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Recommendations for the Use of Antiemetics: Evidence-Based, Clinical Practice Guidelines

From the American Society of Clinical Oncology, Alexandria, VA.

Address reprint requests to American Society of Clinical Oncology, Health Services Research, 225 Reinekers Lane, Suite 650, Alexandria, VA 22314; email guidelines{at}asco.org

THE GOAL OF ANTIEMETIC therapy is to prevent nausea and vomiting completely. This goal is achieved for many patients receiving chemotherapy or radiation therapy, and is based on clinical and basic research that has steadily improved the control of emesis over the last 20 years. As therapy has become more effective, it has also become safer, with few side effects associated with the most commonly used regimens. These regimens are convenient for patients to receive and for health care professionals to administer. However, despite improvements, a significant number of patients still experience emesis, and efforts to reduce this side effect of treatment must continue.

As antiemetic usage has grown, the classes of agents available for antiemetic treatment, the number of agents, and the indications for antiemetics have all increased as well. The prevention of delayed emesis and anticipatory emesis is equal in importance to the need to prevent acute chemotherapy- and radiation-induced emesis. Additionally, managing special and difficult emetic problems and selecting the proper antiemetic approach necessitate identification of the patient's emetic risk.

Although the neuropharmacologic basis of emesis is still incompletely understood, the selection of an appropriate antiemetic regimen is possible and can have an impact on several aspects of clinical care. Goals related to the complete control of emesis, ie, no vomiting, include providing care that is convenient for the patient, treatment that reduces hospitalization and time in the ambulatory setting, and therapy that enhances the patient's quality of life. Additionally, practitioners need to be mindful of reducing costs of treatment while achieving these goals.^1-3

The American Society of Clinical Oncology (ASCO) appreciates these issues and their applicability to the management of patients with cancer. Accordingly, ASCO convened an Expert Panel under the auspices of its Health Services Research Committee to develop recommendations regarding antiemetic therapy (Table 1). This report describes the aims, methods, and results of this Panel's deliberations.

Practice guidelines are systematically developed statements to assist the practitioner and patient decisions about appropriate health care for specific clinical circumstances.⁴ Good clinical guidelines include considerations of validity, reliability, reproducibility, clinical applicability, clinical flexibility, clarity, multidisciplinary process, review of evidence, and documentation.⁴

In formulating recommendations for antiemetic usage, ASCO considered these tenets of guideline development, emphasizing the review of data from controlled clinical trials. The level and grade of evidence can differ; such evidence is rated according to the criteria outlined in Table 2. It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. They cannot be considered to be inclusive of all proper methods of care or exclusive of other treatments reasonably directed at obtaining the same results.

It is also important to note that not all relevant questions regarding emesis in cancer care have been addressed by clinical trials. The antiemetic methods listed in this article have been shown to be beneficial (or not), but additional research in the prevention of emesis is strongly encouraged. In some instances, specific areas of research need are indicated in this article. As ongoing research is completed, helpful results from these trials will be incorporated into updates of these guidelines.

Accordingly, ASCO considers adherence to these guidelines to be voluntary. The ultimate determination regarding their application is to be made by the physician in light of each patient's individual circumstances. In addition, these guidelines describe administration of therapies in clinical practice; they cannot be assumed to apply to interventions performed in the context of clinical trials, given that such clinical studies are designed to test innovative and novel therapies for this symptom in which better treatment is of paramount importance. In that guideline development involves a review and synthesis of the latest literature, practice guidelines also serve to identify important questions for further research and those settings in which investigational therapy should be considered.

METHODS

A methodology similar to that applied in prior ASCO practice guidelines documentation⁵ was used and is described in more detail below.

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 in antiemetics. A patient representative was also included on the Panel. Clinical experts represented all relevant disciplines, including medical oncology, oncology nursing, radiation oncology, pediatric oncology, and oncologic pharmacy practice. A steering committee under the auspices of the Health Services Research Committee chose Panel participants for the clinical practice guideline development process.

Literature Review and Data Collection
Pertinent information from the published literature as of July 1998 was retrieved and reviewed for the creation of these guidelines. MEDLINE (National Library of Medicine, Bethesda, MD) and other databases were searched for pertinent articles. The following keywords or phrases were used: antiemetics, neoplasms, adverse effects, anticipatory + nausea, anticipatory + vomiting, serotonin antagonists, phenothiazines, butyrophenones, cannabinoids, corticosteroids, and metoclopramide. Directed searches were made of the primary articles.

Consensus Development Based on Evidence
The Panel identified topics to be addressed by the guidelines, developed a strategy for completion of the guidelines, and reviewed the literature. The Panel emphasized the inclusion of prospective random-assignment studies. Phase II trials and clinical reports that evaluated less-well-studied areas of antiemetic treatment were also reviewed. The recommendations made by the Expert Panel are based on current methods of emetic treatment and prevention. The guidelines were circulated in draft form through several iterations, and all members of the Panel had opportunities to comment on the recommendations.

The Panel did not attempt to codify established practice. The experts reviewed the available evidence and added their best clinical judgment to make final recommendations, using standardized language to characterize the strength of the evidence. In accordance with the ASCO Health Services Research Policies and Procedures for guidelines, "recommendation" was used when there was level I or II evidence and Panel consensus. "Suggestion" was used when there was level III, IV, or V evidence and Panel consensus. "No guideline possible" was used when there were no data or the Panel could not reach consensus.

Guidelines and Conflict of Interest
The content of the guidelines and the manuscript were reviewed and approved by the Health Services Research Committee and by the ASCO Board of Directors before dissemination. In addition, several practitioners who had not been directly involved in the development of the guidelines were asked to assess the clarity and utility of the document. All participants in the guideline development process complied with the ASCO policy on conflict of interest, which requires disclosure of any financial or other interest that might be construed as constituting an actual, potential, or apparent conflict.⁶

Revision Dates
At annual intervals, the Panel chairpersons and two Panel members designated by the chairpersons will determine the need for revisions to the guidelines based on an examination of current literature. The entire Panel will be reconvened every 3 years to discuss potential changes, or more frequently if new information suggests that more timely modifications may be warranted. Where appropriate, the Panel will recommend the revised guideline to the Health Services Research Committee and the ASCO Board for review and approval.

