intravenous prevention of cisplatin-induced nausea and vomiting. J Clin Oncol doses of dolasetron mesylate and granisetron in patients receiving 10:1969-1975, 1992 high-dose cisplatin chemotherapy. Eur J Cancer 32A:807-813, 1996 68. Riviere A: Dose finding study of granisetron in patients receiving 49. Mantovani G, Maccio A, Bianchi A, et al: Comparison of high-dose cisplatin chemotherapy. Br J Cancer 69:967-971, 1994 granisetron, ondansetron, and tropisetron in the prophylaxis of acute 69. Navari RM, Kaplan HG, Gralla RJ, et al: Efficacy and safety of nausea and vomiting induced by cisplatin for the treatment of head and granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in neck cancer: A randomized controlled trial. Cancer 77:941-948, 1996 the prevention of nausea and vomiting induced by high-dose cisplatin. J 50. Marty M, Kleisbauer JP, Fournal P, et al: Is Navoban (tropise- Clin Oncol 12:2204-2210, 1994 tron) as effective as Zofran (ondansetron) in cisplatin-induced emesis.
70. Soukop M: A comparison of two dose levels of granisetron in Anticancer Drugs 6:15-21, 1995 (suppl 1) patients receiving high-dose cisplatin. Eur J Cancer 26:S15-S19, 1990(suppl 1) 51. Andrews PLR, Bhandari P, Davey PT, et al: Are all 5-HT3 71. Smith IE: A comparison of two dose levels of granisetron in receptor antagonists the same? Eur J Cancer 28A:S2-S6, 1992 (suppl 1) patients receiving moderately emetogenic cytostatic chemotherapy. Eur 52. Beleslin DB: Neurotransmitter receptor subtypes related to J Cancer 26:S19-S23, 1990 (suppl 1) vomiting, in Bianchi AL, Grelot L, Miller AD, et al (eds): Mechanisms 72. Kris MG, Grunberg SM, Gralla RJ, et al: Dose-ranging evalua- and Control of Emesis. London, United Kingdom, John Libbey tion of the serotonin antagonist dolasetron mesylate in patients receiv- Eurotext Ltd, 1992, pp 11-18 ing high-dose cisplatin. J Clin Oncol 12:1045-1049, 1994 53. Blackwell CP, Harding SM: The clinical pharmacology of 73. Thant M, Pendergrass K, Harman G, et al: Double-blind, ondansetron. Eur J Cancer Clin Oncol 25:S21-S24, 1989 randomized study of the dose response relationship across five single 54. Butler A, Hill JM, Ireland SJ, et al: Pharmacological properties doses of IV dolasetron mesylate for prevention of acute nausea and of GR38032F, a novel antagonist at 5-HT3 receptors. Br J Clin vomiting after cisplatin chemotherapy. Proc Am Soc Clin Oncol 15:533, Pharmacol 94:397-412, 1988 1996 (abstr 1727) 55. Hesketh PJ, Gandara DR: Serotonin antagonists: A new class of 74. Pendergrass K, Audhuy B, Hesketh P, et al: Analysis of optimal antiemetic agents. J Natl Cancer Inst 83:613-20, 1991 dose from eight pooled clinical trials assessing the acute antiemetic 56. Wilder-Smith O, Borgeat A, Chappius P, et al: Urinary serotonin efficacy of IV dolasetron mesylate after emetogenic chemotherapy. Proc metabolic excretion during cisplatin chemotherapy. Cancer 72:2239- Am Soc Clin Oncol 15:547, 1996 (abstr 1782) 75. Khojasteh A, Sartiano G, Tapazoglou E, et al: Ondansetron for 57. Andrews PL, Bhandri P: The 5-hydroxytryptamine receptor the prevention of emesis induced by high-dose cisplatin: A multi-center antagonists as antiemetics: Preclinical evaluation and mechanism of dose-response study. Cancer 66:1101-1105, 1990 action. Eur J Cancer 29A:S11-S16, 1993 76. Kris MG, Gralla RJ, Clark RA, et al: Dose-ranging evaluation of 58. Beattie DT, Beresford IJM, Connor HE, et al: The pharmacology the serotonin antagonist GR-C507/75 (GR38032F) when used as an of GR203040, a novel, potent and selective non-peptide tachykinin antiemetic in patients receiving anticancer chemotherapy. J Clin Oncol NK1 receptor antagonist. Br J Pharmacol 116:3149-3157, 1995 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES 77. Rubenstein E, Fauser A, Grote T, et al: Determination of optimal 93. Cubeddu LX, Pendergrass K, Ryan T, et al: Efficacy of oral dolasetron mesylate (DM) dose in prevention of acute nausea and ondansetron, a selective antagonist of 5-HT3 receptors, in the treatment vomiting (ANV) after moderately emetogenic chemotherapy (MECT) of nausea and vomiting associated with cyclophosphamide-based using pooled data from three pivotal trials. Proc Am Soc Clin Oncol chemotherapy. Am J Clin Oncol 17:137-146, 1994 15:532, 1996 (abstr 1722) 94. Dicato MA: Oral treatment with ondansetron in an outpatient 78. Wymenga ANM, Van Der Graaf WTA, Wils JA, et al: A setting. Eur J Cancer 27:518-519, 1991 (suppl) randomized, double-blind, multicentre study comparing daily 2 and 5 95. Clavel M, Bonneterre J, d'Allens H, et al: Oral ondansetron in mg of tropisetron for the control of nausea and vomiting induced by the prevention of chemotherapy-induced emesis in breast cancer low-dose cisplatin- or non-cisplatin-containing chemotherapy. Ann patients: French Ondansetron Study Group. Eur J Cancer 31A:15-19, Oncol 7:505-510, 1996 79. Garbe C, Drechsler S, Fiedler H, et al: Dose comparison of 96. The Italian Group for Antiemetic Research: Ondansetron versus tropisetron (Navoban) 5 mg and 10 mg orally in the prophylaxis of granisetron, both combined with dexamethasone, in the prevention of dacarbazine-induced nausea and emesis. Semin Oncol 21:12-16, 1994 cisplatin-induced emesis. Ann Oncol 6:805-810, 1995 97. Roila F, Tonato M, Cognetti F, et al: Prevention of cisplatin- 80. Ettinger DS, Eisenberg PD, Fitts D, et al: A double-blind induced emesis: A double-blind multicenter randomized crossover comparison of the efficacy of two dose regimens of oral granisetron in study comparing ondansetron and ondansetron plus dexamethasone. J preventing acute emesis in patients receiving moderately emetogenic Clin Oncol 9:675-678, 1991 chemotherapy. Cancer 78:144-151, 1996 98. Smyth JF, Coleman RE, Nicolson M, et al: Dose dexamethasone 81. Harman GS, Omura GA, Ryan K, et al: A randomized, double- enhance control of acute cisplatin induced emesis by ondansetron. BMJ blind comparison of single-dose and divided multiple-dose dolasetron 303:1423-1426, 1991 for cisplatin-induced emesis. Cancer Chemother Pharmacol 38:323- 99. Hesketh PJ, Harvey WH, Harker WG, et al: A randomized, double-blind comparison of intravenous ondansetron alone and in 82. Kaizer L, Warr D, Hoskins P, et al: Effect of schedule and combination with intravenous dexamethasone in the prevention of maintenance on the antiemetic efficacy of ondansetron combined with nausea and vomiting associated with high-dose cisplatin. J Clin Oncol dexamethasone in acute and delayed nausea and emesis in patients receiving moderately emetogenic chemotherapy: A phase III trial by the 100. Joss RA, Bacchi M, Buser K, et al: Ondansetron plus dexametha- National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol sone is superior to ondansetron alone in the prevention of emesis in 12:1050-1057, 1994 chemotherapy-naive and previously treated patients. Ann Oncol 5:253- 83. de Bruijn KM: Tropisetron: A review of the clinical experience.
