Support Care Cancer ( 1998) 6:237- 243
`© Springer-Verlag 1998
`
`REVIEW ARTICLE
`
`David R. G andara
`Fausto Roila
`David Warr
`Martin J. Ed elma n
`Edith A. Per ez
`Richa rd J. Gralla
`
`Consensus proposal for SHT 3 antagonists
`in the prevention of acute emesis related to
`highly emetogenic chemotherapy
`Dose, schedule, and route of administration
`
`Key words Chemotherapy induced
`emesis · Serotonin receptors ·
`Orndansetron · Granisetron ·
`Do lesetron · Tropisetron
`
`Presented in part at the MASCC Consensus
`Conference o n Antiemetic Therapy, Perugia,
`28-29 April 1997
`
`D. R. Gandara, M.D. (G) 1
`U.C. Davis Cancer Center, 4501 X Street,
`Sacramento, CA 95817, USA
`F. Roila, M.D.
`Division of Medical Oncology, Policlinico
`Monteluce, 1-06122 Perugia, Italy
`D. Warr, M.D.
`Ontario Cancer Institute, Princess Margaret
`Hospital, 610 University Avenue, Toronto,
`Ontario, Canada M5G 2M9
`M.J. Edelman, M.D.
`U C Davis Cancer Center, Sacramento,
`CA 95817, USA
`VA Northern California Health Care System,
`Martinez, CA 94553, USA
`E. A. Perez, M.D.
`Mayo Clinic, Jacksonville, 4500 San Pablo
`Road, Jacksonville FL 32224-1865, USA
`R. J. Gralla, M.D.
`Ochsner Clinic, Hematology/Oncology,
`15 14 Jefferson Highway, New Orleans,
`LA 70121, USA
`1 Mailing address:
`University of California, Davis,
`Department of Internal Medicine,
`Division of Hematology & Oncology,
`4501 X Street Suite 3017,
`Sacramento, CA 95817, USA
`Fax: ( I) 510 228 4686
`
`Abstract Selective antagonists to the
`Type 3 serotonin receptor (5HT3) in
`combination with corticosteroids are
`now considered the standard of care
`for the prevention of emesis from
`moderately to highly emetogenic
`chemotherapy. Here we address issues
`of optimal dose, schedule and route of
`administration of four currently
`available selectable 5HT 3 antagonists.
`Thjs paper utilizes an evidence based
`medicine approach to the literature
`regarding this class of drugs,
`emphasizing the results large,
`randomized, controlled trials to make
`formal recommendations concerning
`optimal use of this important new
`class of anti-emetic agents. We
`conclude that for each drug there is a
`plateau in therapeutic efficacy at a
`definable dose level above which
`further dose escalation does not
`improve outcome. Furthermore, a
`single dose is as effective as multiple
`doses or continuous infusion, and
`finally, emerging data demonstrate
`that the oral route is equally
`efficacious as the intravenous route of
`administration, even with highly
`emetogenic chemotherapy.
`
`Introduction
`
`The development of selective antagonists to the 5-
`hydroxytryptaphamine (5HT3) receptor has revolutionized
`the therapeutic approach to chemotherapy-induced emesis
`(CIE) [22, 29, 50]. These agents, in combination with cor-
`ticosteroids, have become a new standard of care for mod-
`erately to highly emetogenic chemotherapy. The four se-
`
`lective 5HT3 antagonists that have completed clinical test-
`ing (ondansetron, granisetron, tropisetron, and dolasetron)
`differ considerably in biological properties such as recep-
`tor specificity, potency, and plasma half-life [2, 51]. N ev-
`ertheless, each has demonstrated relatively equivalent efti-
`cacy in the prevention of CIE in a wide variety of clinical
`settings. As a
`·
`Dr. Reddy's Laboratories, Ltd., et al.
`excellent side e
`v.