Definition of Terms
For cisplatin, high risk is defined as emesis that has been documented to occur in more than 99% of patients. For the high-risk, noncisplatin group, the incidence of emesis is in the 30% to greater than 90% range. Chemotherapeutic agents in the intermediate-risk category induce emesis in 10% to 30% of patients. A less than 10% risk of emesis in patients receiving chemotherapeutic drugs was categorized as low risk.

I. CHEMOTHERAPY-INDUCED EMESIS

In discussing evidence for the control of emesis, it is necessary to outline definitions of control. Emesis, or vomiting, is usually measured by counting the number of vomiting episodes and is the most important end point. With currently available agents, complete control of emesis, ie, no vomiting, is achievable in the majority of patients in the first 24 hours and in approximately 45% of patients during the first 5 to 7 days of chemotherapy. Studies have documented that the complete control end point is a highly accurate and reliable measure.^7-9 The validity of this measure is demonstrated by the fact that complete control of vomiting correlates highly with patients' perception of emesis and with patients' satisfaction with their emetic control.

In contrast, the mechanisms responsible for mediating nausea are less well explained.¹⁰ Nausea, or the perception that emesis may occur, can be judged only by the patient. Various questionnaires, using either visual analog or categorical scales, are in widespread use.^9,11,12 The incidence of nausea correlates well with the incidence of vomiting¹³; however, chemotherapy-induced nausea occurs at a greater frequency than vomiting. Many large random-assignment trials have shown that complete control rates for vomiting are higher than those for the complete control of nausea.^14,15

The concept of total control (no vomiting or nausea) is attractive; however, recent large studies have indicated that the total control rate is essentially identical to the complete nausea control rate. It seems that this additional category does not provide further useful information.^14,15

Lesser control rates, such as major control (zero to two or one to two emetic episodes) or minor control (three to five emetic episodes), have been useful in the past and may still have some value in particularly difficult emetic situations. However, the panelists reached consensus in advising the use of complete control rates for the evaluation of most emetic situations and for use in the guideline development process.

A. Acute Emesis (Vomiting Occurring 0 to 24 Hours After Chemotherapy)
1. Antiemetic Agents: Highest Therapeutic Index

Two classes of agents are in this category, the serotonin receptor antagonists and corticosteroids (Table 3).^16-37 Both classes are highly effective, with few significant side effects when used appropriately, and can be given safely in combination when indicated. These agents have been largely responsible for the ease of use and high effectiveness of antiemetics in clinical practice.

a. Serotonin Receptor Antagonists.
The issues of agent equivalence, drug dosage, drug schedule, and route of administration are discussed separately below. Specific guidelines for differing acute emetic risk settings are given in a later section.

i. Agent equivalence:

Guideline: At equivalent doses, serotonin receptor antagonists have equivalent safety and efficacy and can be used interchangeably based on convenience, availability, and cost.

Level of Evidence: I.

Grade of Recommendation: A.

There are currently four agents of this class commercially available in many countries: dolasetron, granisetron, ondansetron, and tropisetron. Other, similar agents are available in individual countries or are under investigation. The majority of multiple, randomized, well-controlled studies with sufficient patients to precisely estimate differences in treatment have demonstrated that these agents have equivalent antiemetic activity and safety.^38-50 There was unanimity among the Panel members for this conclusion.

These agents exert their activities by the same mechanism, antagonism of the type 3 serotonin (5-hydroxytryptamine [5-HT₃]) receptor.^51-57 They are all highly selective with high affinities for this receptor.^58-60 All clinically relevant antiemetic actions are mediated in this way by these agents. These agents also share the same low side-effect pattern, with mild headache, transient asymptomatic transaminase elevations, and constipation being among the most commonly reported adverse events.^17,18,20,23

The overall conclusion is based on the excellent evidence available for granisetron, ondansetron, and, more recently, dolasetron. The studies with tropisetron are less rigorous (level of evidence: II; grade of recommendation: B), but the Panel found that they are sufficient to allow the confidence in the above-stated conclusion.

ii. Drug dosage:

Guideline: Established, proven doses of all agents are recommended.

Level of Evidence: I.

Grade of Recommendation: A.

Many studies have addressed the question of establishing the ideal doses for these agents. Dolasetron, granisetron, and ondansetron are the best-studied agents in terms of dose-finding^{38,40,45,48,61-77}; few studies have carefully examined tropisetron dosing. With excellent safety profiles through large dosing ranges, toxicity has not been the criterion for determining dosage. It is clear that too low a dose can be found for these agents, with attenuated activity observed at less than optimal doses (listed in Table 3). ^{65,67,73,74,78} Panel members concurred that it is likely that a threshold effect exists. Once all relevant receptors are saturated, higher doses do not enhance any aspect of activity. Two corollaries are also important: sufficient doses must be given to ensure maximum efficacy. Most Panel members agreed that the dose will be the same in all antiemetic settings in which a serotonin receptor antagonist is required. The Panel unanimously concluded that the lowest fully effective dose for each of the agents should be used.

As mentioned above, the question of ideal dose has been best studied with dolasetron, granisetron, and ondansetron. A lesser degree of evidence is found for tropisetron,^79,80 but the conclusion reached was the same.

iii. Drug schedule:

Guideline: Single doses of antiemetics are effective and are preferred for convenience and cost.

Level of Evidence: I.

Grade of Recommendation: A.

Several recent studies have examined the issue of multiple antiemetic doses compared with a single administration. The latter approach, if equally effective, enhances convenience and adherence. A single-dose regimen using the lowest fully effective dose can provide economic benefit and the potential for the fewest side effects. Large, randomized studies with granisetron,⁸⁰ dolasetron,⁸¹ and ondansetron^66,67,82 have indicated the equivalence of single-dose schedules of these agents when compared with multiple-dose regimens of the same agents. Dolasetron has been largely explored as a single-dose agent; however, with the exception of one study,⁴⁷ its single-dose activity is equivalent to single doses of ondansetron,^45,46,48 confirming the utility of this schedule for all three agents. The Panel was unanimous in concluding that single-dose regimens are as active as multiple-dose schedules.

Tropisetron has generally been used in single-dose schedules, with few formal dosing comparisons.^{44,49,79,83,84} The level of evidence is less regarding this agent, but the Panel's conclusion was the same.

iv. Route of administration:

Guideline: At biologically equivalent doses, oral agents are equally effective and are as safe as intravenous antiemetics. In most settings, oral agents are less costly and more convenient; for those reasons, they are recommended over intravenous therapy.