Drugs 43:11-22, 1992 (suppl 3) 101. Latreille J, Pater J, Johnston D, et al: Use of dexamethasone and 84. Dogliotti L, Antonacci RA, Paze E, et al: Three years' experience granisetron in the control of delayed emesis for patients who receive with tropisetron in the control of nausea and vomiting in cisplatin- highly emetogenic chemotherapy: National Cancer Institute of Canada treated patients. Drugs 43:6-10, 1992 (suppl 3) Clinical Trials Group. J Clin Oncol 16:1174-1178, 1998 85. Balfour JA, Goa KL: Dolasetron: A review of its pharmacology and therapeutic potential in the management of nausea and vomiting 102. Carmichael J, Bessel EM, Harris AL, et al: Comparison of induced by chemotherapy, radiotherapy or surgery. Drugs 54:273-298, granisetron alone and granisetron plus dexamethasone in the prophy- laxis of cytotoxic-induced emesis. Br J Cancer 70:1161-1164, 1994 86. Rache K, Schworer H, Kilbinger H: The Pharmacology of 5-HT3 103. Garcia-del-muro X, Vadell C, Flores E, et al: Tropisetron alone Release from Enterochromaffin Cells. 1995, p 18 and in combination with dexamethasone in the prevention of acute and 87. Grote TH, Pineda LF, Figlin RA, et al: Oral dolasetron mesylate delayed cisplatin-induced emesis. Proc Am Soc Clin Oncol 15:553, in patients receiving moderately emetogenic platinum-containing chemo- 1996 (abstr 1725) therapy: Oral Dolasetron Dose Response Study Group. Cancer J Sci Am 104. The Italian Group for Antiemetic Research: Ondansetron ⫹ dexamethasone vs metoclopramide ⫹ dexamethasone ⫹ diphenhydra- 88. Rubenstein EB, Gralla RJ, Hainsworth JD, et al: Randomized, mine in prevention of cisplatin-induced emesis. Lancet 340:96-99, 1992 double-blind, dose response trial across four oral doses of dolasetron for 105. Cunningham D, Dicato M, Verweij J: Optimum anti-emetic the prevention of acute emesis after moderately emetogenic chemother- therapy for cisplatin induced emesis over repeat courses: Ondansetron apy. Cancer 79:1216-1224, 1998 plus dexamethasone compared with metoclopramide, dexamethasone 89. Kris MG, Radford JE, Pizzo BA, et al: Use of an NK-1 receptor plus lorazepam. Ann Oncol 7:277-282, 1996 antagonist to prevent delayed emesis following cisplatin. J Natl Cancer 106. Aapro MS, Plezia PM, Alberts DS, et al: Double-blind cross- Inst 89:817-818, 1997 over study of the antiemetic efficacy of high-dose dexamethasone 90. Fraschini G, Ciociola A, Esparza L, et al: Evaluation of three oral versus high-dose metoclopramide. J Clin Oncol 2:466-471, 1984 dosages of ondansetron in the prevention of nausea chemotherapy. J 107. Cassileth PA, Lusk EJ, Torri S, et al: Antiemetic efficacy of Clin Oncol 9:1268-1274, 1991 dexamethasone therapy in patients receiving cancer chemotherapy.
91. Beck TM, Ciociola AA, Jones SE, et al: Efficacy of oral Arch Intern Med 143:1347-1349, 1983 ondansetron in the prevention of emesis in outpatients receiving 108. Cassileth PA, Lusk EJ, Torri S, et al: Antiemetic efficacy of cyclophosphamide-based chemotherapy. Ann Intern Med 118:407-413, high-dose dexamethasone in induction therapy in acute nonlymphocytic leukemia. Ann Intern Med 100:701-702, 1984 92. Beck T, York M, Chang A, et al: Oral ondansetron 8 mg twice 109. Markman M, Sheidler V, Ettinger DS, et al: Antiemetic efficacy daily is as effective as 8 mg three times daily in the prevention of nausea of dexamethasone: Randomized double-blind crossover study with and vomiting associated with moderately emetogenic cancer chemother- prochlorperazine in patients receiving cancer chemotherapy. N Engl J apy. Cancer Invest 15:297-303, 1997 Med 311:549-552, 1984 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
110. Aapro MS, Alberto DS: High-dose dexamethasone for preven- 127. Grunberg SM, Akerley WA, Krailo MD, et al: Comparison of tion of cisplatinum-induced vomiting. Cancer Chemother Pharmacol metoclopramide and metoclopramide plus dexamethasone for complete protection from cisplatinum-induced emesis. Can Invest 4:379-385, 111. D'Olimpio J, Camacho F, Chrandra P, et al: Antiemetic efficacy of high-dose dexamethasone versus placebo in patients receiving 128. Grunberg SM, Ehler E, McDermed JE, et al: Oral metoclopra- cisplatin-based chemotherapy: A randomized double-blind controlled mide with or without diphenhydramine: Potential for prevention of late clinical trial. J Clin Oncol 3:1133-1135, 1985 nausea and vomiting induced by cisplatin. J Natl Cancer Inst 80:864- 112. Lee B: Methylprednisolone as an antiemetic. N Engl J Med 304:486-498, 1981 129. Hays H: Antiemetic efficacy of metoclopramide. N Engl J Med 113. Osoba D, Erlichman C, Willan A, et al: Superiority of methyl- 306:485-486, 1982 prednisolone succinate over low-dose metoclopramide hydrochloride in 130. Strum SB, McDermed JE, Opfell RW, et al: Intravenous the prevention of nausea and vomiting produced by cancer chemother- metoclopramide: An effective antiemetic in cancer chemotherapy.
