(
`'-
`
`ASCO SPECIAL ARTICLE
`Recommendations 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
`
`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
`tbr antiemetic treatment, the number of agents, and the indica-
`tions 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 necessi-
`late 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 clinicalvarc. 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 oflife. Addition-
`ally, 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 manage-
`ment 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
`Practice guidelines are systematically developed state-
`ments to assist the practitioner and patient decisions about
`appropriate health care for specific clinical circumstances. 4
`
`Good clinical guidelines include considerations o.f validity,
`reliability, reproducibility, clinical applicability, clinical flex-
`ibility, clarity, multidisciplinary process, review of evidence,
`and documentation.4
`In fonnulating 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 obtain-
`ing the same results.
`It is also important to note that not all relevant questions
`regarding emesis in cancer c.are 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 guide-
`lines to be voluntary. The ultimate determination regard-
`ing their application Is to be made by the physician in
`light of each patient's individual circumstances. In addi-
`tion, these guidelines describe administration of thera-
`pies in clinical practice; they cannot be assumed to apply
`to interventions performed in the context of clinical
`trials, given that such cHnica] studies are designed to test
`innovative and novel therapies for this symptom in
`
`From the American Society of Clinical Oncology. Alexandria, VA.
`Adopted 011 Febmary 18, 1999, by the American Society of Clinical
`Oncology.
`Address reprint Yl'quests to American Society of Clinical Oncology.
`Health Services Research, 225 ReinckerJ Lane, Suite 650, Alcxand,ia,
`VA 22314; email guide/ines@asco.o.rg.
`o 1999 by American Society of Clinical Oncology.
`0732-183X/99/1709-297 1
`
`Journal of Clinical Oncology, Vol 17, No 9 (September), 1999: pp 2971-2994
`
`2971
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1013
`
`Exh. 1013
`
`

`
`2972
`
`GRALLA ET AL
`
`Table 1. Summary of Guidelines
`
`Chemotherapy-Induced Emesis
`A. Acute Emesis (vomiting occurring 0 to 24 hours after chemotherapy)
`1. Antiemetic Agents: Highest Therapeutic Index
`a. Serotonin Receptor Antagonists
`Agent equivalence
`At equivalent doses, serotonin receptor antagonists have equivalent safety and efficacy and can be used ilnterchangeably based on convenience,
`availability, and cost.
`II. Drug dosage
`Established, proven doses of all agents are recommended.
`iii. Drug schedule
`Single doses of antlemetlcs are effective and preferred for convenience and cost
`lv. Route of administration
`At biologically equivalent doses, oral agents are equally effective and are as safe as intravenous antieme·tics. In most settings, oral agents are less
`costly 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, Phenothiazlnes, and Cannabinoids
`For chemotherapy witlila high risk of emesis, selective serotonin antagonists (with dexamethasone) are recommended.
`3. Antiemetic Agents: A<!Junctive Drugs-Benzodi;azeplnes and Antihistamines
`Benzodlazeplnes 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 Characterist[cs
`b. Chemothera peutlc Agents
`c. Guidelines
`l(a). High risk: Cisplatin
`The combination of a 5-HT3 antagonist p lus" corticosteroid is recommended before chemotherapy.
`l(b). High risk: nonclsplatin
`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.
`iii, low 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 antiemetlcs appropriate lor the chemotherapeutic agent of
`greatest emetic risk.
`v. Muhlple consecutive days of chemotherapy
`It is suggested that antiemctics 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. Anti emetic Agents
`a. Single Agents
`i. Corticosteroids
`II. Metoclopramlde and serotonin receptor antagonists
`b. Combinations of Agents
`2. Risk Factors for Delayed Emesis
`a. Patient Characteristics
`b. Chemotherapeutic Agents
`c. Guidelines
`l(a). High risk: cioplatin
`For all patients receiving clsplatin. a corticosteroid plus rnetoclopramide or plus a 5-HT3 anlagonistls recommended for lhe prevention of delayed emesis.
`l(b). High risk: nonclsplatln
`A prophylactic corticosteroid as a single agen~ a prophylactic corticosteroid plus metoclopramlde, and a prophylactic corticosteroid plus a 5-HT,
`antagonist are regimens suggested for the prevention of delayed emesis.
`II. lntermedlate-'lowrlsk
`No regular preventive use of anti emetics for delayed emesis Is suggested for patients receiving these chemotherapeutic agents.
`
`Exh. 1013
`
`