`Despite these
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1027
`
`

`
`Support Care Cancer ( 1998) 6:237- 243
`© Springer-Verlag 1998
`
`REVIEW ARTICLE
`
`David R. Gandara
`Fausto Roila
`David Warr
`Martin J. Ed elma n
`Edith A. Per ez
`Richa rd J. Gralla
`
`Consensus proposal for SHT 3 antagonists
`in the prevention of acute emesis related to
`highly emetogenic chemotherapy
`Dose, schedule, and route of administration
`
`Key words Chemotherapy induced
`emesis · Serotonin receptors ·
`Orndansetron · Granisetron ·
`Do lesetron · Tropisetron
`
`Presented in part at the MASCC Consensus
`Conference o n Antiemetic Therapy, Perugia,
`28-29 April 1997
`
`D. R. Gandara, M.D. (G) 1
`U.C. Davis Cancer Center, 4501 X Street,
`Sacramento, CA 95817, USA
`F. Roila, M.D.
`Division of Medical Oncology, Policlinico
`Monteluce, 1-06122 Perugia, Italy
`D. Warr, M.D.
`Ontario Cancer Institute, Princess Margaret
`Hospital, 610 University Avenue, Toronto,
`Ontario, Canada M5G 2M9
`M.J. Edelman, M.D.
`U C Davis Cancer Center, Sacramento,
`CA 95817, USA
`VA Northern California Health Care System,
`Martinez, CA 94553, USA
`E. A. Perez, M.D.
`Mayo Clinic, Jacksonville, 4500 San Pablo
`Road, Jacksonville FL 32224-1865, USA
`R. J. Gralla, M.D.
`Ochsner Clinic, Hematology/Oncology,
`15 14 Jefferson Highway, New Orleans,
`LA 70121, USA
`1 Mailing address:
`University of California, Davis,
`Department of Internal Medicine,
`Division of Hematology & Oncology,
`4501 X Street Suite 3017,
`Sacramento, CA 95817, USA
`Fax: ( I) 510 228 4686
`
`Abstract Selective antagonists to the
`Type 3 serotonin receptor (5HT3) in
`combination with corticosteroids are
`now considered the standard of care
`for the prevention of emesis from
`moderately to highly emetogenic
`chemotherapy. Here we address issues
`of optimal dose, schedule and route of
`administration of four currently
`available selectable 5HT 3 antagonists.
`Thjs paper utilizes an evidence based
`medicine approach to the literature
`regarding this class of drugs,
`emphasizing the results large,
`randomized, controlled trials to make
`formal recommendations concerning
`optimal use of this important new
`class of anti-emetic agents. We
`conclude that for each drug there is a
`plateau in therapeutic efficacy at a
`definable dose level above which
`further dose escalation does not
`improve outcome. Furthermore, a
`single dose is as effective as multiple
`doses or continuous infusion, and
`finally, emerging data demonstrate
`that the oral route is equally
`efficacious as the intravenous route of
`administration, even with highly
`emetogenic chemotherapy.
`
`Introduction
`
`The development of selective antagonists to the 5-
`hydroxytryptaphamine (5HT3) receptor has revolutionized
`the therapeutic approach to chemotherapy-induced emesis
`(CIE) [22, 29, 50]. These agents, in combination with cor-
`ticosteroids, have become a new standard of care for mod-
`erately to highly emetogenic chemotherapy. The four se-
`
`lective 5HT3 antagonists that have completed clinical test-
`ing (ondansetron, granisetron, tropisetron, and dolasetron)
`differ considerably in biological properties such as recep-
`tor specificity, potency, and plasma half-life [2, 51]. N ev-
`ertheless, each has demonstrated relatively equivalent efti-
`cacy in the prevention of CIE in a wide variety of clinical
`settings. As a class, these agents are characterized by an
`excellent side effect profile and a broad therapeutic index.
`Despite these advantages and widespread clinical use, a
`
`Exh. 1027
`
`

`
`238
`
`number of controversies and uncertainties regarding the
`optimal use of these agents in day-to-day clinical practice
`persist.
