2015+ASCO指南：止吐药(更新版)
Antiemetics:American Society of Clinical Oncology Focused Guideline Update
Paul J.Hesketh,Kari Bohlke,Gary H.Lyman,Ethan Basch,Maurice Chesney,Rebecca Anne Clark-Snow,Michael A.Danso,Karin Jordan,Mark R.Somer?eld,and Mark G.Kris
Paul J.Hesketh,Lahey Hospital and Medical Center,Burlington,MA;Kari Bohlke and Mark R.Somer?eld,Ameri-can Society of Clinical Oncology,Alex-andria;Michael A.Danso,Virginia Oncology Associates,Norfolk and Virginia Beach,VA;Gary H.Lyman,Fred Hutchinson Cancer Research Center and University of Washington,Seattle,WA;Ethan Basch,University of North Carolina at Chapel Hill,Chapel Hill,NC;Maurice Chesney,patient representative,Saunderstown,RI;Rebecca Anne Clark-Snow,University of Kansas Cancer Center,Westwood,KS;Karin Jordan,University Hospital,Martin-Luther-University Halle-Wittenberg,Halle,Germany;and Mark G.Kris,Memorial Sloan Kettering Cancer Center,New York,NY.Published online ahead of print at https://www.wendangku.net/doc/f916514787.html, on November 2,2015.ASCO Clinical Practice Guidelines Committee approval:May 12,2015.Editor’s note:This ASCO clinical prac-tice guideline provides recommenda-tions,with comprehensive review and analyses of the relevant literature for each recommendation.Additional infor-mation,including a Methodology Supplement,slide sets,clinical tools and resources,and links to patient information at https://www.wendangku.net/doc/f916514787.html, ,is available at https://www.wendangku.net/doc/f916514787.html,/guidelines/antiemetics and https://www.wendangku.net/doc/f916514787.html,/guidelineswiki .
P.J.H.and M.G.K.were update committee co-chairs.
Authors’disclosures of potential con?icts of interest are found in the article online at https://www.wendangku.net/doc/f916514787.html, .Author contributions are found at the end of this article.
Corresponding author:American Soci-ety of Clinical Oncology,2318Mill Rd,Suite 800,Alexandria,VA 22314;e-mail:guidelines@https://www.wendangku.net/doc/f916514787.html,.
?2015by American Society of Clinical Oncology
0732-183X/15/3399-1/$20.00DOI:10.1200/JCO.2015.64.3635
A B S T R A C T
Purpose
To update a key recommendation of the American Society of Clinical Oncology antiemetic guideline.This update addresses the use of the oral combination of netupitant (a neurokinin 1[NK 1]receptor antagonist)and palonosetron (a 5-hydroxytryptamine-3[5-HT 3]receptor antagonist)for the prevention of acute and delayed nausea and vomiting in patients receiving chemotherapy.Methods
An update committee conducted a targeted systematic literature review and identi?ed two phase III clinical trials and a randomized phase II dose-ranging study.
Results
In one phase III trial,the oral combination of netupitant and palonosetron was associated with higher complete response rates (no emesis and no rescue medications)compared with palono-setron alone in patients treated with anthracycline plus cyclophosphamide chemotherapy (74%v 67%overall;P ?.001).In another phase III trial,the oral combination of netupitant and palonosetron was safe and effective across multiple cycles of moderately or highly emetogenic chemotherapies.In the phase II dose-ranging study,each dose of netupitant (coadministered with palonosetron 0.50mg)produced higher complete response rates than palonosetron alone among patients receiving cisplatin-based chemotherapy.The highest dose of netupitant (ie,300mg)was most effective.
Recommendations
All patients who receive highly emetogenic chemotherapy regimens (including anthracycline plus cyclophosphamide)should be offered a three-drug combination of an NK 1receptor antagonist,a 5-HT 3receptor antagonist,and dexamethasone.The oral combination of netupitant and palonosetron plus dexamethasone is an additional treatment option in this setting.The remaining recommendations from the 2011ASCO guideline are unchanged pending a full update.Additional information is available at https://www.wendangku.net/doc/f916514787.html,/guidelines/antiemetics and https://www.wendangku.net/doc/f916514787.html,/guidelineswiki.
J Clin Oncol 33.?2015by American Society of Clinical Oncology
INTRODUCTION
The goal of this update is to provide oncologists,other health care practitioners,patients,and care-givers with recommendations regarding the use of netupitant and palonosetron (NEPA).NEPA was approved by the US Food and Drug Administration (FDA)in October 2014for use in the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of chemotherapy.NEPA is administered orally and consists of a ?xed dose of 300mg of the neurokinin-1(NK 1)receptor antagonist netupitant combined with 0.50mg of the 5-hydroxytryptamine type 3(5-HT 3)receptor an-tagonist palonosetron.