`
`ASCO ANTIEMETICS GUIDELINES
`
`2973
`
`Table 1. Summary of Guidelines (Cont'd)
`
`C. Anticipatory Emesis
`1 . Prevention
`Use of the most active antiemetic regimons appropriate for the chemotherapy being given to prevent acute or delayed emesis Is suggest<>d. Such regi-
`mens must be used with tho Initial chemotherap;y. rather than after assessment of the patient's emelle response to less etrecllve treatment.
`2. Treatment
`If anticipatory emesis occurs, behavioral therapy with systematic desensitization Is effective and Is suggested.
`D. Special Emelle Problems
`1 . Em esls In Pediatric Oncology
`The combination of a 5-HT, 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 metoclopramlde, for the 5-HT3 antagonist (or add the dopamine antagonist to the regimen).
`II. Radiation-Induced Emesis
`A. Risk Factors for Radiation-Induced Emesis
`1. Guidelines
`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 oflhe 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. Anti emetics 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-
`sis 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.
`
`Table 2. levels and Grade of Evidence for Recommendations280,2o1
`Typo or Evldonoo
`
`Leve[
`
`Evidence is obtained fr.om meta-analysis of muiUple, well-designed,
`controlled studies. Randomized trials have with low false-positive and
`low false-negative errors (high power).
`Evidence Is obtained fr·om at least one well-designed experimental
`study. Randomized trials have high false-positive and/or -negative
`errors (low power).
`Evidence is obtained fr•om well-designed, quasi-experimental studies
`such as nonrandomized, controlled, single-group, pre-post, cohort,
`time, or matched case-control series.
`Evidence is from well-designed, nonexperimental studies, such as
`comparative and correlational descriptive and case studies.
`Evidence Is from case reports and clinical examples.
`
`Ill
`
`IV
`
`V
`
`METHODS
`A methodology similar to that applied in prior ASCO practice
`guidelines documentation' was used and is described in more deteil
`below.
`
`Expert Panel Composition
`The Panel was composed of experts in clinical medicine, clinical
`research, outcomcslbealth 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, !'adiatioo 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, anticipa-
`tory + nausea, anticipatory + vomiting, serotonin antagonists, pheno-
`thiazines, butyrophenoncs, cannabinoids, corticosteroids, and metoclo-
`pramide. Directed searches were made of the primary articles.
`
`Consensus Development Based on Evidence
`The Panel identified topics to be addressed by the guidelines,
`developed n strntegy for completion of the guidelines, and reviewed the
`literature. TI1c Panel emphasized the inclusion of prospective random-
`
`Exh. 1013
`
`A
`
`8
`
`Grade Grade for Recommend'ation
`There is evidence of type I or consistent findings from multiple studies
`of types II, Ill, and IV.
`There Is evidence oltypes II, Ill, and IV, and findings are generally
`consistent.
`There Is evidence of types II, Ill, and IV. but findings are Inconsistent.
`There is little or no systematic empirical evidence.
`
`C
`D
`
`

`
`2974
`
`assignment studies. Phase 11 trials and clinical reports that evaluated
`less-well-studied areas of antiemetic treatment were also reviewed. The
`recommendations made by the Expert Panel arc 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 bad 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 charac·
`terize the strength of the evidence. In accordance with the ASCO Health
`Services Research Policies and Procedures for guidelines, "recommen-
`dation" 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
`l11e content of the guidelines and the manuscript were reviewed and
`approved by the Health Services Research Committee and by theASCO
`Board! of Directors before dissemination. In addition, several practitio-
`ners who had no.t 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 conftict.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 modifica-
`tions may be warranted. Where appropriate, the Panel will recommend
`the revised guideline to tbe 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-Iisk 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
`
`GRALLA ET AL
`
`reliable measure.?-9 The validity of this measure is demon-
`strated 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 categori-
`cal 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 h.ave 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 consens•Js in advising the use of
`complete control rates for the evaluation of most emetic situa-
`tions 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 i.ssues 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 antago-
`nists 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, ondanse-
`tron, and tropisetron. Other, similar agents are available in
`
`Exh. 1013
`
`