`This discussion will address issues of dose, schedule,
`and route of administration of the four selective 5HT3 an-
`tagonists in the prevention of acute emesis induction by
`moderately to highly emetogenic chemotherapy, based on
`an assessment of the best available literature. Rigorously
`designed double-blind randomized trials (phase III) of suf-
`ficient sample size were considered to offer the most valid
`evidence, whereas uncontrolled clinical trials, observation,
`and retrospective analysis each provided weaker evidence
`in support of a proposed recommendation. This approach
`is consistent with recent recommendations regarding evi-
`dence-based medicine [ 17). Selected studies forming the
`basis for recommendations for each agent are summarized
`in selected references. The "No Emesis" rate during the
`initial 24-h observation period (acute emesis) was selected
`as an appropriate therapeutic end-point universally report-
`ed in the trials under consideration.
`In this presentation we have formulated a hypothesis
`regarding each of the three issues to be addressed (dose,
`schedule, and route), summarized data in support of and
`contradictory to the stated hypothesis, reached conclusions
`based on the balance of evidence, and made recommenda-
`tions for use of these agents in clinical practice.
`
`Dose
`
`Hypothesis
`
`Despite preclinical differences, the 5HT3 antagonists are
`characterized clinically by: ( 1) a threshold effect for re-
`sponse, (2) a modest dose-response curve, and (3) a pla-
`teau in therapeutic efficacy extending over a several-fold
`range in dose.
`If valid, the therapeutic implications are considerable;
`they can be summarized as follows: (I) more is not neces-
`sarily better, and (2) breakthrough emesis may be due to
`other mediators and/or receptors and not due to inadequate
`5HT3 receptor blockade [28, 62).
`If this hypothesis regard ing dose is valid, how then do
`we justify the existing uncertainties regarding optimal
`dose of the available 5HT3 antagonists? For two agents in
`particular (ondansetron and granisetron) there is wide vari-
`ability in the "approved" single dose level for prevention
`of acute emesis from highly emetogenic chemotherapy. If
`approved s.ingle dose levels are contrasted between the
`United States and Europe, there is an apparent paradox: in
`the United States the approved dose of ondansetron
`(32 mg or approximately .45 mg/kg) is four-fold that in
`Europe (8 mg ), while for granisetron, exactly the opposite
`is true (I 0 meg/kg vs 3 mg or 40 meg/kg). Is it possible
`that the lower dose level for each agent is already on the
`therapeutic plateau, or do these lower doses fall some-
`where along the dose response curve?
`
`In view of the above considerations, analysis of best
`available literature regarding dose was performed for each
`of the four 5HT3 antagonists which have completed clini-
`cal testing. Both dose-response studies of individual
`agents and comparative trials between agents were consid-
`ered. Study designs incorporating overlapping issues of
`schedule are addressed in the next section on this topic.
`
`Highly emetogenic chemotherapy
`
`Cisplatin-based chemotherapy at doses over 50 mg/m2
`serves as a model for highly emetogenic chemotherapy.
`Randomized studies have generally demonstrated superi-
`ority of 5HT3 antagonists over high-dose intravenous met-
`oclopramide, the previous standard, for prevention of
`acute CIE from cisplatin [I 0, 13, 26, 44, 60]. Furthermore,
`the addition of dexamethasone has consistently improved
`efficacy compared to a 5HT3 antagonist alone, establishing
`this combination as a standard for patients receiving
`cispla6n-based therapy [30, 54). Dose ranging studies of
`these agents generally demonstrate evidence of a dose re-
`sponse curve consistent with the hypothesis stated above
`[23, 24, 38, 40, 46, 54, 61, 63, 64]. There are conflicting
`data regarding the optimal single dose of ondansetron for
`prevention of acute CIE from cisplatin. While a study pub-
`lished by Beck et al. led to the conclusion that a 32-mg
`dose was superior to 8 mg, particularly in patients receiv-
`ing high dose cisplatin (> 100 mg/m2), a similarly de-
`signed study by Seynaeve showed that the 8 mg dose was
`equally effective [3, 58]. In both studies, single dose ad-
`ministration was equivalent to other approved dose sched-
`ules (see below). Furtlher evidence in support of a single
`8 mg ondansetron dose comes from the studies of the Ital-
`ian Group for Antiemetic Research (IGAR) and from Ruff,
`an 8 mg dose showing equal efficacy to either a 32 mg
`dose level, or 3 mg of granisetron, respectively [33, 57].