apy. Clin Invest Med 9:225-231, 1986 JAMA 247:2683-2686, 1982 114. Osoba D, Erlichman C, Willan A, et al: Failure of methylpred- 131. Allan SG, Cornbleet MA, Warrington PS, et al: Dexamethasone nisolone acetate to prolong the antinauseant effect of intravenous and high dose metoclopramide: Efficacy in controlling cisplatin induced methylprednisolone sodium succinate in patients receiving chemother- nausea and vomiting. BMJ 289:878-879, 1984 apy. Clin Invest Med 11:377-379, 1988 132. Anthony LB, Krozely MG, Woodward NJ, et al: Antiemetic 115. Roila F, Basurto C, Minotto V, et al: Methylprednisolone versus effect of oral versus intravenous metoclopramide in patients receiving metoclopramide for prevention of nausea and vomiting in breast cancer cisplatin: A randomized, double-blind trial. J Clin Oncol 4:98-103, 1984 patients treated with intravenous cyclophosphamide methotrexate 133. Allen JC, Gralla R, Reilly L, et al: Metoclopramide: Dose- 5-flourouracil: A double-blind randomized study. Oncology 45:346- related toxicity and preliminary antiemetic studies in children receiving cancer chemotherapy. J Clin Oncol 3:1136-1141, 1985 116. Campora E, Chiari S, Bruzzi P, et al: The antiemetic efficacy of 134. Kris MG, Tyson LB, Gralla RJ, et al: Extrapyramidal reactions methylprednisolone compound with metoclopramide in out-patients with high-dose metoclopramide. N Engl J Med 309:433-434, 1983 receiving adjuvant CMF chemotherapy for breast cancer: A randomized trial. Tumori 71:459-462, 1985 135. Owens NJ, Schauer AR, Nightingale CH, et al: Antiemetic 117. Jez E, Sulkes A, Ochayen L, et al: Methylprednisolone versus efficacy of prochlorperazine, haloperidol, and droperidol in cisplatin- metoclopramide as antiemetic treatment in patients receiving adjuvant induced emesis. Clin Pharm 3:167-170, 1984 cyclophosphamide, methotrexate, 5 fluorouracil (CMF) chemotherapy: 136. Grunberg SM, Gala KV, Lampenfeld M, et al: Comparison of A randomized crossover blind study. J Chemother 1:365-368, 1989 the antiemetic effect of high-dose intravenous metoclopramide and 118. Chiara S, Campora E, Lionetto R, et al: Methylprednisolone for high-dose intravenous haloperidol in a randomized double-blind cross- the control of CMF-induced emesis. Am J Clin Oncol 10:264-267, 1987 over study. J Clin Oncol 2:782-787, 1984 119. Morrow G, Laughner J, Bennett J: Prevalence of nausea and 137. Silvey L, Carpenter JT, Wheeler RH, et al: A randomized vomiting and other side effects in patients receiving cytoxan, methotrex-ate, fluorouracil (CMF) therapy with and without prednisone. Proc Am comparison of haloperidol plus dexamethasone versus prochlorperazine Soc Clin Oncol 3:105, 1984 (abstr C-408) plus dexamethasone in preventing nausea and vomiting in patients 120. Kris MG, Gralla RJ, Tyson LB, et al: Improved control of receiving chemotherapy for breast cancer. J Clin Oncol 6:1397-1400, cisplatin-induced emesis with high-dose metoclopramide and with combinations of metoclopramide, dexamethasone, and diphenhydra- 138. Bregni M, Siena S, DiNicola M, et al: Tropisetron plus mine: Results of consecutive trials in 255 patients. Cancer 55:527-534, haloperidol to ameliorate nausea and vomiting associated with high- dose alkylating agent cancer chemotherapy. Eur J Cancer 27:561-565, 121. Italian Group for Antiemetic Research: Double-blind, dose- finding study of four intravenous doses of dexamethasone in the 139. Moertel CG, Reitemeier RJ, Gage R: A controlled clinical prevention of cisplatin-induced acute emesis. J Clin Oncol 16:2937- evaluation of antiemetic drugs. JAMA 186:116-118, 1963 140. Goldstein D, Levi JA, Woods RL, et al: Double-blind random- 122. Herrstedt J, Aapro MS, Smyth JF, et al: Corticosteroids, ized cross-over trial of dexamethasone and prochlorperazine as anti- dopamine antagonists and other drugs. Support Care Cancer 6:204-214, emetics for cancer chemotherapy. Oncology 46:105-108, 1989 141. Carr BI, Blayney DW, Goldberg DA, et al: High doses of 123. Fozard JR, Mobarok Ali ATM: Blockade of neuronal trypt- prochlorperazine for cisplatin-induced emesis: A prospective, random amine receptors by metoclopramide. Eur J Pharmacol 49:109-112, 1978 dose-response study. Cancer 60:2165-2169, 1987 124. Alavi JB, Torri S, Glick JH: High dose oral metoclopramide: An 142. Saller R, Hellenbrect D: High doses of metoclopramide or effective antiemetic agent. Proc Am Soc Clin Oncol 3:109, 1984 (abstr droperidol in the prevention of cisplatin-induced emesis. Eur J Cancer Clin Oncol 22:1199-1203, 1986 125. Gralla RJ, Braun TJ, Squillante A, et al: Metoclopramide: Initial 143. Einhorn L: Nabilone: An effective antiemetic agent in patients clinical studies of high dose regimens in cisplatin-induced emesis, in receiving cancer chemotherapy. Cancer Treat Rev 9:55-61, 1982 Poster D (ed): The Treatment of Nausea and Vomiting Induced by 144. Frytak S, Moertel CG, O'Fallon JR, et al: Delta-9-tetrahydrocan- Cancer Chemotherapy. New York, NY, Masson, 1981, pp 167-176 nabinol as an antiemetic for patients receiving cancer chemotherapy.
126. Gralla RJ, Itri LM, Pisko SE, et al: Antiemetic efficacy of Ann Intern Med 91:825-830, 1979 high-dose metoclopramide: Randomized trials with placebo and prochlor- 145. Herman TS, Einhorn LH, Jones SE, et al: Superiority of perazine in patients with chemotherapy-induced nausea and vomiting.
nabilone over prochlorperazine as an antiemetic in patients receiving N Engl J Med 305:905-909, 1981 cancer chemotherapy. N Engl J Med 300:1295-1297, 1979 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES 146. McCabe M, Smith FP, MacDonald JS, et al: Efficacy of 164. Kris MG, Gralla RJ, Clark RA, et al: Consecutive dose-finding tetrahydrocannabinol in patients refractory to standard antiemetic trials adding lorazepam to the combination of metoclopramide plus therapy. Invest New Drugs 6:243-246, 1988 dexamethasone: Improved subjective effectiveness over the combina- 147. Chang AE, Shiling DJ, Stillman RC, et al: Delta-9-tetrahydro- tion of diphenhydramine plus metoclopramide plus dexamethasone.