The ?rst American Society of Clinical Oncol-ogy (ASCO)guideline for the use of antiemetics was published in 1999,1with updates in 20062and 2011.3Pending a full update of the 2011guideline,this update provides expedited guidance regarding a new agent to prevent chemotherapy-induced nau-sea and vomiting.Recommendations regarding other agents will be addressed in a subsequent,com-prehensive guideline update.
GUIDELINE UPDATE QUESTION
Should NEPA be incorporated into existing recom-mendations for the prevention of chemotherapy-induced nausea and vomiting?
J OURNAL OF C LINICAL O NCOLOGY
A S C O S P E C I A L A R T I C L E
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1
https://www.wendangku.net/doc/f916514787.html,/cgi/doi/10.1200/JCO.2015.64.3635The latest version is at Published Ahead of Print on November 2, 2015 as 10.1200/JCO.2015.64.3635
METHODS
Guideline Update Process
ASCO uses a signals4approach to facilitate guideline updating.This approach is intended to identify new,potentially practice-changing data(ie, signals)that might translate into revised practice recommendations.The ap-proach relies on routine literature searching and the expertise of ASCO guide-line panel members to identify signals.The Methodology Supplement (available at https://www.wendangku.net/doc/f916514787.html,/guidelines/antiemetics)provides additional infor-mation about the signals approach.
For this update,the publication of phase III clinical trials followed by FDA approval of a new antiemetic provided the signal.The decision to address the new drug as part of an update was made by the update committee co-chairs(P.J.H., M.G.K.)and two steering committee members(G.H.L.,E.B.).The full ASCO Update Committee(Appendix Table A1,online only)was then convened to review the evidence.
Evidence was collected through a systematic review of the medical liter-ature.Publications were included if they were phase II or III randomized clinical trials of NEPA among patients with a malignant neoplasm.These publications were identi?ed by searching PubMed,with no date restrictions,
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for the term“netupitant.”Of the32publications identi?ed,three met the eligibility criteria and form the evidence base for this update.
The update committee contributed to the development of the guideline, provided critical review,and?nalized the guideline recommendation.All ASCO guidelines are reviewed and approved by the ASCO Clinical Practice Guidelines Committee.
Guideline Disclaimer
The clinical practice guideline update and other guidance published herein are provided by ASCO to assist providers in clinical decision making. The information herein should not be relied on as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care.With the rapid development of scienti?c knowledge,new evidence may emerge between the time information is developed and when it is published or read.The information is not contin-ually updated and may not re?ect the most recent evidence.The information addresses only the topics speci?cally identi?ed herein and is not applicable to other interventions,diseases,or stages of diseases.This information does not mandate any particular course of medical care.Furthermore,the information is not intended to substitute for the independent professional judgment of the treating provider,because the information does not account for individual variation among patients.Recommendations re?ect high,moderate,or low con?dence that the recommendation re?ects the net effect of a given course of action.The use of words like“must,”“must not,”“should,”and“should not”indicates that a course of action is recommended or not recommended for either most or many patients,but there is latitude for the treating physician to select other courses of action in individual cases.In all cases,the selected course of action should be considered by the treating provider in the context of treating the individual https://www.wendangku.net/doc/f916514787.html,e of the information is voluntary.ASCO provides this information on an as-is basis and makes no warranty,express or implied,regarding the information.ASCO speci?cally disclaims any warranties of merchantability or?tness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.
This is the most recent information as of the publication date.For the most recent information or to submit new evidence,please visit https://www.wendangku.net/doc/f916514787.html,/guidelines/antiemetics and the ASCO Guidelines Wiki (https://www.wendangku.net/doc/f916514787.html,/guidelineswiki).
Guideline and Con?icts of Interest
The update committee was assembled in accordance with the ASCO Con?icts of Interest Management Procedures for Clinical Practice Guidelines (summarized at https://www.wendangku.net/doc/f916514787.html,/rwc).Members of the commitee completed the ASCO disclosure form,which requires disclosure of?nancial and other interests that are relevant to the subject matter of the guideline,including
Antiemetics:Focused Update of ASCO Guideline
https://www.wendangku.net/doc/f916514787.html,?2015by American Society of Clinical Oncology3
relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline.Categories for disclosure include employment;leadership;stock or other ownership;honoraria,consulting or advisory role;speaker’s bureau; research funding;patents,royalties,other intellectual property;expert testi-mony;travel,accommodations,or expenses;and other relationships.In accor-dance with these procedures,the majority of the members of the commitee did not disclose any such relationships.