`For granisetron, the balance of evidence from both
`dose-response studies of this agent and comparative trials
`against ondansetron supports a recommended dosing level
`of I 0 meg/kg [ 46, 4 7, 54, 60). The dose-ranging studies of
`Navari and Riviere suggest that dose levels of 2 or
`5 meg/kg are suboptimal, while there is a relative plat,eau
`above I 0 meg/kg, with slightly higher, but probably cl ini-
`cally insignificant, no emesis rates at 40 meg/kg [46, 54].
`The comparative trial by Navari adds further support in
`favour of the I 0-mcg/kg dose, with identical no emesis
`rates for 10 vs 40 meg/kg in comparison to an approved
`and effective multiple dose schedule of ondansetron
`(0.15 mg/kg x 3) [47].
`The dose ranging study of Van Belle and the compara-
`tive trial by Marty both support a 5 mg single dose admin-
`istration of tropisetron as effective in highly emetogenic
`cisplabn-based chemotherapy, with the study of Van Belle
`suggesting no further improvement in efficacy at dose lev-
`els up to 40 mg [45, 64].
`
`Exh. 1027
`
`

`
`Table I Recommendations:
`5HT3 antagonists in cisplatin
`chemotherapy-induced emesis
`
`Agent
`
`Ondansetron
`Granisetron
`
`Tropisetron
`Dolasetron
`
`Daily dose
`
`Schedule
`
`Route
`
`Consensus
`
`Confidence
`
`8mg
`10 meg/kg
`2mg
`5 mg
`1.8 mg/kg
`
`Single dose
`Single dose
`Single dose
`Single dose
`Single dose
`
`i.v.
`i.v.
`p.o.
`i.v.
`i.v.
`
`High
`High
`High
`High
`High
`
`High
`High
`Moderate
`Moderate
`High
`
`239
`
`Table 2 Recommendations: oral 5HT3 antagonists in moderately
`emetogenic chemotherapy
`
`Agent
`
`Daily dose
`
`Schedule
`
`Consensus Confidence
`
`Initial dose-ranging studies of dolasetron did not clear-
`ly define the lowest effective dose, while the subsequent
`comparative trial of Hesketh supports a dose level of
`1.8 mg/kg as effective, with no evidence of clinically sig-
`nificant improvement in efficacy at 2.4 mg/kg [32, 40, 63].
`Since the emetogenic potential of cisplatin is dose re-
`lated, the emesis from regimens in which cisplatin is given
`at low daily doses differs in severity and pattern from that
`induced by high-dose cisplatin. Several comparative stud-
`ies have evaluated the antiemetic efficacy of the 5HT3 re-
`ceptor antagonists in this setting, and have demonstrated
`equal or superior activity to high-dose metoclopramide or
`alizapride [7, 21 , 59]. These trials have also shown that an-
`tiemetic efficacy of 5HT3 antagonists is improved by the
`addition of a corticosteroid, similar to results with high-
`dose cisplatin [19, 48, 53].