cannabinol as an antiemetic in cancer patients receiving high-dose Cancer Treat Rep 69:1257-1262, 1985 methotrexate. Ann Intern Med 91:819-24, 1979 165. Laszlo J, Clark RA, Hanson DC, et al: Lorazepam in cancer 148. Sallan SE, Zinberg NE, Frei E III: Antiemetic effect of patients treated with cisplatin: A drug having antiemetic, amnestic, and delta-9-tetrahydrocannabinol in patients receiving cancer chemother- anxiolytic effects. J Clin Oncol 3:864-869, 1985 apy. N Engl J Med 293:795-797, 1975 166. Maher J: Intravenous lorazepam to prevent nausea and vomit- 149. Sallan SE, Cronin C, Zellen M, et al: Antiemetics in patients ing associated with cancer chemotherapy. Lancet 1:91-92, 1981 receiving chemotherapy for cancer: A randomized comparison of 167. Baltzer L, Pisters KMW, Kris MG, et al: High-dose ondanse- delta-9-tetrahydrocannabinol and prochlorperazine. N Engl J Med tron (OND) plus dexamethasone (DEX) for the prevention of nausea 302:135-138, 1980 and vomiting with multiple day cisplatin chemotherapy. Proc Am Soc 150. Pomeroy M, Fennelly JJ, Towers M: Prospective randomized Clin Oncol 12:462, 1993 (abstr 1607) double-blind trial of nabilone versus domperidone in the treatment of 168. Gebbia V, Testa A, Valenza R, et al: Oral granisetron with or cytotoxic-induced emesis. Cancer Chemother Pharmacol 17:285-288, without methylprednisolone versus metoclopramide plus methylpred- nisolone in the management of delayed nausea and vomiting induced by 151. Niiranen A, Mattson K: Antiemetic efficacy of nabilone and dexamethasone: A randomized study of patients with lung cancer cisplatin-based chemotherapy. Cancer 76:1821-1828, 1995 receiving chemotherapy. Am J Clin Oncol 10:325-329, 1987 169. Smith DB, Newlands ES, Rustin GJ, et al: A phase I/II study of 152. Plasse TF, Gorter RW, Krasnow SH, et al: Recent clinical the 5-HT3 antagonist GR38032F in the anti-emetic prophylaxis of experience with dronabinol. Pharmacol Biochem Behav 40:695-700, patients receiving high-dose cisplatin chemotherapy. Cancer Chemother Pharmacol 25:291-294, 1990 153. Gralla RJ, Tyson LB, Bordin LA, et al: Antiemetic therapy: A 170. Gralla RJ, Tyson LB, Kris MG, et al: The management of review of recent studies and a report of a random assignment trial chemotherapy-induced nausea and vomiting. Med Clin North Am comparing metoclopramide with delta-9-tetrahydrocannabinol. Cancer Treat Rep 68:163-172, 1984 171. Sullivan JR, Leyden MJ, Bell R: Decreased cisplatin-induced 154. Chang AE, Shiling DJ, Stillman RC, et al: A prospective nausea and vomiting with chronic alcohol ingestion. N Engl J Med evaluation of delta-9-tetrahydrocannabinol as an antiemetic in patients 309:796, 1983 (letter) receiving adriamycin and Cytoxan chemotherapy. Cancer 47:1746- 172. Roila F, Tonato M, Basurto C, et al: Antiemetic activity of high doses of metoclopramide combined with methylprednisolone versus 155. Levitt M, Faiman C, Hawks R, et al: Randomized double-blind metoclopramide alone in cisplatin-treated cancer patients: A random- comparison of delta-9-tetrahydrocannabinol (THC) and marijuana as ized double-blind trial of the Italian Oncology Group for Clinical chemotherapy antiemetics. Proc Am Soc Clin Oncol 3:91, 1984 (abstr Research. J Clin Oncol 5:141-149, 1987 173. Morrow GR: The effect of a susceptibility to motion sickness 156. Tyson LB, Gralla RJ, Clark RA, et al: Phase 1 trial of on the side effects of cancer chemotherapy. Cancer 55:2766-2770, 1985 levonantradol in chemotherapy-induced emesis. Am J Clin Oncol 174. Morrow GR: Chemotherapy-related nausea and vomiting: Etiology and management. CA Cancer J Clin 39:89-104, 1989 157. Cunningham D, Forrest GJ, Soukoup M, et al: Nabilone and 175. Roila F, Bracarda S, Tonato M, et al: Ondansetron (GR38032) prochlorperazine: A useful combination for emesis induced by cytotoxic in the prophylaxis of acute and delayed cisplatin-induced emesis. Clin drugs. BMJ 291:864-865, 1985 Oncol 2:268-272, 1990 158. Greenblatt DJ, Shader RI, Abernathy DL: Current status of 176. Tonato M, Roila F, Del Favero A: Methodology of antiemetic benzodiazepines (first of two parts). N Engl J Med 309:354-358, 1983 trials: A review. Ann Oncol 2:107-114, 1991 159. Greenblatt DJ, Shader RI, Abernathy DR: Current status of 177. Pollera CF, Giannarelli D: Prognostic factors influencing cis- benzodiazepines (second of two parts). N Engl J Med 309:410-416, platin-induced emesis. Cancer 64:1117-1122, 1989 178. Pater J, Slamet L, Zee B, et al: Inconsistency of prognostic 160. Kris MG, Gralla RJ, Clark RA, et al: Antiemetic control and factors for post-chemotherapy nausea and vomiting. Support Care prevention of side effects of anti-cancer therapy with lorazepam or Cancer 2:161-166, 1994 diphenhydramine when used in combination with metoclopramide plusdexamethasone: A double-blind, randomized trial. Cancer 60:2816- 179. Morrow G: Behavioral factors influencing the development and expression of chemotherapy-induced side effects. Br J Cancer 19:554- 161. Bishop JF, Olver IN, Wolf MM, et al: Lorazepam: A random- 561, 1992 (suppl) ized, double-blind, crossover study of a new antiemetic in patients 180. Osoba D, Zee B, Warr D, et al: Quality of life studies in receiving cytotoxic chemotherapy and prochlorperazine. J Clin Oncol chemotherapy-induced emesis. Oncology 53:92-95, 1996 (suppl) 181. Osoba D, Zee B, Pater J, et al: Determinants of post- 162. Bowcock SJ, Stockdale AD, Bolton JAR, et al: Antiemetic chemotherapy nausea and vomiting in patients with cancer. J Clin Oncol prophylaxis with high dose metoclopramide or lorazepam in vomiting induced by chemotherapy. BMJ 288:1879, 1984 182. Craig JB, Powell BL: Review: The management of nausea and 163. Friedlander ML, Kearsley JH, Sims K, et al: Lorazepam as an vomiting in clinical oncology. Am J Med Sci 293:34-44, 1987 adjunct to antiemetic therapy with haloperidol in patients receiving 183. Laszlo J: Treatment of nausea and vomiting caused by cancer cytotoxic chemotherapy. Aust N Z J Med 13:53-56, 1983 chemotherapy. Cancer Treat Rev 9:3-9, 1982 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
184. Lindley CM, Bernard S, Fields SM: Incidence and duration of 201. Rudd JA, Jordan CC, Naylor RJ: The action of the NK 1 chemotherapy-induced nausea and vomiting in the outpatient oncology tachykinin receptor antagonist CP 99,994 to antagonise the acute and population. J Clin Oncol 7:1142-1149, 1989 delayed emesis induced by cisplatin in the ferret. Br J Pharmacol 185. Cubeddu LX, Hoffman IS, Fuenmayor NT, et al: Antagonism of 119:931-936, 1996 serotonin S3 receptors with ondansetron prevents nausea and emesis 202. Milano S, Blower P, Romain D, et al: The piglet as a suitable induced by cyclophosphamide-containing chemotherapy regimens. J animal model for studying the delayed phase of cisplatin-induced Clin Oncol 8:1721-1727, 1990 emesis. J Pharmacol Exp Ther 274:951-961, 1995 203. Kris MG, Gralla RJ, Clark RA, et al: Incidence, course, and 186. Cubeddu LX, Hoffmann IS, Fuenmayor NT, et al: Efficacy of severity of delayed nausea and vomiting following the administration of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced high-dose cisplatin. J Clin Oncol 3:1379-1384, 1985 nausea and vomiting. N Engl J Med 322:810-816, 1990 204. Kris MG, Gralla RJ, Tyson LB, et al: Controlling delayed 187. Hesketh PJ, Kris MG, Grunberg SM, et al: A proposal for vomiting: Double-blind, randomized trial comparing placebo, dexa- classifying the acute emetogenicity of cancer chemotherapy. J Clin methasone alone, and metoclopramide plus dexamethasone in patients Oncol 15:103-109, 1997 receiving cisplatin. J Clin Oncol 7:108-114, 1989 188. Antiemetic Subcommittee of the Multinational Association of 205. Roila F, Boschetti E, Tonato M: Predictive factors of delayed Supportive Care in Cancer: Prevention of chemotherapy- and radio- emesis in cisplatin treated patients and antiemetic activity and tolerabil- therapy-induced emesis: Results of the Perugia Consensus Conference.