`
`ASCO ANTIEMETIC$ GUIDELINES
`
`2975
`
`Antiemetic Agent (lnlde name)
`
`OosaRango
`
`Schoduro (for acuiB chemotherapy·
`induced emesis, um!ess otherwise noted)
`
`Evidence
`(type and grade)
`
`Table 3. Antiemeuc Agents, Doses, and AdminlstraUon Schedule
`
`100 mg or 1.8 mg/kg IV
`100mgPO
`1 mg or 0.01 mg/kg IV
`2mgPO
`8 mg or 0 .15 mg/kg IV
`Oral doses vary (12·24 mg/ d) (8 mg doses usually
`used in delayed or RT emesis)
`SmgiV
`5mgPO
`
`One time, before chemotherapy
`One time, before chemotherapy
`One time, before chemotherapy
`One time, before chemotherapy
`One time, before chemotherapy
`One lime, before chemotherapy (two to three times
`daily In delayed or RT emesis)
`One time, before chemotherapy
`One time, before chemotherapy
`
`Agents w ith highest therapeutic Index
`Serotonin receptor antagonlsls
`Dolasetron (Anzemer)
`Dolasetron (Anzemet)
`Granlsetron (Kytrl~
`Granlsetron (Kytrlq
`Ondansetron (Zofran)
`Ondansetron (Zofran)
`
`Tropisetron (Navoban)
`Tropisetron (Navoban)
`Conlcosteroids
`Dexamethasone· (Decadron)
`M ethylprednlsolone (Medroq
`Agents of lower therapeutic index
`Dopamine receptor antagonists
`Metoclopramlde (Reg/an)
`
`20mgiV
`40 mgto 125 mg
`
`2 mg/kg to 3 mg/kg IV
`
`I, A
`II, A
`I, A
`I, A
`I, A
`II, B
`
`Ill, B
`Ill, B
`11, a
`V, D
`
`I, A
`
`IV, D
`II, B
`III·IV. C
`
`One time, before chemotherapy
`One time, before chemotherapy
`
`Before chemotherapy and 2 hours after chemo-
`therapy
`Two to four times a day for delayed emesis
`Every 3 to 4 hours
`Every 3 to 4 hours
`
`Metoclopramide (Raglan)
`Prochlorperazlne (Compazlne)
`Proochlorperazine (Compazlne)
`
`20 mg to 0.5 mg/ kg PO for delayed emesis or RT
`10mg to 30 mg IV
`10to20mgPO
`
`individual countries or are under investigation. The majority
`of multiple, randomized, well-controlled studies with suffi-
`cient patients to precisely estimate differences in treatment
`have demonstrated that these agents have equivalent anti-
`emetic activity and safety.38-50 There was unanimity among
`the Panel members for this conclusion.
`These agents exett their activities by the same mecha-
`nism, antagonism of the type 3 serotonin (5-hydroxytrypta-
`mine [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 trans-
`aminase elevations, and constipation being among the most
`commonly reported adverse events.t7,18,2o,n
`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: ll; 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 Recommendotion: 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 tem1s of dose-
`
`finding38•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 tha n 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 unani-
`mously concluded that the lowest fully effective dose for
`each ofthe 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
`
`Exh. 1013
`
`

`
`2976
`
`effective dose can provide economic benefit and the poten-
`tial for the fewest side effects. Large, randomized studies
`with granisetron, 80 dolasetron,81 and ondansetron66•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
`singl<e-dosc 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 sched-
`ules, 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 administr:afion:
`Guideline: At biologic~lly equivalent doses, oral agents
`are equally effective and are as safe as intravenous antiemet-
`ics. 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 equiva-
`lence, dosage, and schedules are based on intravenous
`administration. An emerging body of fmmal 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 arc 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 granis-
`etron 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 corticoste-
`roids. Oral dolasetron was tested in patients receiving
`chemotherapy of intennediate ernetogenicity25•47·87•88 and
`cisplatin,89 and in comparison with intravenous ondansetron,
`in a large randomized study. 47 Again, similar efficacy was
`reported. Both ondansetron90·95 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
`
`GRALLA ET Al
`
`Panel r·eached consensus that oral and intravenous routes are
`similar in efficacy, espec-ially 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 pa-
`tients receiving highly emetogenic chemotherapy20,33,3S,96•
`10s (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 interchange-
`ably.
`Level of Evidence: IV and Expert Consensus.
`Grade of Recommendation: C.
`The corticosteroids most frequently studied for use as
`antiemetics have been dexarnetbasone106·111 and methylpred-
`nisolone.112·118 Some reports have used prednisone. 119 Al-
`though 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 compating 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 be-
`cause of the published experience with these agents.
`ii. Drug dose and schedule:
`Guideline: Single doses of corticosteroids are recom-
`mended.
`Level of Evidence: II.
`Grade of Recommendation: B.
`Some comparison trials have explored these issues. W7
`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 ad-
`dressed 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 demon-
`strated improved efficacy and equivalent adverse effects
`with dexamethasone given at 20 mg (with serotonin antago-
`
`Exh. 1013
`
`

`
`ASCO ANTIEMETICS GUIDELINES
`
`nists) 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 rec-
`ommended.
`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 arc antagonists of dopamine type 2
`receptors. Foremost in this group is the substituted benza-
`mide, mctoc!opramide. At higher doses, however, metoclop-
`ramide acts primarily as a serotonin receptor antagonist
`{Tabl'e 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, akatbisia, and sedation.17,18,20,133,134
`Butyrophenones (such as haloperidol and droperidol)135-
`ns and phenothiazines (prochlorperazine and thiethylpera-
`zine)126·139·140 have antiemetic activity mediated by their
`antidopaminergic actions. Efficacy is generally lower than
`with metoclopramide.136 Side effects include dystonic reac-
`tions, akathisia, sedation, and postural hypotension (espe-
`cially with intravenous phenothiazines).l41,142
`Cannabinoids, both as plant extracts (dronabinol) and as
`semisynthetic agents (nabilone and levonantradol), have
`been found to have antiemetic activity when used alone143-
`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 mcto