`
`Moderately emetogenic chemotherapy
`
`Intravenous cyclophosphamide, doxorubicin, epirubicin,
`and carboplatin, alone or in combination, have been used
`as the emetogenic challenge in studies evaluating the effi-
`cacy of 5HT3 antagonists in moderately emetogenic che-
`motherapy. Corticosteroids, with or without other agents,
`have been the principal antiemetics used in patients receiv-
`ing this type of therapy. Comparative studies of 5-HT3 re-
`ceptor antagonists have shown them to be superior in anti-
`emetic activity to metoclopramide [I , 6, 9, 18, 36, 42, 6 1]
`alizapride [11, 14], and phenothiazines [43, 49, 65]. When
`compared with dexamethasone alone, the 5-HT3 receptor
`antagonists show equivalent, but not superior, antiemetic
`efficacy [34, 35]. Furthermore, a trial by the IGAR demon-
`strated that the combination of granisetron plus dexam-
`ethasone was superior
`to dexamethasone alone or
`granisetron alone (complete protection from acute vomit-
`ing in 93%, 71% and 72%, respectively) [34]. Thus, the
`combination of a corticosteroid and a 5HT3 antagonist ap-
`pears to provide optimal antiemetic therapy in patients re-
`ceiving this type of chemotherapy. Oral 5HT3 antagonists
`are appropdate in this setting, and there is a large body of
`literature to support this route of administration, as dis-
`cussed later.
`Appropriate dose selection of oral 5HT 3 antagonists for
`moderately emetogenic chemotherapy has been problemat-
`ic, in part due to interactive issues of schedule. Early trials
`of oral ondansetron utilized a multiple-dose schedule, and
`these regimens have since become standard practice. Infor-
`mative trials regarding oral ondansetron dosing in this
`
`Ondansetron 12- 16 mg
`Granisetron 2 mg
`
`Tropisetron -·
`
`Dolasetron
`
`100-200 mg Each day
`
`t.i.d. or b.i.d. High
`High
`Each day
`(or b.i.d.)
`
`-·
`
`High
`
`High
`High
`
`-·
`
`Moderate
`
`-·
`
`" insufficient data available
`
`clinical setting include those of Beck and Cubbedu, dem-
`onstrating a plateau in efficacy at a total daily dose of
`12 mg (4 mg TID), and a large trial by Dicato et a!., in
`which 8 mg of ondansetron twice daily was equivalent to
`8 mg three times daily [ 4, 12, 15]. Thus, a daily dose of
`12-16 mg represents a fully effective dose level of oral
`ondansetron in moderately emetogenic chemotherapy.
`An oral dose-ranging trial of granisetron reported by
`Bleiberg et al. [ 17] compared 0.25 mg b.i.d., 0.5 mg b.i.d.,
`1.0 mg b.i.d., and 2 mg b.i.d .. All dose levels were superior
`to 0.25 mg, and there was no increase in efficacy above the
`J.O mg b.i.d. level. Similar results for 7-day efficacy were
`obtained by Hacking et al [24]. As discussed below in the
`section on Schedule, a subsequent trial demonstrated
`equivalence of 1.0 mg b.i.d. and 2.0 mg as a single dose.
`Therefore, the most appropriate total daily oral dose of
`granisetron appears to be 2 mg. Studies by Rubenstein and
`Fauser have defined effective oral dose levels of dolasetron
`as 100-200 mg administered as a single dose [18, 56].
`There is insufficient information at present to allow us to
`make recommendations on the oral dosing of tropisetron.
`In general, these dosing recommendations for oral ad-
`ministration of 5HT3 antagonists result in dosing ratios of
`1.5- 2: I relative to the recommended single dose levels
`when they are given i. v. (Tables 1, 2). These dosing rec-
`ommendations appear reasonable in view of the reported
`oral bioavailability of approximately 60% for 5HT3 antag-
`onists as a drug class [22, 50].
`
`Conclusions
`
`Etfective dose levels have been established tor each of the
`four 5HT3 antagonists in both moderately and hig hly
`emetogenic chemotherapy. The lowest fully effective dose
`of each agent should be used in clinical practice.
`
`Exh. 1027
`
`

`
`240
`
`Schedule
`
`Hypothesis
`
`If given at an effective dose level, a single dose provides
`adequate 5HT3 blockade for prevention of acute emesis. If
`valid, the implications regarding schedule of administra-
`tion (for acute CIE) are as follows: (I) administration of
`multiple doses is unnecessary, and (2) breakthrough eme-
`sis during the acute phase may be related to other media-
`tors/receptors. If a model for schedule is developed based
`on this hypothesis, then multiple doses will only provide a
`better therapeutic outcome if the initial dose were subopti-
`mal, or if optimal therapeutic efficacy were dependent on
`the either plasma half-life or duration of receptor blockade
`during the acute phase.