ity of metoclopramide or dexamethasone: A randomized single-blind Ann Oncol 9:811-819, 1998 study. Am J Clin Oncol 14:238-242, 1991 189. Cupissol DR, Serrou B, Caubel M: The efficacy of granisetron 206. Koo WH, Ang PT: Role of maintenance oral dexamethasone in as a prophylactic anti-emetic and intervention agent in high-dose prophylaxis of delayed emesis caused by moderately emetogenic cisplatin-induced emesis. Eur J Cancer 26:S23-S27, 1990 chemotherapy. Ann Oncol 7:71-74, 1996 190. Jantunen IT, Kataja VV, Muhonen TT: An overview of random- 207. Kris MG, Radford J, Pizzo B, et al: Dose ranging antiemetic ized studies comparing 5-HT3 receptor antagonists to conventional trial of the NK-1 receptor antagonist CP-122,721: A new approach for antiemetics in the prophylaxis of acute chemotherapy-induced vomit- acute and delayed emesis following cisplatin. Proc Am Soc Clin Oncol ing. Eur J Cancer 33:66-74, 1997 15:547, 1996 (abstr 1780) 208. Clark R, Kris M, Tyson L, et al: Antiemetic trials to control 191. Hainsworth JD: The use of ondansetron in patients receiving delayed vomiting following high-dose cisplatin. Proc Am Soc Clin multiple-day cisplatin regimens. Semin Oncol 19:48-52, 1992 Oncol 5:257, 1986 (abstr 1005) 192. Hainsworth JD, Omura GA, Khojasteh A, et al: Ondansetron 209. Strum S, McDermed J, Abrahano-Umall R, et al: Management (GR 38032F): A novel antiemetic effective in patients receiving a of cisplatin (DDP)-induced delayed-onset nausea (N) and vomiting (V): multiple-day regimen of cisplatin chemotherapy. Am J Clin Oncol Preliminary results with 2 drug regimens. Proc Am Soc Clin Oncol 4:263, 1985 (abstr C-1024) 193. Sledge GW, Einhorn L, Nagy C, et al: Phase III double-blind 210. Johnston D, Latreille J, Laberge F, et al: Preventing nausea and comparison of intravenous ondansetron and metoclopramide as anti- vomiting during days 2-7 following high-dose cisplatin chemotherapy emetic therapy for patients receiving multiple-day cisplatin-based (HDCP): A study by the National Cancer Institute of Canada Clinical chemotherapy. Cancer 70:2524-2528, 1992 Trials Group (NCIC CTG). Proc Am Soc Clin Oncol 14:529, 1995 194. Bremer K: A single-blind study of the efficacy and safety of intravenous granisetron compared with alizapride plus dexamethasone 211. Navari RM, Madajewicz S, Anderson N, et al: Oral ondansetron in the prophylaxis and control of emesis in patients receiving 5-day for the control of cisplatin-induced delayed emesis: A large multicenter, cytostatic therapy: The Granisetron Study Group. Eur J Cancer 28A: double-blind, randomized comparative trial of ondansetron versus placebo. J Clin Oncol 13:2408-2416, 1995 195. Nicolai N, Mangiarotti B, Salvioni R, et al: Dexamethasone 212. Pater JL, Lofters WS, Zee B, et al: The role of the 5-HT3 plus ondansetron versus dexamethasone plus alizapride in the preven- antagonists ondansetron and dolasetron in the control of delayed onset tion of emesis induced cisplatin-containing chemotherapies for urologi- nausea and vomiting in patients receiving moderately emetogenic cal cancers. Eur Urol 23:450-456, 1993 chemotherapy. Ann Oncol 8:181-185, 1997 196. Rath U, Upadhyaya BK, Arechavala E, et al: Role of ondanse- 213. Roila F: Dexamethasone, granisetron, or both for the preven- tron plus dexamethasone in fractionated chemotherapy. Oncology tion of nausea and vomiting during chemotherapy for cancer. N Engl JMed 332:1-5, 1995 214. Ossi M, Anderson E, Freeman A: 5-HT3 receptor antagonists in 197. Kris MG, Tyson LB, Clark RA, et al: Oral ondansetron for the the control of cisplatin-induced delayed emesis. Oncology 53:78-85, control of delayed emesis after cisplatin: Report of a phase II study and a review of completed trials to manage delayed emesis. Cancer 215. Passalacqua R, Cocconi G, Bella M, et al: Double-blind, 70:1012-1016, 1992 randomized trial for the control of delayed emesis in patients receiving 198. Gandara DR, Harvey WH, Monaghan GG, et al: The delayed- cisplatin: Comparison of placebo vs. adrenocorticotropic hormone emesis syndrome from cisplatin: Phase III evaluation of ondansetron (ACTH). Ann Oncol 3:481-485, 1992 versus placebo. Semin Oncol 19:67-71, 1992 216. Italian Group for Antiemetic Research: Ondansetron versus 199. Kris MG, Pisters KMW, Hinkley L: Delayed emesis following metoclopramide, both combined with dexamethasone, in the prevention anticancer chemotherapy. Support Care Cancer 2:297-300, 1994 of cisplatin-induced delayed emesis. J Clin Oncol 15:124-130, 1997 200. Rudd JA, Jordan CC, Naylor RJ: Profiles of emetic action of 217. Andrykowski MA, Redd WH, Hatfield AK: Development of cisplatin in the ferret: A potential model of acute and delayed emesis.
anticipatory nausea: A prospective analysis. J Consult Clin Psychol Eur J Pharmacol 262:R1-R2, 1994 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
ASCO ANTIEMETICS GUIDELINES 218. Andrykowski MA, Jacobsen PB, Marks E, et al: Prevalence, 238. Morrow GR: Effect of hierarchy in the systematic desensitiza- predictors, and course of anticipatory nausea in women receiving tion treatment of anticipatory nausea in cancer patients: A component adjuvant chemotherapy for breast cancer. Cancer 62:2607-2613, 1988 comparison with relaxation only, counseling, and no treatment. Cognit 219. Andrykowski MA: Development of anticipatory nausea in Ther Res 10:421-446, 1986 cancer chemotherapy: A review and synthesis. Psychosom Med 52:458- 239. Redd WH, Andrykowski MA: Behavioral intervention in cancer treatment: Controlling aversion reactions to chemotherapy. J 220. Burish TG, Carey MP: Conditioned aversive responses in Consult Clin Psychol 20:1018-1029, 1982 cancer chemotherapy patients: Theoretical and developmental analysis.