Level of Evidence: I.

Grade of Recommendation: A.

Intravenous and oral routes have been studied with these agents. Most of the conclusions concerning drug equivalence, dosage, and schedules are based on intravenous administration. An emerging body of formal trials is now becoming available concerning the oral route compared with the intravenous in the administration of various serotonin receptor antagonists. All of these agents have undergone pharmacologic testing. Excellent absorption is found with all agents: reports indicate 50% to 80% bioavailability with these drugs.⁸⁵ Because 5-HT₃ receptors are found in the enterochromaffin cells in the gut, with vagal afferent fibers in this area,⁸⁶ it has been suggested that oral administration may be particularly appropriate for these agents.

Large, randomized studies have shown that, in the settings of both highly emetogenic chemotherapy and chemotherapy of intermediate emetogenicity, a single dose of oral granisetron demonstrates similar efficacy when compared with a single intravenous dose of ondansetron.^14,15 Only extremely small differences were found; these differences were even smaller when both agents were combined with corticosteroids. Oral dolasetron was tested in patients receiving chemotherapy of intermediate emetogenicity^25,47,87,88 and cisplatin,⁸⁹ and in comparison with intravenous ondansetron, in a large randomized study.⁴⁷ Again, similar efficacy was reported. Both ondansetron^90-95 and tropisetron⁷⁹ are known to be active when given orally; however, studies have not been as formalized with the oral form of these drugs. The Panel reached consensus that oral and intravenous routes are similar in efficacy, especially when given in combination with corticosteroids,³³ but the level of evidence is somewhat less for this conclusion than it is for those reported above.

b. Corticosteroids.
Corticosteroids also have a high therapeutic index when used for acute chemotherapy-induced emesis. They are among the most frequently used antiemetics, with single-agent use being appropriate in low-risk settings. They are especially valuable when given in combination with serotonin receptor antagonists in patients receiving highly emetogenic chemotherapy^{20,33,35,96-105} (this is covered in more detail in a later section). Issues of equivalence and route of administration, as well as drug dose and schedule, are discussed together.

i. Agent equivalence and route of administration:

Guideline: At equivalent doses, corticosteroids have equivalent safety and efficacy and can be used interchangeably.

Level of Evidence: IV and Expert Consensus.

Grade of Recommendation: C.

The corticosteroids most frequently studied for use as antiemetics have been dexamethasone^106-111 and methylprednisolone.^112-118 Some reports have used prednisone.¹¹⁹ Although efficacy has been reported with these agents, there have been no comparison trials. Dexamethasone has the advantages of being available in many dosage formulations and accessible in generic forms in many countries.

There are no formal trials comparing oral with parenteral corticosteroids. Knowledge of acceptable bioavailability and corticosteroid utility in many indications for these agents has encouraged their use in the oral form.

In the absence of comparison studies, most panelists recommended dexamethasone or methylprednisolone because of the published experience with these agents.

ii. Drug dose and schedule:

Guideline: Single doses of corticosteroids are recommended.

Level of Evidence: II.

Grade of Recommendation: B.

Some comparison trials have explored these issues.¹⁰⁷ Until recently, these trials have typically been consecutive dose-level investigations rather than randomized studies. Findings suggest that single doses are as effective as multiple-dose schedules. Although few studies have addressed this issue, there is no benefit to starting the corticosteroid the day before chemotherapy.¹²⁰ To date, there is no evidence that doses of dexamethasone greater than 20 mg are more effective.¹²⁰ A recent randomized study demonstrated improved efficacy and equivalent adverse effects with dexamethasone given at 20 mg (with serotonin antagonists) compared with dexamethasone at lower doses.¹²¹ Side effects of single corticosteroid doses are rare, although elevations of serum glucose levels and sleep disturbances occur.¹²² The Panel achieved consensus that single-dose regimens are most appropriate.

2. Antiemetic Agents: Lower Therapeutic Index—Dopamine Antagonists, Butyrophenones, Phenothiazines, and Cannabinoids
Guideline: For chemotherapy with a high risk of emesis, selective serotonin antagonists (with dexrazoxane) are recommended.

Level of Evidence: I.

Grade of Recommendation: A.

There are several classes of agents with antiemetic activity that are less efficacious than the serotonin receptor antagonists or corticosteroids. These other agents generally have more side effects because they are less selective than the serotonin receptor antagonists.

Several of these agents are antagonists of dopamine type 2 receptors. Foremost in this group is the substituted benzamide, metoclopramide. At higher doses, however, metoclopramide acts primarily as a serotonin receptor antagonist (Table 3).¹²³ Antiemetic efficacy with metoclopramide is slightly less than that seen with the selective serotonin receptor antagonists.^120,124-132 Side effects include acute dystonic reactions, akathisia, and sedation.^{17,18,20,133,134}

Butyrophenones (such as haloperidol and droperidol)^135-138 and phenothiazines (prochlorperazine and thiethylperazine)^126,139,140 have antiemetic activity mediated by their antidopaminergic actions. Efficacy is generally lower than with metoclopramide.¹³⁶ Side effects include dystonic reactions, akathisia, sedation, and postural hypotension (especially with intravenous phenothiazines).^141,142

Cannabinoids, both as plant extracts (dronabinol) and as semisynthetic agents (nabilone and levonantradol), have been found to have antiemetic activity when used alone^143-150 or in combination with other agents.^151,152 The activity of dronabinol (given in oral doses varying from 2.5 mg per dose to 10 mg/m²) has been shown to be significantly less than that of metoclopramide in a randomized, double-blinded trial with patients receiving cisplatin.¹⁵³ Activity reported for dronabinol in patients receiving methotrexate was not seen by the same investigator testing the agent in patients receiving cyclophosphamide and doxorubicin.¹⁵⁴ Inhalant marijuana has been compared with dronabinol in only one randomized, double-blind trial with patients receiving chemotherapy of intermediate emetic risk.¹⁵⁵ The inhalant and the oral cannabinoids were not effective in either arm of the study. There was no efficacy, side effect, or pharmacologic advantage for either agent or route; however, there was a modest patient preference for the oral dronabinol in this cross-over, blinded trial. These agents cause frequent dizziness, sedation, hypotension, and dysphoria, especially in older adults.^156,157

The Panel was unanimous in finding that in acute chemotherapy-induced emesis, especially in the high-risk setting, there is no group of patients for whom agents of lower therapeutic index (metoclopramides, phenothiazines, butyrophenones, and cannabinoids) are appropriate as first-choice antiemetic drugs. These agents should be reserved for patients intolerant of or refractory to serotonin receptor antagonists and corticosteroids.