`
`Highly emetogenic chemotherapy
`
`As discussed below, there is substantial evidence in sup-
`port of the proposed hypothesis regarding schedule.
`Schedule-effects are best assessed
`in
`studies of
`ondansetron, the first 5HT3 antagonist developed. Early
`clinical trials ofi.v. ondansetron in cisplatin chemotherapy
`explored a variety of schedule-related issues, including
`variable dosing intervals, number of doses, and schedules
`incorporating continuous infusion [30, 39]. In general,
`these studies demonstrated that shortening the dosing in-
`terval or increasing the number of doses did not improve
`efficacy. A continuous infusion schedule following an
`8 mg i.v. bolus was also found to be effective [44]. How-
`ever, as demonstrated in the subsequent studies of Beck
`and Seynaeve, multiple dose administration or continuous
`infusion schedules of onda:nsetron proved no more effec-
`tive than single dose adminiistration [3, 58]. Based on these
`observations, development of the three other 5HT3 antago-
`nists quickly evolved into determining optimal levels for
`i. v. single-dose administration.
`
`Moderately emetogenic chemotherapy
`
`Oral administration of 5I-IT3 antagonists by multiple-dose
`schedules has been extensively studied and is highly effec-
`tive in the prevention of acute emesis from moderately
`emetogenic chemotherapy regimens. However, it remains
`unclear that multiple doses are superior to a fully effective
`single dose, since few studies have addressed this issue in
`moderately emetogenic chemotherapy. In a randomized
`double-blind trial, however, oral granisetron at a single
`dose of 2 mg was equally effective a standard divided-dose
`schedule (I mg twice daily), with no emesis rates of 82%
`and 77%, respectively [16]. In a similar fashion, a trial by
`Kaizer et al. showed no difference
`in efficacy of
`ondansetron 16 mg i. v. as a single dose, versus 8 mg i. v.
`
`plus 8 mg p.o. 12 h later [37]. These findings are compati-
`ble with the hypothes.is that a fully effective dose of a
`5HT 3 antagonist need be administered only once in the
`prevention of acute CTE, regardless of the emetogenic
`challenge.
`
`Conclusions
`
`Single dose intravenous administration is equally effica-
`cious to multiple dose or continuous infusion schedules
`and is the preferred schedule of adminlstration for preven-
`tion of acute emesis from highly emetogenic chemothera-
`py. For moderately emetogenic chemotherapy, few studies
`have compared single versus multiple oral doses. Howev-
`er, when direct comparisons have been performed, oral
`single-dose administration at the appropriate dose level
`has been equivalent to multiple doses, and is an acceptable
`a I ternative.
`
`Route
`
`Hypothesis
`
`Oral administration of the 5HT3 antagonists is equally effi-
`cacious as intravenous (i.v.) administration.
`Obviously, the most important implication of this hy-
`pothesis, if valid, is that since oral administration is gener-
`ally less expensive and less resource intensive, this route
`may be preferable. There are three qualifiers to be consid-
`ered in regard to this hypothesis: (1) there should be good
`oral drug bioavailability, (2) there must be an intact gas-
`trointestinal track to ensure absorption, and (3) compliance
`must be assured.
`
`Moderately to highly emetogenic chemotherapy
`
`As a class, 51-IT 3 antagonists exhibit good drug bio-
`availability when administered by the oral route. While
`oral use is of proven efficacy for moderately emetogenic
`chemotherapy, to date there has been very little informa-
`tion regarding oral dos.ing for CIE from cisplatin. Howev-
`er, there is now emerging support for the administration of
`selective 5HT3 antagonists by the oral route even in the
`prevention of cisplatin-induced emesis. In a study by Her-
`on [27], a standard combination of high-dose i. v. metoclo-
`pramide plus dexamethasone was compared with oral
`granisetron 1 mg alone (b.i.d.) or ora l granisetron plus
`dexamethasone in cisplatin-treated patients. The no emesis
`rates were: oral granisetron (56%), metoclopramide/d ex-
`amethasone (52%), and granisetron/dexamethasone (66%).
