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`IPR2016-00712
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`@>(<,9>()8=–)(E+<(-8*A(::8*=89+(-9*=(@+e+@)+*Be8@9,)*/
`g((˜)+-@+=:(*e,)f8-8E+-Efa:9+¢F8–<(9,E(-+@;>(<,9>()8=–h(E+<(-*£D¢D¤/
`©,*8=)(=+98-9F+<(E:a<+-(£««5<E¤<8–d(*ad*9+9a9(Fe,)8=)(=+98-9£«05<E¤.1
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`'()*+,-./011231041541260112789+,-8:;,<=)(>(-*+?(;8-@()7(9A,)B3C-@/D::)+E>9*)(*()?(F/GHIJIKLMNIOMPIJQPNRHMJMOOLJRSQRMTPUQVPTRWISIXSTNLYINMPQPVZTSU [MRHTLRRHII\XSIJJ[SMRRIPXISUMJJMTPTZ]^^]_
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`^HIUTRHISQXV}PNLYIN
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`IXIQRNQMOVZTSZSQYRMTPQRINNTJIJTZYHIUTRHISQXV
`{I\QUIRHQJTPI²pUKjlTS}´NQMOV
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`jSTYHOTSXISQ‚MPI²qUKjlTS}´InISV¼TSInISVÀH
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`vIRTYOTXSQUMNI²q€¼qUKjlTS}´IMRHISInISV¼TSInISVÀH
`¿{MXHIPHVNSQUMPIp³€³qUKjlTS}´IMRHISInISV¼TSInISVÀH
`¿TSQ‚IXQUzq_³€pUKjlTS}´IMRHISInISV¼TSInISVÀH
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`wIIjSMPYMXOIJTZ›UIJMJ^TPRSTOµi›€²¶
`D-9+(<(9+@)(E+<(-**>,a:Fd(@>,*(-d8*(F,-(<(9,E(-+@=,9(-9+8:,e9>(@>(<,9>()8=–)(E+<(-8*A(::8*=89+(-9*=(@+e+@)+*Be8@9,)*/
`g((˜)+-@+=:(*e,)f8-8E+-Efa:9+¢F8–<(9,E(-+@;>(<,9>()8=–h(E+<(-*£D¢D¤/
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`f,-+9,)e,)F–*9,-+@)(8@9+,-*Ãa*(F+=>(->–F)8<+-(e,)F–*9,-+@)(8@9+,-*/
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`^OMPMYQOGSMQOJ¯]^^]WIOMInIJRHQRRHIWIJRUQPQKIUIPRTZQPVYQPYISXQRMIPRMJMPQYOMPMYQORSMQO_jQSRMYMXQRMTPMPYOMPMYQORSMQOJMJIJXIYMQOOVIPYTLSQKIN_
`
`'()*+,-./011231041541260112789+,-8:;,<=)(>(-*+?(;8-@()7(9A,)B3C-@/D::)+E>9*)(*()?(F/GHIJIKLMNIOMPIJQPNRHMJMOOLJRSQRMTPUQVPTRWISIXSTNLYINMPQPVZTSU [MRHTLRRHII\XSIJJ[SMRRIPXISUMJJMTPTZ]^^]_
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`kSQPMJIRSTP²€pUKjlNQMOVTS²UKjlWMNTSq_q²UK‡yK
`µUQ\MULU ²UK¶}´
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`{TOQJIRSTP²qqUKjlNQMOVTS²_rUK‡yK}´TS²qqUK}´
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`|QOTXISMNTO²€pUKjlInISV¼€ÀHXSP
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`{STPQWMPTO³€²qUKjlIMRHISInISVoTSInISVÀH
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`]QWMOTPI²€pUKjlWMN
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`{I\QUIRHQJTPI²pUKjlTS}´NQMOVzMZPTRXSInMTLJOVKMnIP
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`f,-+9,)e,)F–*9,-+@)(8@9+,-*Ãa*(F+=>(->–F)8<+-(e,)F–*9,-+@)(8@9+,-*/
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`
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`kSQPMJIRSTPpUKjlNQMOV
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` Practice Guidelines
`
`îùúñóüûõñòîü î#õöñøñîùøöîüøòñøòôòî
`Antiemesis
`in Oncology — v.3.2008
`ùúñóüûþî

$Í%ßÑÏíÍÓÔÍåÒìå&áÏæÏáÍÏæÒíÏÔçÏÍßÔíÍÔÒÓÐãÍçÓÔÑÏÔÑÑÖÍÍ
`
`Manuscript
`
`All recommendations are category 2A unless otherwise noted.