3. Antiemetic Agents: Adjunctive Drugs—Benzodiazepines and Antihistamines
Guideline: Benzodiazepines and antihistamines are useful adjuncts to antiemetic drugs, but are not recommended as single agents.

Level of Evidence: II.

Grade of Recommendation: B.

Benzodiazepines, most commonly lorazepam, have been widely given, both in combination and as single agents.¹⁵⁸--¹⁶⁶ Trials, including randomized, blinded studies with lorazepam in combination regimens, have indicated limited antiemetic activity for this agent.¹⁶⁰ However, because of its potent antianxiety effects, lorazepam was believed to be a useful addition to the active antiemetics given in the combination. In general, lorazepam and similar drugs should be viewed as adjunctive agents rather than as useful antiemetics themselves.

Antihistamines have been administered both as antiemetics and as adjunctive agents to prevent dystonic reactions with dopamine antagonists.^120,160 Drugs such as diphenhydramine, hydroxyzine, and benztropine have been the most commonly used agents. Studies have not shown antiemetic activity for these drugs.¹²⁰ Diphenhydramine can prevent extrapyramidal reactions¹²⁰; however, because dopamine receptor antagonist agents are no longer first-choice drugs, the role for antihistamines is limited.

4. Antiemetic Agents: Combinations of Antiemetics
Guideline: It is recommended that serotonin antagonists be given with corticosteroids.

Level of Evidence: I.

Grade of Recommendation: A.

Extensive research has shown that combinations of antiemetics are significantly more effective than single agents when used with chemotherapy that is likely to induce emesis. Among the antiemetic agents listed in the highest therapeutic index category, corticosteroids given in combination with a serotonin receptor antagonist yield the greatest antiemetic protection in repeated, multicenter, randomized studies designed with sufficient numbers of patients to precisely estimate treatment effects.^{20,33,62,97-100,104,105,167-169} Side effects are usually low with these combinations. For patients receiving cisplatin or noncisplatin chemotherapy of high emetic risk (as discussed below in Risk Factors for Acute Emesis under High-Risk Cisplatin), these combinations are the regimens of choice. The Panel was unanimous in its recommendation that in these emetic situations, when a serotonin antagonist is indicated, a corticosteroid should also be given unless the use of the latter agent is strongly contraindicated.

Older, well-conducted, randomized trials^131,160 have also demonstrated that corticosteroids given in combination with agents in the lower therapeutic index category, such as metoclopramide, also give superior efficacy when compared with the single agent in high-risk emetic situations. In these situations, however, a large random-assignment trial showed that a serotonin receptor antagonist added to a corticosteroid was superior to a high-dose metoclopramide added to a corticosteroid.¹⁷⁰ The benefit was in terms of both efficacy and fewer side effects.

5. Risk Factors for Acute Emesis
Two major categories predicting risk of acute emesis (emesis occurring in the first 24 hours) or of differences in antiemetic control can be identified. These factors involve patient characteristics and the chemotherapeutic agents.

a. Patient Characteristics.
Several patient factors, some confirmed by multivariate analysis, have been shown to predict poor antiemetic control.^18,171-180 These factors include poor control with prior chemotherapy, female sex, a low chronic alcohol intake or history, and younger age. The last factor, age, is a less consistent finding in trials. However, the majority of the panelists indicated that this is a factor to be considered. Chronic alcohol intake can include a prior, rather than a current, history of high alcohol use (frequently defined as the use of more than 100 g of alcohol per day for a period of several years). In general, the higher the alcohol intake history, the lower the emetic risk with chemotherapy. Pre-existing nausea and certain health-related quality-of-life variables, eg, low social functioning and high fatigue scores, may also be predictive factors.^181,182

b. Chemotherapeutic Agents.
Agents should be classified by emetogenic potential, to aid in selection of the appropriate antiemetic. Prospective documentation of the potential of a chemotherapeutic drug to cause emesis has been rigorously established for only a few agents. General categories based on experience rather than on specific data have been useful, but they do not provide precise differentiation among chemotherapy drugs.^{7,91,93,183-187} A recent publication has endeavored to establish categories based on data.¹⁸⁸ It has tried to place both single agents and chemotherapy combinations in a classification scheme based on the actual incidence of emesis. Although this approach was encouraged by the Panel, consensus could not be reached because there is no clear evidence of the emetic potential for the majority of chemotherapeutic agents and combinations.

c. Guidelines.
To formulate guidelines, a classification based on antiemetic recommendations is needed. Outlined below is the rationale for such a classification by emetic risk of the chemotherapy agent (Table 4, A, B, and C). Table 4 is adapted from other reviews, such as that listed in the Perugia Consensus Conference,¹⁸⁹ and ranks the drugs from highest to lowest risk within each category. It was possible to reach agreement for these treatment-related categories. It was difficult to place in the proper category those agents that seem to be at the borderline between risk categories. These categories are outlined, as follows:

Guideline: The combination of a 5-HT₃ antagonist plus a corticosteroid is recommended before chemotherapy.

Level of Evidence: I.

Grade of Recommendation: A.

The literature clearly documents the incidence of emesis with cisplatin.^126,187,190 These data are valuable in antiemetic studies for several reasons: (1) the usefulness of cisplatin in oncology; (2) cisplatin causes emesis in all patients (> 99% risk without active antiemetics); and (3) cisplatin provides a model for antiemetic testing. Trials to date show that if an antiemetic is useful in cisplatin-induced emesis, it will be at least as effective with other chemotherapy drugs.¹⁹¹

The risk of emesis with cisplatin ( 50 mg/m²) is universal, but other factors can alter the risk. As the dose of cisplatin increases, the ability to prevent acute and delayed emesis decreases. This observation has placed cisplatin at the top of any classification scheme and often in a category of its own. The treatment guideline for cisplatin is independent of dose or infusion time of the agent.

Because of the careful documentation of cisplatin-induced emesis with numerous well-conducted trials, the Panel was unanimous in its recommendation for treatment. Large, multicenter, randomized trials have shown the rate of complete control of acute emesis (occurring in the first 24 hours) to be approximately 75% (range, 58% to 96%), after high-dose cisplatin using the recommended regimen.¹⁹¹

i(b). High risk – noncisplatin:

Guideline: Use of a combination of a 5-HT₃ antagonist plus a corticosteroid before chemotherapy is recommended.