`In a recently completed phase III trial, oral granisetron
`(2 mg) was compared with i.v. ondansetron (32 mg) in pa-
`tients receiving cisplatin-based (> 60 mg/m2) chemothera-
`py [20]. Concomitant dexamethasone (I 0-20 mg) was ad-
`ministered in 80% of patients. Rates of total control (no
`
`Exh. 1027
`
`

`
`241
`
`nausea, no emesis, and no rescue) were similar in the two
`treatment arms, 55% with oral granisetron and 58% with
`i.v. ondansetron, while the no emesis rate was marginally
`higher with ondansetron (67%) than with granisetron
`(61 %). Although a single study, this was a large (n = I 054)
`and well-designed trial (double-blind, stratified by gen-
`der), and the results support the use of oral 5HT3 antago-
`nists, even in cisplatin-treated patients. Adding further
`support is a similarly designed comparative trial by Perez
`eta!. of oral granisetron versus i.v. ondansetron with mod-
`erately emetogenic chemotherapy, which also demonstrat-
`ed equal efficacy for these 2 routes of administration [52].
`
`Conclusions
`
`Assuming an intact gastrointestinal tract to ensure absorp-
`tion, and good compliance, the oral route is an acceptable
`alternative to intravenous administration. For moderately
`emetogenic chemotherapy, oral administration of 5HT3 an-
`tagonists is well established, usually in combination with a
`corticosteroid.ln cisplatin-induced CIE, preliminary sup-
`port exists for granisetron at a 2-mg oral dose in combina-
`tion with dexamethasone.
`
`Overall summary and recommendations
`
`Based on analysis of best available literature regarding
`dose, schedule, and route of 5HT3 antagonists for preven-
`tion of acute emesis from moderately to highly emetogenic
`chemotherapy, summary conclusions are as follows:
`I. Dose: It is recommended that a fully effective dose lev-
`el of each agent be administered. Cost-effectiveness
`dictates that this be the minimum fully effective dose.
`However, underdosing these agents which are character
`ized by an excellent side effect profile and high thera-
`peutic index should be avoided.
`
`Level of consensus: high
`Level of confidence: high
`2. Schedule: If given at an effective dose level, it is unnec-
`essary to administer multiple intravenous doses or deliv
`er these agents as a continuous infusion.
`Level of consensus: high
`Level of confidence: high
`3.Route:Administration of 5HT3 antagonists by the oral
`route is well established for moderately emetogenic che-
`motherapy. Preliminary data suggest that the oral route
`is also equivalent to intravenous administration, even in
`patients receiving high dose cisplatin.
`Levelofconsensus: high
`Level of confidence: high
`4.0verall: The combination of a 5HT 3 antagonist plus a
`corticosteroid represent the standard of care for patients
`receiving moderate to highly emetogenic chemotherapy.
`Levelofconsensus: high
`Level of confidence: high
`
`Consensus recommendations for each specific agent in the
`prevention of acute emesis from highly and moderately
`emetogenic chemotherapy are presented in Tables I and 2,
`respectively. These recommendations represent an analysis
`of best available literature, using an evidence-based medi-
`cine approach, as well as reflecting the input of discus-
`sants and participants during this consensus conference.
`In conclusion, the 5HT3 antagonists have substantially
`improved the management of CIE, and these agents in
`combination with corticosteroids can be considered the
`standard of care in patients receiving moderately to highly
`emetogenic chemotherapy. Nevertheless, many patients
`continue to experience CIE, often related to late break-
`through or delayed emesis. It is likely that the majority of
`these episodes are mediated through non-5HT3-induced
`mechanisms. Further improvements in ttherapy await better
`definition of the underlying pathophysiology of these
`events and development of selective antagonists to the in-
`volved receptors.
`
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