240. Redd WH, Jacobsen PB, Die-Trill M, et al: Cognitive/ J Consult Clin Psychol 54:593-600, 1986 attentional distraction in the control of conditioned nausea in pediatric 221. Morrow GR: Prevalence and correlates of anticipatory nausea cancer patients receiving chemotherapy. J Consult Clin Psychol 55:391- and vomiting in chemotherapy patients. J Natl Cancer Inst 68:585-588, 241. Burish TG, Lyles JN: Effectiveness of relaxation training in 222. Morrow GR: Clinical characteristics associated with the devel- reducing the aversiveness of chemotherapy in the treatment of cancer. J opment of anticipatory nausea and vomiting in cancer patients undergo- Behav Ther Exp Psychiatry 10:357-361, 1979 ing chemotherapy treatment. J Clin Oncol 2:1170-1176, 1984 242. Burish TG, Carey MP, Krozely MG, et al: Conditioned side 223. Morrow GR, Dobkin PL: Anticipatory nausea and vomiting in effects induced by cancer chemotherapy: Prevention through behavioral cancer patients undergoing chemotherapy treatment: Prevalence, etiol- treatment. J Consult Clin Psychol 55:42-48, 1987 ogy, and behavioral interventions. Clin Psychol Rev 8:517-556, 1988 243. Burish TG, Tope DM: Psychological techniques for controlling 224. Morrow GR, Lindke J, Black PM: Predicting development of the adverse side effects of cancer chemotherapy: Findings from adecade of research. J Pain Symptom Manage 7:287-301, 1992 anticipatory nausea in cancer patients: Prospective examination of eight 244. Jurgens H, McQuade B: Ondansetron as prophylaxis for clinical characteristics. J Pain Symptom Manage 6:215-223, 1991 chemotherapy and radiotherapy induced emesis in children. Oncology 225. Morrow GR, Rosenthal SN: Models, mechanisms and manage- ment of anticipatory nausea and emesis. Oncol 53:4-7, 1996 (suppl 1) 245. Carden PA, Mitchell SL, Waters KD, et al: Prevention of 226. Morrow GR, Lindke J, Black PM: Anticipatory nausea develop- cyclophosphamide/cytarabine-induced emesis with ondansetron in chil- ment in cancer patients: Replication and extension of a learning model.
dren with leukemia. J Clin Oncol 8:1531-1535, 1990 Br J Psychol 82:61-72, 1991 246. Pinkerton CR, Williams D, Wootton C, et al: 5-HT3 antagonist 227. Aapro MS, Kirchner V, Terrey JP: The incidence of anticipatory ondansetron: An effective outpatient antiemetic in cancer treatment.
nausea and vomiting after repeat cycle chemotherapy: The effect of Arch Dis Child 65:822-825, 1990 granisetron. Br J Cancer 69:957-960, 1994 247. Stevens RF: The role of ondansetron in paediatric patients: A 228. Alba E, Bastus R, de Andres L, et al: Anticipatory nausea and review of three studies. Eur J Cancer 27:S20-S22, 1991 (suppl 1) vomiting: Prevalence and predictors in chemotherapy patients. Oncol- 248. Dolgin MJ, Katz ER, McGinty K, et al: Anticipatory nausea and ogy 46:26-30, 1989 vomiting in pediatric cancer patients. Pediatrics 75:547-552, 1985 229. Challis GB, Stam HJ: A longitudinal study of the development 249. Zeltzer L, Kellerman J, Ellenberg L, et al: Hypnosis for of anticipatory nausea and vomiting in cancer chemotherapy patients: reduction of vomiting associated with chemotherapy and disease in The role of absorption and autonomic perception. Health Psychol adolescents with cancer. J Adolesc Health Care 4:77-84, 1983 250. Zeltzer L, LeBaron S, Zeltzer PM: The effectiveness of 230. Chin SB, Kucuk O, Peterson R, et al: Variables contributing to behavioral intervention for reduction of nausea and vomiting in children anticipatory nausea and vomiting in cancer chemotherapy. Am J Clin and adolescents receiving chemotherapy. J Clin Oncol 2:683-690, 1984 Oncol 15:262-267, 1992 251. Zeltzer LK, Dolgin MJ, LeBaron S, et al: A randomized, 231. Jacobsen PB, Bovbjerg DH, Redd WH: Anticipatory anxiety in controlled study of behavioral intervention for chemotherapy distress in women receiving chemotherapy for breast cancer. Health Psychol children with cancer. Pediatrics 88:34-42, 1991 252. Okamoto S, Takahashi S, Tanosaki R, et al: Granisetron in the 232. Jacobsen PB, Bovbjerg DH, Schwartz MD, et al: Conditioned prevention of vomiting induced by conditioning for stem cell transplan- emotional distress in women receiving chemotherapy for breast cancer.
tation: A prospective randomized study. Bone Marrow Transplant J Consult Clin Psychol 63:108-114, 1995 233. Kvale G, Hugdahl K, Asbjornsen A, et al: Anticipatory nausea 253. Or R, Drakos P, Nagler A, et al: The anti-emetic efficacy and and vomiting in cancer patients. J Consult Clin Psychol 59:894-898, tolerability of tropisetron in patients conditioned with high-dose chemotherapy (with and without total body irradiation) prior to bone 234. Morrow GR: Susceptibility to motion sickness and chemother- marrow transplantation. Support Care Cancer 2:245-248, 1994 apy-induced side effects. Lancet 1:390-391, 1984 (letter) 254. Spitzer TR, Grunberg SM, Dicato MA: Antiemetic strategies 235. Fallowfield LJ: Behavioural interventions and psychological for high-dose chemoradiotherapy-induced nausea and vomiting. Sup- aspects of care during chemotherapy. Eur J Cancer 28A:S39-S41, 1992 port Care Cancer 6:233-236, 1998 255. Bosi A, Guidi S, Messori A, et al: Ondansetron versus 236. Morrow GR, Morrell C: Behavioral treatment for the anticipa- chlorpromazine for preventing emesis in bone marrow transplant tory nausea and vomiting induced by cancer chemotherapy. N Engl J recipients: A double-blind randomized study. J Chemother 5:191-196, Med 307:1474-1480, 1982 237. Morrow GR, Asbury R, Hammon S, et al: Comparing the 256. Crenier L, Lemoine F, Bastin G, et al: A comparative study on effectiveness of behavioral treatment for chemotherapy-induced nausea the efficacy of the different 5-HT3 antagonists to control acute emesis in and vomiting when administered by oncologists, oncology nurses, and blood stem cell transplantation. Support Care Cancer 4:253, 1996 clinical psychologists. Health Psychol 11:250-256, 1992 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