Level of Evidence: I, II, III, and Expert Consensus.

Grade of Recommendation: A-B.

Documentation of risk for some of the chemotherapy agents in this category (Table 4A), such as cyclophosphamide,⁹³ is well established. Overall, the risk of emesis in this category is greater than 30% and less than that seen with cisplatin. If the classification were based on the incidence of emesis, rather than on treatment recommendations, a case could be made to place some of these drugs in a separate, higher-risk group (dacarbazine, nitrogen mustard, extremely high doses of cyclophosphamide) in which the risk of acute emesis is greater than 90%.¹⁸⁸

Other commonly used agents in this category are the anthracyclines, the nitrosoureas, and cytarabine. For these agents, especially when given in higher doses, it is expected that the majority of patients would have emesis if not given effective antiemetics. The Panel was unanimous in its treatment recommendation for the agents in this category.

The type and level of evidence varied according to the agent. As mentioned above, there are level I data for cyclophosphamide, the anthracyclines, and combinations of these agents. In these instances, several large, randomized, multicenter trials have documented 85% to 90% complete control of acute emesis, using the recommended regimen.¹⁹¹ A lower level of evidence has been demonstrated for agents such as dacarbazine.

ii. Intermediate risk:

Guideline: A corticosteroid is suggested for patients treated with agents of intermediate emetic risk.

Level of Evidence: III, IV, and Expert Consensus.

Grade of Recommendation: B, D.

Table 4B lists several commonly used chemotherapy agents in this category. Without treatment, many patients, but not the majority, would have emesis. The risk of emesis is in the 10% to 30% range for agents in this group. The emesis induced by these agents is also easier to control than that found in the greater-risk categories. The first few agents in this list were considered by some Panel members to be on the border of the upper category; the lower few were listed in the low-risk group by some panelists. Evidence for emetic risk is often found as part of phase I and II chemotherapeutic trials for the newer agents in this category, rather than as part of comparative antiemetic studies.

The Panel agreed that the complete control rate should exceed 90% with the use of a single dose of a corticosteroid. There is no formal documentation of efficacy with antiemetic treatments for these lower-risk chemotherapy agents.

iii. Low risk:

Guideline: It is suggested that for patients treated with agents of low emetic risk, no antiemetic be routinely administered before chemotherapy.

Level of Evidence: V and Expert Consensus.

Grade of Recommendation: D.

Few antiemetic studies were found that used these chemotherapeutic agents, which are listed in Table 4C. With a low perception of risk (much less than 10% for most agents), it is understandable that trials were not conducted. Because the agents in this category are older agents (all of the agents have been in use for at least 20 years), enumeration of the emetic incidence was not often given as part of the drug-testing process. Although most hormonal agents are not included in Table 4C, an exception is made for tamoxifen, which is so commonly given and is of low risk for inducing emesis. Some of the agents listed at the top of this category would be placed in the intermediate-risk category by some panelists. The Panel reached the following consensus for treatment of this group.

As in all the categories, individual patients, especially those with poor emetic control and prior drug administration, may require alteration of their antiemetic regimen. Panelists agreed that antiemetic control should exceed 95% in this group. Occasional use of a single dose of a corticosteroid, or as-needed prescribing of oral metoclopramide or a phenothiazine, is common.

iv. Combination chemotherapy:

Guideline: The Panel suggests that when combination chemotherapy is given, the patient should be given antiemetics appropriate for the chemotherapeutic agent of greatest emetic risk.

Level of Evidence: IV.

Grade of Recommendation: D.

When combination chemotherapy is given, the patient should be treated for the agent in the combination with the highest emetic risk.¹⁸⁸ For example, if low-risk agents are added to cisplatin therapy, the patient should be given antiemetics appropriate for cisplatin. If low-risk chemotherapy is added to an anthracycline regimen, the patient should be given antiemetics recommended for noncisplatin high-risk agents (the anthracycline category). The Panel was unanimous in this recommendation.

The Panel could not reach consensus concerning added emetic risk if patients are given combinations of chemotherapeutic agents in which all the drugs are in the low emetic risk categories. It has been suggested that these combinations may raise the emetic risk one category higher, but there is no definitive evidence at this time. In the absence of firm evidence, the panelists nonetheless believed that oncologists should be aware of this issue and should carefully evaluate the emetic experience of patients given these chemotherapy combinations. Most experts would continue to treat patients given these chemotherapy combinations with the antiemetics appropriate for the chemotherapeutic agent of the greatest emetic risk.

v. Multiple consecutive days of chemotherapy:

Guideline: It is suggested that antiemetics appropriate for the risk class of the chemotherapy, as outlined above, be administered for each day of the chemotherapy.

Level of Evidence: II and III.

Grade of Recommendation: B.

Few studies have assessed vomiting control for specific chemotherapy combinations. There is, however, some evidence that dexamethasone combined with metoclopramide is useful for patients receiving oral cyclophosphamide, methotrexate, and fluorouracil.³⁰ If the chemotherapy can be given as effectively and safely on day 1 of a multiple-day cycle, the likelihood of controlling emesis will be improved. When chemotherapy likely to induce emesis is given on several consecutive days with antiemetics (best demonstrated with cisplatin and with dacarbazine), control of emesis decreases. The explanation for this has not been elucidated; however, it may be that problems of both delayed and anticipatory emesis are added to the difficulty of controlling acute chemotherapy-induced emesis. 5-HT₃ antagonists plus dexamethasone are especially indicated in high-risk settings,^192-197 because the risk of dystonic reactions with dopamine antagonists increases with consecutive-day therapy (particularly in younger patients). If appropriate for the chemotherapy administered, antiemetics for delayed emesis should be given after the completion of the chemotherapy.

B. Delayed Emesis (Vomiting Occurring > 24 Hours After Chemotherapy)

The neuropharmacologic mechanism of delayed emesis is not well understood.^9,18,198-203 Prevention of this problem has been based on empiric results.^{24,29,30,47,82,89,92,128,160,168,176,186,204}--²¹⁵ Fewer agents have been tested or are commonly used for this indication than for acute emesis.