RESULTS
Two phase III randomized trials and one phase II randomized trial form the evidence base for this update5-7(Tables1and2).A phase III trial compared NEPA with palonosetron among1,449patients receiv-ing anthracycline plus cyclophosphamide chemotherapy for solid tu-mors.5Patients in both arms received dexamethasone on day1only. Use of palonosetron and dexamethasone(rather than three-drug reg-imen)by the control group was speci?ed by regulatory agencies. Compared with palonosetron,NEPA resulted in higher rates of com-plete response(no emesis or rescue medication)during both the acute and delayed phases.The secondary end points of no emesis,no signif-icant nausea,and complete protection(complete response and no signi?cant nausea)were also better in the NEPA arm.The safety pro?le of NEPA was generally similar to that of palonosetron.Ninety-four of725patients in the NEPA arm reported a severe adverse event, but only?ve(0.7%)had a severe treatment-related adverse event.The most common treatment-related adverse events were headache (NEPA arm,3.3%;palonosetron arm,3.0%)and constipation(both arms,2.1%).
The safety and ef?cacy of NEPA over repeated cycles of chemo-therapy were evaluated in a second phase III trial.6The study enrolled chemotherapy-naive patients treated with highly or moderately eme-togenic chemotherapy.Patients with breast cancer treated with an-thracycline plus cyclophosphamide chemotherapy were not eligible. Study participants were randomly assigned to treatment with NEPA or oral aprepitant plus oral palonosetron.Participants in both study arms received dexamethasone on a schedule based on chemotherapy emetogenicity.Only descriptive statistics were provided,with no for-mal testing of between-group differences.Ninety-eight percent of patients completed cycle one,75%completed at least four cycles,and 40%completed six cycles.The rate of complete response with NEPA remained high across cycles.Treatment-emergent adverse events oc-curred in86%of patients in the NEPA arm and91.3%of patients in the aprepitant plus palonosetron arm;a majority of these events were mild or moderate.Adverse effects that were considered to be related to the study drug occurred in10.1%of patients in the NEPA arm and 5.8%of patients in the aprepitant plus palonosetron arm.The most common treatment-related adverse events in the NEPA arm were constipation(3.6%)and headache(1.0%).Only one adverse event was classi?ed as severe and possibly related to antiemetic treatment:A patient in the NEPA arm experienced acute psychosis in cycle one and discontinued treatment.This event was also thought to be possibly related to dexamethasone.Adverse events did not increase across study cycles.
The randomized phase II dose-ranging trial enrolled694 chemotherapy-naive patients with solid tumors who were scheduled to receive cisplatin-based chemotherapy.7Patients were randomly assigned to one of?ve different antiemetic treatment arms:netupitant at100,200,or300mg,eachcombinedwithoralpalonosetron0.50mg; oral palonosetron0.50mg alone;or an exploratory arm of standard 3-day aprepitant plus intravenous ondansetron32mg.All patients received oral dexamethasone on days1through4.The primary anal-ysis compared each dose of NEPA with palonosetron;the study was
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not powered to detect a difference between NEPA and aprepitant plus https://www.wendangku.net/doc/f916514787.html,pared with palonosetron alone,each dose of NEPA produced higher overall complete response rates(no emesis or res-cue).Complete response rates with the highest dose of NEPA were statistically signi?cantly higher than those of palonosetron alone dur-ing both the acute and delayed phases.The highest dose of NEPA was also signi?cantly associated(P?.05)with improvements in the sec-ondary outcomes of no emesis,no signi?cant nausea,and complete protection.The frequency and intensity of adverse events were gener-ally similar across study arms,and a majority of adverse events were mild or moderate.The most common treatment-related adverse events were hiccups and headache.One serious event in a NEPA-treated patient(NEPA200)was felt to be treatment related:The patient experienced loss of consciousness,recovered30minutes after onset, and discontinued treatment.On the basis of these results,the highest dose of NEPA(300mg)was selected for further development.
The chemotherapy agents used in each arm of each study are listed in Table2.The safety and ef?cacy of NEPA in weekly or every-2-week chemotherapy regimens have not been evaluated.