`
`disagreement.
`
`Overview
`
`ùúðü ðþòõü÷üóþîü î#ýñòõòî
`Guidelines Index
`ÎÓãÒàÒÔìÍÐÏÑáàÑÍÐÓãÍÑàÒãáßàÒÓÔÍÓÍßÍãáàÒÑàÏäÍÐÏáÏÍäßàåèß+Í
`Antiemesis Table of Contents
`çÓÔàÐÓááÏíÍ+ÍàåÏÍÐßÒÔÖÍÎÓãÒàÒÔìÍÒÑÍàÐÒììÏÐÏíÍ+ÍßÏÐÏÔàÍÒãäáÑÏÑÍàÓÍàåÏÍ
`MS References
`æÓãÒàÒÔìÍçÏÔàÏÐÍ(áÓçßàÏíÍÒÔÍàåÏÍãÏíááß*ÍÐÓãÍàåÏÍçåÏãÓÐÏçÏäàÓÐÍàÐÒììÏÐÍ
`6ÓÔÏÚÍäåßÐ+ÔÍßÔíÍìßÑàÐÓÒÔàÏÑàÒÔßáÍ(ê*ÍàÐßçàÍ(æÒßÍæßìßáÍßÏÐÏÔàÍÒÏÐÑ*ÚÍ
`ùúñóüûþî $Í%ßÑÏíÍÓÔÍáÓèÏÐ&áÏæÏáÍÏæÒíÏÔçÏÍÒÔçáíÒÔìÍçáÒÔÒçßáÍ
`ßÔíÍçÏÐÏÐßáÍçÓÐàÏÖÍÎÓãÒàÒÔìÍÓççÐÑÍèåÏÔÍÏÏÐÏÔàÍÒãäáÑÏÑÍßÐÏÍÑÏÔàÍ
`Pathophysiology of Emesis
`ÏäÏÐÒÏÔçÏÍßÔíÍÔÒÓÐãÍçÓÔÑÏÔÑÑÖÍ
`ÐÓãÍàåÏÍæÓãÒàÒÔìÍçÏÔàÏÐÍàÓÍàåÏÍÑßáÒæßàÒÓÔÍçÏÔàÏÐÚÍßíÓãÒÔßáÍãÑçáÏÑÚÍ
`Vomiting results from stimulation of a multistep reflex pathway
`ùúñóüûþî'$Í%ßÑÏíÍÓÔÍáÓèÏÐ&áÏæÏáÍÏæÒíÏÔçÏÍÒÔçáíÒÔìÍçáÒÔÒçßáÍ
`.×
`ÍÍ
`ÐÏÑäÒÐßàÓÐ+ÍçÏÔàÏÐÚÍßÔíÍçÐßÔÒßáÍÔÏÐæÏÑÖ
`controlled by the brain. Vomiting is triggered by afferent impulses to the
`ÏäÏÐÒÏÔçÏÍßÔíÍÔÓÔÔÒÓÐãÍçÓÔÑÏÔÑÑÍ(àÍÔÓÍãß)ÓÐÍíÒÑßìÐÏÏãÏÔà*ÖÍ
`NCCN Categories of Evidence and Consensus
`vomiting center (located in the medulla) from the chemoreceptor trigger
`åÏÍçåÏãÓÐÏçÏäàÓÐÍàÐÒììÏÐÍ6ÓÔÏÚÍæÓãÒàÒÔìÍçÏÔàÏÐÚÍßÔíÍêÍàÐßçàÍåßæÏÍ
`Category 1: Based on high-level evidence and uniform consensus.