1. Antiemetic Agents
a. Single Agents. i. Corticosteroids:

These agents are the most consistently useful drugs for the prevention of delayed emesis.^{47,205-207,211} As shown repeatedly in clinical trials, their widespread availability in oral form, low cost, and benefit make corticosteroids the single most appropriate agents for this indication. Side effects are of some concern because corticosteroids are typically used for 2 to 4 days. Adrenal insufficiency after corticosteroid usage is not a problem for this relatively brief period; however, hyperglycemia in susceptible patients requires attention. As with corticosteroids in many other settings, including for acute chemotherapy-induced emesis, the doses and schedules have not been determined by formal testing. Most trials have given the agents twice daily. Dexamethasone has been the agent tested most frequently, often at the dose of 8 mg for 2 to 3 days, occasionally tapering to 4 mg for 1 or 2 additional days. Most panelists recommended oral use of the agent. There are reports of dexamethasone given intramuscularly, but there is no clear advantage to this route. Panelists agreed unanimously that corticosteroids should be part of any regimen for delayed emesis, unless there is a strong contraindication to their usage.

There are some reports of the use of adrenocorticotropic hormone in delayed emesis,²¹⁶ but formal trials are few and panelists did not see any advantage for this agent over more readily available and easily administered corticosteroids.

ii. Metoclopramide and serotonin receptor antagonists:

Several trials have reported efficacy for oral metoclopramide given in combination with corticosteroids.^{168,205,206,209,210,217} Doses typically vary between 20 mg and 40 mg (or 0.5 mg/kg) given two to four times per day for 3 to 4 days. This agent is generally well-tolerated, with few acute dystonic reactions in the adult population (the group for which dystonic reactions are significantly less frequent). Akathisia (restlessness) may occur in some patients. This side effect may be related to dopamine receptor antagonism. Initial reports indicated some efficacy for oral prochlorperazine^209,210 with corticosteroids. There are no formal reports, however.

Studies have yielded conflicting results concerning the use of serotonin antagonists for delayed emesis. Ondansetron and granisetron have been given either singly^{17,18,65,82,176,198,199,212} or in combination with corticosteroids,^{30,47,168,211,213,214,217} but trial results have varied in regard to whether or not these agents are effective against delayed emesis. One randomized study indicates efficacy of a serotonin antagonist for delayed emesis in patients receiving chemotherapy of intermediate emetogenicity.⁸² The doses and schedules of these drugs have not been formally determined. Usually, these agents have been given orally twice a day, with ondansetron administered at 8 mg per dose and granisetron at 1 mg or 2 mg per dose. Side effects have been few and are similar to those reported for the use of these agents in acute chemotherapy-induced emesis.

There is little evidence for the use of other classes of agents for the prevention of delayed chemotherapy-induced emesis.

b. Combinations of Agents. In delayed emesis, as with acute vomiting, combination regimens seem to be the most effective. In a random-assignment trial with patients receiving cisplatin, the oral combination of metoclopramide plus dexamethasone was significantly more effective than dexamethasone alone.²⁰⁵ There are conflicting results with regard to serotonin receptor antagonist use with corticosteroids. In one comparison study, granisetron did not add to the efficacy of the corticosteroid²¹¹; however, in another large comparison trial, the combination of ondansetron plus dexamethasone was equivalent to the combination of metoclopramide plus dexamethasone.²¹⁷ The majority of the panelists favored the use of combination antiemetics in high-risk settings for delayed emesis.

Few reports address the incidence and treatment of delayed emesis in children receiving cancer chemotherapy.¹³³ Dopamine antagonists, especially when given over several consecutive days, cause a high incidence of dystonic reactions and are not a good choice for general multiple-day use in the pediatric population.^133,134

2. Risk Factors for Delayed Emesis
Risk factors for delayed emesis include patient characteristics and the chemotherapy being administered, as is the case for acute chemotherapy-induced emesis. Oncologists must be aware of these factors to identify patients who need preventive treatment on a routine basis and individuals who may be at greater risk.

a. Patient Characteristics. The most important patient characteristic predicting for greater risk for delayed emesis is poor control of acute chemotherapy-induced emesis.^9,206,214 Patients who experience acute emesis with chemotherapy are significantly more likely to have delayed emesis. Thus, any patient characteristic that predicts a greater risk for acute emesis (such as female sex, emesis with prior cycles of chemotherapy, and low prior alcohol intake history) should be considered as a predictive factor for delayed emesis as well.

b. Chemotherapeutic Agents. Delayed emesis was initially described in patients receiving cisplatin.^204,206,214 Only recently has the problem been formally outlined in patients given other chemotherapy.^82,186,207 The risk of delayed emesis in patients receiving many chemotherapy drugs has not been studied. The recommendations listed in Table 5 are tempered by a lack of formal data in many settings.

c. Guidelines. i(a). High risk: cisplatin:

Guideline: In all patients receiving cisplatin, a corticosteroid plus metoclopramide or a 5-HT₃ antagonist is recommended for the prevention of delayed emesis.

Level of Evidence: I.

Grade of Recommendation: A.

Trials have indicated that the majority of patients receiving cisplatin will experience delayed emesis if not given preventative antiemetics, with reports indicating an incidence of 60% to nearly 90%.^{17,18,128,168,176,198,199,204-206,211,212,217} The rate seems to increase with higher total doses of cisplatin, and delayed emesis occurs with both single doses and multiple daily doses of cisplatin. The Panel recommended that antiemetics be given to prevent delayed emesis in patients receiving cisplatin. Most panelists recommended a combination of antiemetics that includes a corticosteroid, as outlined in Table 4A.

Trials indicate that the above regimen can give rates of complete control of delayed emesis in the range of 50% to more than 70%, compared with only 11% to 30% control without antiemetics.^204,205 A large, multicenter, randomized trial²¹⁷ obtained equivalent rates of control with corticosteroids plus either metoclopramide or ondansetron, showing that either regimen could be given. The low side-effect rates in the adult population with both regimens do not indicate a clear choice for either combination. The markedly lower cost of the metoclopramide regimen and similar efficacy are strong points in favor of this combination.

i(b). High risk: non-cisplatin:

Guideline: A prophylactic corticosteroid as a single agent, a prophylactic corticosteroid plus metoclopramide, and a prophylactic corticosteroid plus a 5-HT₃ antagonist are regimens suggested for the prevention of delayed emesis.

Level of Evidence: III-V.