257. Gilbert CJ, Ohly KV, Rosner G, et al: Randomized, double- 266. Scarantino CW, Ornitz RD, Hoffman LG, et al: On the blind comparison of a prochlorperazine-based versus a metoclopramide- mechanism of radiation-induced emesis: The role of serotonin. Radiat based antiemetic regimen in patients undergoing autologous bone Oncol Biol Phys 30:825-830, 1994 marrow transplantation. Cancer 76:2330-2337, 1995 267. Danjoux E, Rider WD, Fitzpatrick PJ, et al: The acute radiation 258. Agura ED, Brown MC, Schaffer R, et al: Antiemetic efficacy syndrome. Clin Radiol 30:581-584, 1979 and pharmacokinetics of intravenous ondansetron infusion during 268. Lippens RJ, Broeders GC: Ondansetron in radiation therapy of chemotherapy conditioning for bone marrow transplant. Bone Marrow brain tumors in children. Pediatr Hematol Oncol 13:247-252, 1996 Transplant 16:213-222, 1995 269. Miralbell R, Coucke P, Behrouz F, et al: Nausea and vomiting in 259. Abbott B, Ippoliti C, Neumann J, et al: Standard practice fractionated radiotherapy: A prospective on demand trial of tropisetron rescue protocol of granisetron (Kytril) for antiemetic control in bone marrow for non-responders to metoclopramide. Eur J Cancer 31A:1461-1464, 1995 transplant (BMT) patients receiving highly emetogenic chemotherapy 270. Westbrook GJ, Barrett A: Vomiting associated with whole body with or without total body irradiation (TBI). Blood 88:252b, 1996 irradiation. Clin Radiol 38:263-266, 1987 271. Schwella N, Konig V, Schwerdtfeger R, et al: Ondansetron for (abstr) (suppl 1) efficient emesis control during total body irradiation. Bone Marrow 260. Barbounis V, Koumakis G, Vassilomanolakis M, et al: A phase Transplant 13:169-171, 1994 II study of ondansetron as antiemetic prophylaxis in patients receiving 272. Kirkbride P, Pater J, Zee B, et al: A phase III study of the high-dose polychemotherapy and stem cell transplantation. Support efficacy of dexamethasone (DEX) in the prophylaxis of radiation induced Care Cancer 3:301-306, 1995 emesis (RIE). Proc Am Soc Clin Oncol 17:51a, 1998 (abstr 196) 261. Spitzer TR, Bryson JC, Cirenza E, et al: Randomized double- 273. Priestman TJ, Roberts JT, Lucraft H, et al: Results of a blind, placebo-controlled evaluation of oral ondansetron in the preven- randomized, double-blind comparative study of ondansetron and meto- tion of nausea and vomiting associated with fractionated total-body clopramide in the prevention of nausea and vomiting following irradiation. J Clin Oncol 12:2432-2438, 1994 high-dose upper abdominal irradiation. Clin Oncol 2:71-75, 1990 262. Hunter AE, Prentice HG, Pothecary K, et al: Granisetron, a 274. Priestman TJ, Roberts JT, Upadhyaya BK: A prospective selective 5-HT3 receptor antagonist, for the prevention of radiation- randomized double-blind trial comparing ondansetron versus prochlor- induced emesis during total body irradiation. Bone Marrow Transplant perazine for the prevention of nausea and vomiting in patients undergoing fractionated radiotherapy. Clin Oncol 5:358-363, 1993 263. Prentice HG, Cunningham S, Gandhi L, et al: Granisetron in the 275. Franzen L, Nyman J, Hagberg H, et al: A randomised placebo prevention of irradiation-induce emesis. Bone Marrow Transplant controlled study with ondansetron in patients undergoing fractionated radiotherapy. Ann Oncol 7:587-592, 1996 264. Tiley C, Powles R, Catalano J, et al: Results of a double-blind 276. Priestman SG, Priestman TJ, Canney PA: A double-blind placebo controlled study of ondansetron as an antiemetic during total randomised cross-over comparison of nabilone and metoclopramide in body irradiation in patients undergoing bone marrow transplantation.
the control of radiation-induced nausea. Clin Radiol 38:543-544, 1987 Leuk Lymphoma 7:317-321, 1992 277. Ungerleider JT, Andrysiak TA, Fairbanks LA, et al: Tetrahydro- 265. Scarantino CW, Ornitz RD, Hoffman LG, et al: Radiation- cannabinol vs. prochlorperazine: The effects of two antiemetics on induced emesis: Effects of ondansetron. Semin Oncol 19:38-43, 1992 patients undergoing radiotherapy. Radiology 150:598-599, 1984 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
Bezwoda: Evidence of Fabrication in Original Article
Bezwoda et al also report the P value from the 2 comparing the number of complete responses as "P ⬍ .01." Its correct value is P ⫽ To the Editor: The recent publication of the clinical trial by 8 ⫻ 10⫺7, which is implausibly small for a trial of this size.
Stadtmauer et al1 showing no benefit to high-dose chemotherapy inmetastatic breast cancer led us to re-examine the earlier positive report of Bezwoda et al,2 which, notoriously, has now been withdrawn.3,4 It is apparent that although Bezwoda claims merely that he "misrep- Memorial Sloan-Kettering Cancer Center resented" his results, he undertook detailed fabrication. He clearly New York, NY describes the treatment regimen/schedule for both the experimental andcomparison groups in Table 1, and in Table 2 he gives precise figuresfor the amount of various agents said to have been received by patientscorrect to 1 milligrams per square meter per week. Yet his audited reports revealed a completely different treatment regimen for the comparison group.
Furthermore, there may be evidence in the original publication that 1. Stadtmauer EA, O'Neill A, Goldstein LJ, et al: Conventional- Bezwoda's data were falsified, or at the very least, suspicious. The dose chemotherapy compared with high-dose chemotherapy plus au- number of complete responses (CR) in control patients with soft tissue tologous hematopoietic stem-cell transplantation for metastatic breast metastases is given as four in Table 6, whereas the total number of CRs cancer. N Engl J Med 342:1069-1076, 2000 in controls is given in Table 5 as only two. The number of CRs in 2. Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy experimental subjects with soft tissue metastases is similarly greater with hematopoietic rescue as primary treatment for metastatic breast than the total number of CRs in this group.
cancer: A randomized trial. J Clin Oncol 13:2483-2489, 1995 Bezwoda et al2 state that 49 patients had "two or more [metastatic] 3. Grady D: Breast cancer researcher admits falsifying data. New sites" and 41 patients had "more than two sites" (p 2485, column 1).
York Times, February 5, 2000, p 9 Given that there are a total of 90 patients in the trial, all patients must 4. Wits fires cancer researcher: Press release of the University of the have had at least two metastatic sites. Yet Table 4 gives the average Witwatersrand Medical School, Johannesburg, South Africa, March 10, number of metastatic sites per patient by group as 1.8 and 1.6.
The September 1999 article by Gralla et al, "Recommendations for the Use of Antiemetics: Evidence-Based, Clinical Practice Guidelines" (J Clin Oncol 17:2971–2994, 1999), contained errors in the numbering of references. For a correct copyof this article in its entirety, please email [email protected].
Journal of Clinical Oncology, Vol 18, No 15 (August), 2000: p 2933 Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
relationship to trial treatment, were significantly less often reported withletrozole (10.9% for 2.5 mg, 14.9% for 0.5 mg) than with megestrolacetate (28.6%). The SAE led to discontinuation in 2.9% of patients onletrozole 2.5 mg, 4.3% on letrozole 0.5 mg, and 10.6% on megestrolacetate. The most frequently reported non-SAEs (irrespective ofrelationship to trial treatment) were musculoskeletal pain (36%, 34%,and 36% for letrozole 2.5 mg, letrozole 0.5 mg, and megestrol acetate,respectively), nausea (12%, 19%, and 9%), dyspnea (12%, 11%, and16%), headache (13%, 14%, and 9%), arthralgia (13%, 10%, and 9%),peripheral edema (12%, 8%, and 11%), and fatigue (11%, 6%, and11%).