`ùúñóüûþî$Í%ßÑÏíÍÓÔÍßÔ+ÍáÏæÏáÍÓÍÏæÒíÏÔçÏÍàÍÐÏáÏçàÑÍãß)ÓÐÍ
`zone, pharynx and gastrointestinal (GI) tract (via vagal afferent fibers),
`ãßÔ+ÍÔÏÐÓàÐßÔÑãÒààÏÐÍÐÏçÏäàÓÐÑÖÍëçàÒæßàÒÓÔÍÓÍàåÏÑÏÍÐÏçÏäàÓÐÑÍ+Í
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`Category 2A: Based on lower-level evidence including clinical
`and cerebral cortex. Vomiting occurs when efferent impulses are sent
`çåÏãÓàåÏÐßäÏàÒçÍßìÏÔàÑÍÓÐÍàåÏÒÐÍãÏàßÓáÒàÏÑÍãß+ÍÏÍÐÏÑäÓÔÑÒáÏÍÓÐÍ
`experience and uniform consensus.
`
` ÷÷îûñüýýñøöùúõüøòîùûñîùúñóüûþî îôø÷ñòòîüúðñûõòñîøüúñöî
`from the vomiting center to the salivation center, abdominal muscles,
`çåÏãÓàåÏÐßä+&ÒÔíçÏíÍÏãÏÑÒÑÖÍåÏÍäÐÒÔçÒäßáÍÔÏÐÓÐÏçÏäàÓÐÑÍÒÔæÓáæÏíÍ
`Category 2B: Based on lower-level evidence including clinical
`respiratory center, and cranial nerves.”
`ÒÔÍàåÏÍÏãÏàÒçÍÐÏÑäÓÔÑÏÍßÐÏÍàåÏÍÑÏÐÓàÓÔÒÔÍ(Ü&å+íÐÓ+àÐ+äàßãÒÔÏÍ7Ü&8Õ9*Í
`experience and nonuniform consensus (but no major disagreement).
`.ÕÚ./
`ñûõñî
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`The chemoreceptor trigger zone, vomiting center, and GI tract have
`Category 3: Based on any level of evidence but reflects major
`ÒÔçáíÏÍßçÏà+áçåÓáÒÔÏÚÍçÓÐàÒçÓÑàÏÐÓÒíÚÍåÒÑàßãÒÔÏÚÍçßÔÔßÒÔÓÒíÚÍÓäÒßàÏÚÍ
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`many neurotransmitter receptors. Activation of these receptors by
`ßÔíÍÔÏÐÓéÒÔÒÔ&.Í(Þ;&.*ÍÐÏçÏäàÓÐÑÚÍèåÒçåÍßÐÏÍáÓçßàÏíÍÒÔÍàåÏÍæÓãÒàÒÔìÍ
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`chemotherapeutic agents or their metabolites may be responsible for
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`çåÏãÓàåÏÐßä+ÍàÐÏßàãÏÔàÖÍêÔÍßííÒàÒÓÔÚÍÔßÑÏßÍßÔíÍæÓãÒàÒÔìÍçßÔÍÐÏÑáàÍÒÔÍ
`chemotherapy-induced emesis. The principal neuroreceptors involved
`ãÏàßÓáÒçÍÒãßáßÔçÏÑÚÍíÏìÏÔÏÐßàÒÓÔÍÓÍÑÏá&çßÐÏÍßÔíÍÔçàÒÓÔßáÍßÒáÒà+ÚÍ
`in the emetic response are the serotonin (5-hydroxytryptamine [5-HT3])
`ëÔàÒÏãÏàÒçÍßìÏÔàÑÍçßÔÍáÓçéÍíÒÏÐÏÔàÍÔÏÐÓÔßáÍäßàåèß+ÑÚÍÏÏÐàÍàåÏÒÐÍ