Grade of Recommendation: B-D.

Only recently has prospectively gathered information become available concerning the incidence of delayed emesis in patients receiving chemotherapy in this category.^{47,82,207,213} In particular, among patients receiving cyclophosphamide, anthracyclines, carboplatin, or combinations of these agents, the incidence of delayed emesis varied from 20% to 30% in patients not given prophylactic antiemetics for delayed emesis. Use of a corticosteroid as part of the acute emesis regimen was associated with a lower incidence of delayed emesis. The majority of panelists recommended that a delayed emesis regimen be given with this degree of risk, but data are lacking concerning efficacy and specific regimen choices.

Formal trials are needed to determine the length of treatment for delayed emesis regimens in this category. Most panelists recommended using the same dosages as given for cisplatin-induced emesis, although it is possible that fewer days of antiemetic treatment (ie, 2 days) may be needed for these chemotherapy agents.

ii. Intermediate-low risk:

Guideline: No regular preventive use of antiemetics for delayed emesis is suggested for patients receiving these chemotherapeutic agents.

Level of Evidence: V and Expert Consensus.

Grade of Recommendation: D.

Few studies have addressed the issues of either the incidence or prevention of delayed emesis in patients receiving these chemotherapy agents. The opinion of the panelists is that the risk is quite low for most patients; groups of patients receiving these drugs who are at greater risk have not been identified.

Although no prophylactic use of antiemetics is recommended, it may be reasonable for patients to have a small supply of oral dexamethasone, dopamine receptor antagonists, or metoclopramide for use if needed.

C. Anticipatory Emesis

Anticipatory or conditioned emesis may occur in patients who have had poor control of either acute or delayed emesis with prior chemotherapy.^218-228 Some factors that predispose patients to anticipatory emesis have been identified,^229-234 including a history of motion sickness.^174,235

1. Prevention
Prevention of chemotherapy-induced emesis is seen as the best strategy for preventing anticipatory emesis. Consensus was reached concerning prevention and treatment of anticipatory emesis, as outlined below.

Guideline: Use of the most active antiemetic regimens appropriate for the chemotherapy being given to prevent acute or delayed emesis is suggested. Such regimens must be used with the initial chemotherapy, rather than after assessing the patient's emetic response with less effective treatment.

Level of Evidence: III.

Grade of Recommendation: D.

2. Treatment
Guideline: If anticipatory emesis occurs, behavioral therapy with systematic desensitization is effective and is suggested.^236-244

Level of Evidence: III.

Grade of Recommendation: B.

d. Special Emetic Problems
1. Emesis in Pediatric Oncology

Guideline: The combination of a 5-HT₃ antagonist plus a corticosteroid is suggested before chemotherapy in children receiving chemotherapy of high emetic risk.

Level of Evidence: III.

Grade of Recommendation: B.

Studies in children receiving chemotherapeutic agents have documented the efficacy of several antiemetics. The most commonly used and best demonstrated antiemetics in children are the serotonin receptor antagonists, which are often given with corticosteroids.^245-248 Although the activity of such agents is well-documented, dosing studies have not clearly established the best doses or special dosing considerations by age, weight, or square meter of body surface area. Typically used doses follow the adult regimens (eg, ondansetron 0.15 mg/kg and granisetron 0.01 mg/kg). The absence of dystonic reactions and the low side-effect profile in general have made these agents excellent choices for use in pediatrics. Predisposition to acute dystonic reactions with dopamine antagonists and metoclopramide have been well documented, especially with consecutive daily use of these antiemetics.

Although studies have not systematically outlined emetic risk factors in children, it seems that the chemotherapy selected (with similar classifications as for adults) and prior emetic experience with chemotherapy are important predictors of risk.²⁴⁹

As is the case with dose-finding trials, few comparative antiemetic studies have been conducted in children. Until such studies are conducted, the Panel, led by the pediatric consultant, agreed that the antiemetic recommendations for adults (with doses adjusted for the pediatric population) are reasonable at this time. The major exception is that dopamine receptor antagonists (as outlined in Delayed Emesis) are not considered good choices for children receiving chemotherapy. Behavioral intervention for reduction of nausea and vomiting may also have some value.^250-252

2. High-Dose Chemotherapy
Guideline: A 5-HT₃ antagonist combined with a corticosteroid is suggested.

Level of Evidence: II and III.

Grade of Recommendation: C.

High-dose chemotherapy, often given as part of a bone marrow transplant or autologous stem-cell transplantation program, presents many concurrent problems in the control of emesis.^253,254 First, the chemotherapy is generally categorized as high or intermediate risk as part of a combination. Second, it is often given on consecutive days. Third, the patient may also be receiving radiation therapy, including total-body irradiation. Fourth, the patient may also have other medical problems or may be receiving other supportive care medicines likely to cause emesis. Fifth, the majority of patients have experienced emesis with prior chemotherapy or irradiation. These are not only problems in emetic control, but they are confounding factors that make clinical research in this area and comparison between different studies difficult.

Some investigators have suggested that higher doses of serotonin receptor antagonists are more effective in this setting.²⁵⁵ If so, this is the only situation in which such dose escalation would be beneficial. It is difficult to understand this argument based on the concept of the threshold dose saturating all relevant receptors.

Few randomized trials have been done in the setting of high-dose chemotherapy.^253,256-259 Recommendations are based on phase II studies performed in patients with a variety of different risk factors.^260,261

3. Vomiting and Nausea Despite Optimal Prophylaxis in Current or Prior Cycles
Guideline: The Panel suggests 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 substituting a dopamine receptor antagonist such as high-dose metoclopramide for the 5-HT₃ antagonist (or add the dopamine antagonist to the regimen).

Level of Evidence: V and Panel Consensus.

Grade of Recommendation: D and Panel Consensus.

Approaching the patient who has not had good control with the initial use of antiemetics for chemotherapy-induced emesis presents several problems. The patient is predisposed to anticipatory emesis, and if the most effective antiemetics were given with the prior cycle of chemotherapy, good control is not likely with the next treatment. When presented with such a patient, the physician should review several factors. These factors include antiemetic agent, chemotherapy, and tumor status.