To date, letrozole is the only aromatase inhibitor that has shown superiority over two other endocrine therapies, megestrol acetate andaminoglutethimide, including superiority in overall survival over thereference aromatase inhibitor, aminoglutethimide.1,2 We think it isimportant to report the new data to the oncologic community.
Fig 1. Duration of clinical benefit (complete response plus partial re-
sponse plus stabilization of disease for longer than or equal to 24 weeks).
Novartis Pharma AG Arrows denote censored observations. MA, megestrol acetate.
Novartis Pharma SA patients in the megestrol acetate arm remained on trial treatment without evidence of progression of disease.
The updated results for overall survival showed no statistically significant difference between treatments (comparison of letrozole 2.5 mg to megestrol acetate, hazard ratio of 0.86; 95% confidence interval, 1. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new oral 0.67 to 1.11). Median overall survival was 25 months for letrozole aromatase inhibitor for advanced breast cancer: Double-blind random- 2.5 mg (75th percentile, 45 months) and 21.5 months for both letrozole ized trial showing a dose effect and improved efficacy and tolerability 0.5 mg (75th percentile, 42 months) and megestrol acetate (75th compared with megestrol acetate. J Clin Oncol 16:453-461, 1998 percentile, 36 months).
2. Gershanovich M, Chaudri HA, Campos D, et al: Letrozole, a new The updated safety information was similar, as it was previously: oral aromatase inhibitor: Randomised trial comparing 2.5 mg daily, both doses of letrozole were generally well tolerated compared with 0.5 mg daily and aminoglutethimide in postmenopausal women with megestrol acetate. Serious adverse events (SAEs), irrespective of advanced breast cancer. Ann Oncol 9:639-645, 1998 The September 1999 ASCO Special Article by Gralla et al, entitled ‘‘Recommendations for the Use of Antiemetics: Evidence-Based, Clinical Practice Guidelines'' (J Clin Oncol 17:2971-2994, 1999), contained an error on page 2977 undersection 2, Antiemetic Agents: Lower Therapeutic Index-Dopamine Antagonists, Butyrophenones, Phenothiazines, andCannabinoids. The first sentence in this section should read: Guideline: For chemotherapy with a high risk of emesis, selective serotonin antagonists (with dexamethosone)are recommended.
The September 1999 reply by Alain Ravaud and Binh Nguyen Bui to the letter-to-the-editor by Paul L.R. Mitchell and C.
Ross Pinkerton (J Clin Oncol 17:3002, 1999) contained an error in the chemotherapy regimens in the second to last paragraph.
The correct regimens are: MAID (mesna, doxorubicin, ifosfamide, dacarbazine), DVCP (doxorubicin, etoposide, cyclophos-phamide, cisplatin), and VIP/VPH (etoposide, ifosfamide, cisplatin).
Downloaded from jco.ascopubs.org on September 20, 2011. For personal use only. No other uses without permission.
Copyright 1999 American Society of Clinical Oncology. All rights reserved.
Source: http://www.qu.edu.qa/pharmacy/program/PharmD_internships/pharmd_resources_Hematology_Oncology/1A_Recommendations_for_the_Use_of_Antiemetics.pdf
chu-tours.fr
de la Société Française de Neurologie Pédiatrique e de Congrès VINCI-TOURS EVENEMENTS Palais des Congrès S. de la VAISSIERE Membres du Bureau Secrétariat du Congrès - Ant Congrès 154 avenue de Lodève / 34070 Montpellier Tél. : 04 67 10 92 23 / E-mail : [email protected] Conception graphique : www.kom-graphik.pro Bienvenue à Tours Toute l'équipe de Neuropédiatrie est heureuse de vous accueillir à Tours du 21 janvier au 24 janvier 2015 pour ce 25ème congrès de la Société Française de Neurologie Pédiatrique. Cette année, nous reprendrons le déroulement habituel de notre congrès : Troubles des Apprentissages le mercredi 21 janvier avec la session de Neuro-Ophtalmologie et de Neuro-ORL qui est une nouveauté de cette édition, Séances plénières en parallèle le jeudi 22 et le vendredi 23 janvier, Congrès du Personnel Soignant et session recherche en parallèle le vendredi. Et enfin commissions scientifiques le samedi 24 janvier au matin. Les thèmes retenus nous permettront de couvrir les principaux champs de la Neurologie pédiatrique : la neurologie fœtale et périnatale, les affections génétiques et du développement, les affections du système nerveux périphérique, les anomalies de la substance blanche, les maladies métaboliques, inflammatoires, et vasculaires, sans oublier bien sûr l'épileptologie qui prendra une large place cette année.Une large place sera faite également aux Communications orales et aux Posters. Nous comptons sur votre présence, votre participation et votre enthousiasme pour faire de ce congrès un succès.Nous sommes très heureux et très fiers de vous accueillir en Touraine, «Jardin de la France».
southcheshireccg.nhs.uk
BRIEFING: Penile Prostheses for Erectile Dysfunction Mr. John P Hampson Public Health Specialist Cheshire West & Chester Council March 1st 2014 INTRODUCTION Erectile dysfunction has been defined as the inability to achieve and maintain a penile erection adequate for satisfactory sexual intercourse. It affects the quality of life for both patients and partners and is associated with relationship difficulties. Simple lifestyle measures such as regular exercise, smoking cessation and weight loss are effective options in men with these risk factors who have mild erectile dysfunction. Treatments include oral phosphodiesterase (PDE) inhibitors, vacuum erection devices, intracavernosal and intraurethral prostaglandins. 1 Two main types of penile prostheses are available – these are the semi-rigid or malleable type and also an inflatable version. The latter is more cosmetically acceptable. 2 This report is a rapid review of the literature which describes the effectiveness and place in management of penile prostheses in erectile dysfunction. METHOD A literature search of Medline and Embase was conducted using the keywords penile prosthesis, effectiveness and cost-effectiveness. In addition, the websites and databases of Cochrane, SIGN, NHS Evidence, NICE, Department of Health and the general internet were also searched. PATIENT OUTCOMES & SATISFACTION A retrospective study (2010) in Brazil analysed the effect of penile prostheses and interviewed 139 men. Nearly two thirds (64%) returned to the same sexual performance as they had before developing erectile dysfunction. Follow-up was for 40 months. 3 In a separate study, 69 men (presenting after nerve sparing radical prostatectomy) were given either tadalafil or a penile prosthesis. A significant difference was observed in the International Index of Erectile Function (IIEF) score. Follow-up was for up to 2 years. 4 Patient and partner satisfaction are generally high. One review recorded a patient and partner satisfaction rate as over 90%. 5 In a different study, couple satisfaction rate was 82% (n = 46 operations). No indication of the time period was given. 6 Efficacy and satisfaction following penile prosthesis implants were assessed using the IIEF score in 96 men. Significantly higher scores were obtained in the prosthesis group which tended to maximise after 12 months. 7 Perhaps the largest study (n =224) was conducted in Chinese men over 10 years. After six months, satisfaction rates were reported to be 89%. 8 However, most of these studies are observational.