DISCUSSION InbothaphaseIIItrialinpatientsreceivingthecombinationofananthra-cycline and cyclophosphamide and a large phase II dose-ranging trial in patients receiving cisplatin,NEPA(combined NK1/5-HT3receptor an-tagonist)combined with dexamethasone was superior to palonosetron combined with dexamethasone in the prevention of chemotherapy-induced nausea and vomiting.In a second phase III trial in patients receiving highly or moderately emetogenic chemotherapy over multiple cycles of treatment,NEPA was also effective in preventing nausea and vomiting.NEPAwaswelltoleratedinallthreestudies,withasafetypro?le similar to that of the control arms.Dosing information for NEPA and other antiemetics is summarized in Table3.
UPDATED RECOMMENDATION
All patients who receive highly emetogenic chemotherapy regimens (including anthracycline plus cyclophosphamide)should be offered a
Antiemetics:Focused Update of ASCO Guideline
https://www.wendangku.net/doc/f916514787.html,?2015by American Society of Clinical Oncology5
three-drug combination of an NK1receptor antagonist,a5-HT3re-ceptor antagonist,and dexamethasone.The oral combination of NEPA plus dexamethasone is an additional treatment option in this setting.The remaining recommendations from the2011ASCO guide-line are unchanged pending a full update.The full set of recommen-dations is listed in the Bottom Line Box.
COST CONSIDERATIONS
Formal cost-effectiveness analyses of NEPA are not yet available.Be-cause NEPA is an all-oral regimen,it will require patients to both?ll and pay for a prescription.The out-of-pocket cost will vary by insur-ance plan,and this point should be discussed with patients.The value of NEPA will be in?uenced by the cost and effectiveness of other antiemetic options,and these will be explored more fully in the planned,comprehensive update of the ASCO antiemetic guideline.Of particular interest are emerging data on the psychotropic medication olanzapine.Olanzapine is inexpensive,but high-quality evidence of ef?cacy and safety has been lacking.Additional evidence from two completed phase III studies is eagerly anticipated.
AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at https://www.wendangku.net/doc/f916514787.html,.
AUTHOR CONTRIBUTIONS
Administrative support:Kari Bohlke
Manuscript writing:All authors
Final approval of manuscript:All authors
REFERENCES
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2.Kris MG,Hesketh PJ,Somer?eld MR,et al: American Society of Clinical Oncology guideline for antiemetics in oncology:Update2006.J Clin Oncol 24:2932-2947,2006
3.Basch E,Prestrud AA,Hesketh PJ,et al:Anti-emetics:American Society of Clinical Oncology clin-ical practice guideline update.J Clin Oncol29:4189-
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AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Antiemetics:American Society of Clinical Oncology Focused Guideline Update
The following represents disclosure information provided by authors of this manuscript.All relationships are considered compensated.Relationships are
self-held unless noted.I?Immediate Family Member,Inst?My Institution.Relationships may not relate to the subject matter of this manuscript.For more information about ASCO’s con?ict of interest policy,please refer to https://www.wendangku.net/doc/f916514787.html,/rwc or https://www.wendangku.net/doc/f916514787.html,/site/ifc.
Paul J.Hesketh
No relationship to disclose
Kari Bohlke
No relationship to disclose
Gary H.Lyman
Research Funding:Amgen(Inst)
Ethan Basch
No relationship to disclose
Maurice Chesney
Stock or Other Ownership:Teva Pharmaceutical Industries,
Bristol-Myers Squibb,P?zer,P?zer(I),Procter&Gamble,Walgreens, Walgreens(I)
Rebecca A.Clark-Snow
Honoraria:Merck Consulting or Advisory Role:Merck,Tesaro
Travel,Accommodations,Expenses:Merck
Michael A.Danso
No relationship to disclose
Karin Jordan
Consulting or Advisory Role:Merck,Merck Sharp&Dohme,Helsinn Therapeutics,Pro Strakan
Mark R.Somer?eld
No relationship to disclose
Mark G.Kris
Consulting or Advisory Role:AstraZeneca,Clovis Oncology,ARIAD Pharmaceuticals,Genentech/Roche,P?zer,Daiichi Sankyo,Threshold Pharmaceuticals,Array BioPharma
Research Funding:Puma Biotechnology(Inst),P?zer(Inst)
Antiemetics:Focused Update of ASCO Guideline
https://www.wendangku.net/doc/f916514787.html,?2015by American Society of Clinical Oncology
Hesketh et al
Acknowledgment
We thank Mariana Chavez MacGregor,Alex Solky,and the American Society of Clinical Oncology Clinical Practice Guidelines Committee for their thoughtful reviews of and insightful comments on this guideline document.
Appendix
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