It is important to evaluate whether appropriate antiemetics for the patient's chemotherapy and risk factors were given previously, and if they were given at the proper dose and schedule. If not, corrections in the antiemetic regimen could be helpful. If the patient were receiving chemotherapy with lower emetic risk, then adjustment of the regimen to that typically used for a higher-risk group should be tried. Because all serotonin antagonists share the same mechanism of action, it is unlikely that substitution of one for another would be superior to using the original agent, but well-designed studies investigating this have not been performed. If the patient received an oral regimen, the physician could consider giving agents intravenously, although there is no demonstration that this will improve efficacy. If the patient is likely to have increased anxiety before the subsequent chemotherapy, the possibility of anticipatory emesis warrants attention. How poor was the control? One or two episodes of emesis with cisplatin is not an ideal outcome, but it still reflects substantial efficacy of the antiemetics, with not much likelihood that another regimen would be superior.

Can the chemotherapy be altered to lessen emesis while still maintaining antitumor efficacy? Alteration could include avoiding multiple-day chemotherapy, lengthening infusion time, stopping an agent, or substituting with a chemotherapeutic drug less likely to induce emesis, if possible and prudent. Clearly, maintaining a good antitumor response, or maximizing the chance of avoiding recurrence in the adjuvant setting, is of primary importance; however, in a palliative setting, consideration of improvement in the chemotherapy regimen, if unacceptable emesis is occurring, should be given.

Finally, if the patient is having poor control with appropriate antiemetics, early evaluation of the tumor response is reasonable. Is the chemotherapy achieving its goal? Is response occurring, or is the patient receiving palliation worth the side effects? If the pattern of the occurrence of the emesis is not typical for the chemotherapy, are there other disease-related factors (such as intestinal obstruction or brain metastases) that may be causing the emesis? Can one rule out other medications (pain medicines, bronchodilators) or other disease factors (infection, gastritis) that could be complicating the treatment and evaluation of emesis?

II. RADIATION-INDUCED EMESIS

A. Risk Factors for Radiation-Induced Emesis
The risk of emesis with radiotherapy varies with the treatment administered.^262-271 Only a minority of patients receive radiation therapy of high emetic potential, and in that group of patients, the problem can be difficult to prevent or manage. Controversy, due to a lack of systematic evaluation, exists concerning definitions of emetic risk groups. As with chemotherapy-induced emesis, it is the identification of these risk groups that indicates whether antiemetic therapy should be given routinely on a preventative basis or whether antiemetics should be reserved for treatment as needed by individual patients. The radiation oncology literature indicates that treatment field is one of the major determinants of emetic risk. More difficult to define, but also important considerations for risk, are the dose of radiotherapy administered per fraction and the pattern of fractionation. Using available data and clinical experience, the Panel reached consensus on definitions of radiotherapy-induced emesis risk groups (Table 5).

1. Guidelines a. High Risk: Total-body irradiation (TBI). Guideline: The Panel suggested giving a serotonin receptor antagonist with or without a corticosteroid before each fraction and for at least 24 hours after.

Level of Evidence: II and III

Grade of Recommendation: B and C.

Review of the results of trials that used radiation allows for a series of recommendations. The highest-risk group includes patients treated with TBI. The Panel was unanimous in its recommendation.

Complete control rates with 5-HT₃ antagonists for TBI vary between 50% and 90%.^254,263,272 The role of corticosteroids in combination with 5-HT₃ antagonists has not been studied. If this approach adds efficacy, as occurs with chemotherapy, such regimens would be appropriate for this group. Some panelists advised giving corticosteroids to patients receiving TBI because of the marked risk in this situation and findings in preliminary reports.²⁷³ There are reports that serotonin receptor antagonists are more effective than metoclopramide or phenothiazines.^264,274

b. Intermediate Risk: Hemibody irradiation, upper abdomen, abdominal-pelvic, mantle, craniospinal irradiation, and cranial radiosurgery. Guideline: The Panel suggested giving a serotonin receptor antagonist or a dopamine receptor antagonist before each fraction.

Level of Evidence: II and III.

Grade of Recommendation: B.

Existing evidence suggests that preventative treatment is better than intervention on an as-needed basis in this group (see Table 5 for group definition) and that serotonin receptor antagonists are more effective than metoclopramide or phenothiazines.^264,274 There may be smaller differences between these agents in intermediate-risk settings than in higher-risk settings, and therefore dopamine receptor antagonists may be more appropriate, particularly in patients receiving craniospinal or lower-half-body radiotherapy, where there is somewhat less risk of emesis.²⁷⁵ There is also some evidence to suggest that in fractionated radiotherapy, the efficacy of 5-HT₃ antagonists may decrease after the first week of treatment,²⁷⁶ making it difficult to suggest what the optimal duration of prophylactic treatment should be.

Trials indicate that both serotonin and dopamine receptor antagonist agents are effective for patients who require treatment in this group, with most studies indicating better control with serotonin receptor antagonists.^274,275 In trials, cannabinoids (such as nabilone and levonantradol) have not provided adequate control of emesis and have had a higher rate of side effects than seen with dopamine or serotonin receptor antagonists.²⁷⁷ A recent study indicates that dexamethasone has efficacy similar to 5-HT₃ antagonists when given to patients receiving radiotherapy to the upper abdomen.²⁷⁵

c. Low Risk: Radiation of the Cranium Only, Breast, Head and Neck, Extremities, Pelvis, and Thorax. Guideline: The Panel suggested that treatment be given on an as-needed basis only. Dopamine or serotonin receptor antagonists are advised. Antiemetics should be continued prophylactically for each remaining radiation treatment day.

Level of Evidence: IV and V.

Grade of Recommendation: B-D.

The incidence of emesis in this patient group, as defined in Table 5, is relatively low (0% to 30%). Treatment should be reserved for those patients who experience nausea and vomiting. With a paucity of trials, and because of the previously mentioned evidence that the difference in efficacybetween 5-HT₃ antagonists and dopamine antagonists is smaller in intermediate- and low-risk settings, dopamine antagonists are recommended for routine use with 5-HT₃ antagonists reserved for rescue.

APPENDIX

ACKNOWLEDGMENTS

The Expert Panel expresses its gratitude to Drs Douglas W. Blayney, George J. Bosl, Allen B. Bredt, David R. Gandara, Patricia A. Ganz, John D. Hainsworth, Robert M. Langdon, Jr, Rudolph M. Navari, T.J. Priestman, and Fausto Roila for their thoughtful reviews of earlier versions of the guidelines.

NOTES

Adopted on February 18, 1999, by the American Society of Clinical Oncology.

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