`ÔàÐÒÏÔàÍíÏäáÏàÒÓÔÚÍßÔÓÐÏÒßÚÍíÏçáÒÔÏÍÓÍàåÏÍäßàÒÏÔà,ÑÍäÏÐÓÐãßÔçÏÍÑàßàÑÍ
`and dopamine receptors.‘‘’'‘4 Other neuroreceptors involved in emesis
`ÏÏçàÑÍßàÍíÒÏÐÏÔàÍäÓÒÔàÑÍíÐÒÔìÍàåÏÍçÓÐÑÏÍÓÍÏãÏÑÒÑÚÍÓÐÍÏåßæÏÍ
`ßÔíÍãÏÔàßáÍÑàßàÑÚÍèÓÔíÍíÏåÒÑçÏÔçÏÚÍÏÑÓäåßìÏßáÍàÏßÐÑÚÍßÔíÍ
`include acetylcholine, corticosteroid, histamine, cannabinoid, opiate,
`Chemotherapy-induced nausea and vomiting (emesis) can significantly
`.&/
`Ñ+ÔÏÐìÒÑàÒçßáá+ÍèÒàåÍÓàåÏÐÍßÔàÒÏãÏàÒçÍßìÏÔàÑÍàÓÍäÓàÏÔàÒßàÏÍßÔÍßÔàÒÏãÏàÒçÍ
`ÍÍ
`èÒàåíÐßèßáÍÐÓãÍäÓàÏÔàÒßáá+ÍÑÏáÍÓÐÍçÐßàÒæÏÍßÔàÒçßÔçÏÐÍàÐÏßàãÏÔàÖ
`and neurokinin-1 (NK-1) receptors, which are located in the vomiting
`affect a patient’s quality of life, leading to poor compliance with further
`ÏÏçàÖÍ<åÏÔÍÑÏíÍßàÍßÍçÏÐàßÒÔÍçÓÔçÏÔàÐßàÒÓÔÚÍÏßçåÍßÔàÒÏãÏàÒçÍßìÏÔàÍ
`and vestibular centers of the brain.‘5
`chemotherapy treatment. In addition, nausea and vomiting can result in
`äÐÏíÓãÒÔßÔàá+ÍáÓçéÑÍÓÔÏÍÐÏçÏäàÓÐÍà+äÏÖÍëÍÒÔßáÍçÓããÓÔÍäßàåèß+ÍÓÐÍ
`åÏÍÒÔçÒíÏÔçÏÍßÔíÍÑÏæÏÐÒà+ÍÓÍÔßÑÏßÍßÔíÛÓÐÍæÓãÒàÒÔìÍÒÔÍäßàÒÏÔàÑÍ
`metabolic imbalances, degeneration of self-care and functional ability,
`ÏãÏÑÒÑÍåßÑÍ+ÏàÍàÓÍÏÍÒíÏÔàÒÒÏíÖÍåÏÐÏÓÐÏÚÍÔÓÍÑÒÔìáÏÍßìÏÔàÍçßÔÍÏÍ
`ÐÏçÏÒæÒÔìÍçåÏãÓàåÏÐßä+ÍßÐÏÍßÏçàÏíÍ+ÍÔãÏÐÓÑÍßçàÓÐÑÚÍÒÔçáíÒÔì0Í
`Antiemetic agents can block different neuronal pathways, exert their
`nutrient depletion, anorexia, decline of the patient’s performance status
`ÏäÏçàÏíÍàÓÍäÐÓæÒíÏÍçÓãäáÏàÏÍäÐÓàÏçàÒÓÔÍÐÓãÍàåÏÍæßÐÒÓÑÍÏãÏàÒçÍ
`(.*ÍàåÏÍÑäÏçÒÒçÍçåÏãÓàåÏÐßäÏàÒçÍßìÏÔàÑÍÑÏí1Í(×*ÍíÓÑßìÏÍÓÍàåÏÍ
`effects at different points during the course of emesis, or behave
`and mental status, wound dehiscence, esophageal tears, and
`äåßÑÏÑÍÓÍçåÏãÓàåÏÐßä+ÖÍ
`ßìÏÔàÑ1Í(Õ*ÍÑçåÏíáÏÍßÔíÍÐÓàÏÍÓÍßíãÒÔÒÑàÐßàÒÓÔÍÓÍàåÏÍßìÏÔàÑ1ÍßÔíÍ(/*Í
`synergistically with other antiemetic agents to potentiate an antiemetic
`withdrawal from potentially useful or curative anticancer treatment.”
`ÒÔíÒæÒíßáÍäßàÒÏÔàÍæßÐÒßÒáÒà+Í(ÏìÚÍßìÏÚÍÑÏÚÍäÐÒÓÐÍçåÏãÓàåÏÐßä+ÚÍåÒÑàÓÐ+ÍÓÍ
`effect. When used at a certain concentration,