Accurate capture of the symptom experience is essential to gauging efficacy, safety, and tolerability of cancer treatments. The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed by the National Cancer Institute to allow direct patient self-reporting of symptomatic adverse events in cancer clinical trials. Its content validity has been established in accordance with recommended practices for novel patient-reported outcome (PRO) instruments

Atkinson, T.M.

Basch, E.

Dueck, A.C.

Hay, J.L.

Mendoza, T.R.

Minasian, L.M.

Mitchell, S.A.

Rogak, L.J.

Journal of Pain and Symptom Management

Carolina Digital Repository

W‘‘MSeCaPRActiacerverAdtheselcliestticinsACTdeonexaCT‘‘nsymriesymPRpreis a gto expDan(Ncog(59schcanwhteranhat Do ‘‘None,’’ ‘‘Mild,’’oderate,’’ ‘‘Severe,’’ and ‘‘Veryvere’’ Mean to Patients Withncer? Content Validity ofO-CTCAE Response Scalescurate capture of the symptom experience is essen-l to gauging efficacy, safety, and tolerability of can- treatments.1 The Patient-Reported Outcomes sion of the Common Terminology Criteria for verse Events (PRO-CTCAE)2 was developed by  National Cancer Institute to allow direct patient f-reporting of symptomatic adverse events in cancer nical trials.3e5 Its content validity has been ablished in accordance with recommended prac-es for novel patient-reported outcome (PRO) truments.6,7lthough we previously reported that the PRO-CAE response options were acceptable to respon-nts,5 this analysis extends those findings by focusing  comprehension of the response options. For mple, can patients delineate between PRO-CAE response options for a given attribute? Does ever/none/not at all’’ indicate the absence of a ptom, or is it interpreted as the patient is not expe-ncing a noticeable attribute of that symptom (i.e., a ptom is not severe)? Our aims were to determine if O-CTCAE response options are 1) accurately com-hended, including that ‘‘never/none/not at all’’ selected when the respondent is not experiencing iven symptom and 2) nonoverlapping, that is, able distinguish respondents with different symptom eriences.ata were drawn from two studies (NCT01031641 d NCT02158637). For the qualitative phase CT01031641), we analyzed data from one-on-one nitive interviews conducted with 127 patients % female, 72% white/non-Hispanic, 35% high-ool education or less) receiving treatment for cer.5 For any symptomatic adverse events (AEs) ere a PRO-CTCAE attribute was reported as >0, in-viewers asked (for a minimum of two symptoms d their respective attributes per interview): ‘‘For thisitem you chose x, what makes that a better choice than(x þ 1)? What makes that a better choice than(x  1)?’’ The purpose of this probing was to establishthat the patient was considering the difference betweenproximal responses along the continuum of options.To confirm the monotonicity of PRO-CTCAEresponse choices, we analyzed data from a psychomet-ric study (NCT02158637) of 940 patients currentlyundergoing treatment for cancer (57% female, 63%white/non-Hispanic, 32% high-school education orless).4 Patients completed PRO-CTCAE and the Euro-pean Organization for Research and Treatment of Can-cer Quality of Life Questionnaire (EORTC QLQ-C30).8We compared mean EORTC QLQ-C30 Health-RelatedQuality of Life (HRQL) summary scores9 across sub-groups with worsening PRO-CTCAE item scores usingJonckheere-Terpstra tests.10Seventy-two of 78 PRO-CTCAE symptom terms(92%) were probed. All respondents with a PRO-CTCAE item response >0 (99/127) were able todifferentiate between adjacent response choices. Inthe subsample of respondents who selected ‘‘never/none/not at all’’ (35/127) for one or more PRO-CTCAE items, all participants correctly explained tothe interviewer that this response choice meant thatthey were not experiencing a symptom. For example,a patient was asked about how much dizziness inter-fered with their usual activities. They selected ‘‘some-what,’’ defined as ‘‘something that might interferewith plansdyou wouldn’t take the chance of goingsomewhere alone.’’ To this patient, ‘‘quite a bit’’ meant‘‘you wouldn’t be able to go anywhere, even if you hadsomeone with you and needed to get something done.’’Another patient was asked why they selected ‘‘none’’ inresponse to pain severity, to which they responded‘‘I do not experience pain at all.’’ Additional examplesare displayed in Table 1. In the psychometric study, sig-nificant (all P < 0.05) monotonically decreasing meanHRQL scores were observed across worsening PRO-CTCAE score groups for the majority (108/124[87%]) of PRO-CTCAE items (Fig. 1).In response to probing, all study participants pro-vided accurate and meaningful explanations for selec-tion of a given PRO-CTCAE response over its proximalalternatives. Moreover, all participants indicated thatchoosing ‘‘never/none/not at all’’ meant the symp-tom was absent. Statistically significant, conceptuallyrelevant associations between PRO-CTCAE responsechoices and HRQL were seen across a substantial ma-jority of the PRO-CTCAE items.Taken together, these results provide strong evi-dence that PRO-CTCAE response options are wellcomprehended and that each of the ordinal responsechoices is nonoverlapping, serving to distinguishTable 1Example Patient Explanations of Response Options by Attribute and Adverse Event (N ¼ 127)Attribute Symptomatic Adverse EventPatient Definition of Response(X  1) (X) (X þ 1)Severity Pain Moderated‘‘when you are inpain and it hurts ‘bad, bad’’’Severed‘‘when you are in pain and it’s gettingworse’’Very severed‘‘when you are in pain and it doesn’tstop and it hurts a lot’’Severity Problems with concentration Mildd‘‘able to get the task donebut may take more time tofocus’’Moderated‘‘takes even more time to get a taskdone’’Severed‘‘unable to accomplish a task’’Severity Shortness of breath Mildd‘‘breathe through thenose only, at a faster pace’’Moderated‘‘need to breathe through the nose andmouth’’Severed‘‘fainting or passing out due to the inabilityto catch a breath’’Severity Felt like nothing couldcheer you upNoned‘‘not there’’ Mildd‘‘does not feel if it is a reaction’’ Moderated‘‘can recognize it and realize it is aproblem’’Frequency Nausea Occasionallyd‘‘every other dayor so’’Frequentlyd‘‘every day I felt some sort of nausea’’ Almost constantlyd‘‘constantly experiencingnausea’’Frequency Headache Neverd‘‘never happens’’ Rarelyd‘‘some time during the day’’ Occasionallyd‘‘three or four times a week’’Frequency Hot flashes Neverd‘‘not once in the lastweek’’Rarelyd‘‘one or two times’’ Occasionallyd‘‘every other day or so’’Interference Arm or leg swelling Somewhatd‘‘interfering with25%e50% of activities in aday’’Quite a bitd‘‘interfering with 50%e75% ofactivities in a day’’Very muchd‘‘interfering with 75%e100% ofactivities in a day’’Interference Fatigue A little bitd‘‘doesn’t interferewith daily activitiesmuchdwouldn’t put offgardening’’Somewhatd‘‘would put off gardening but be ableto do something less strenuous’’Quite a bitd‘‘wouldn’t be able to do anotheractivity that was more strenuous than gardening’’Interference Frequent urination A little bitd‘‘I’m aware of it andmay have to compensate forit’’Somewhatd‘‘you have to make more compensationbut not interfering too much (don’t have to callin sick to work)’’Quite a bitd‘‘having to miss work or social events’’Amount Hair loss Not at alld‘‘none, notnoticeable’’A little bitd‘‘hair falling out naturally’’ Somewhatd‘‘noticing more than usual on thebrush’’X refers to the patient response, with X  1 representing the proximal lower response choice and X þ 1 representing the proximal higher response choice on the response scale for a specific attribute.Fig. 1. Mean European Organization for Research andTreatment of Cancer Quality of Life Questionnaire (EORTCQLQ-C30) Health-Related Quality of Life (HRQL) summaryscores (higher scores represent better HRQL) show statisti-cally significant declines across worsening Patient-ReportedOutcomes version of the Common Terminology Criteriafor Adverse Events Item Response.respondents with meaningfully different symptomexperiences.Thomas M. Atkinson, PhDMemorial Sloan Kettering Cancer Center,New York, New York, USAE-mail: atkinsot@mskcc.orgJennifer L. Hay, PhDMemorial Sloan Kettering Cancer Center,New York, New York, USAAmylou C. Dueck, PhDMayo Clinic, Scottsdale, Arizona, USASandra A. Mitchell, PhDNational Cancer Institute, Rockville,Maryland, USATito R. Mendoza, PhDUniversity of Texas MD Anderson CancerCenter, Houston, Texas, USALauren J. Rogak, MAMemorial Sloan Kettering Cancer Center,New York, New York, USALori M. Minasian, MDNational Cancer Institute, Rockville,Maryland, USAEthan Basch, MD, MScLineberger Comprehensive Cancer Center,University of North Carolina, Chapel Hill,North Carolina, USAhttps://doi.org/10.1016/j.jpainsymman.2017.10.024Clinicaltrials.gov: NCT02158637 and NCT01031641.Disclosures and AcknowledgmentsThis work was supported by National CancerInstitute contracts HHSN261200800043C and HHS-N261200800001E, as well as a National Institutes ofHealth support grant (P30 CA08748-50), whichprovides partial support for the Patient-ReportedOutcomes, Community-Engagement, and LanguageCore Facility. The sponsors had no involvement inthe study design, collection, analysis, interpretation,writing, or decision to submit the report forpublication.References1. Kluetz PG, Chingos DT, Basch EM, Mitchell SA. Patient-reported outcomes in cancer clinical trials: measuring symp-tomatic adverse events with the National Cancer Institute’sPatient-Reported Outcomes Version of the Common Termi-nology Criteria for Adverse Events (PRO-CTCAE). Am SocClin Oncol Educ Book 2016;35:67e73.2. Patient-Reported Outcomes version of the Common Ter-minology Criteria for Adverse Events (PRO-CTCAE). NationalCancer Institute - Division of Cancer Control & Population Sci-ences. Available from https://healthcaredelivery.cancer.gov/pro-ctcae/. Accessed September 5, 2017.3. Basch E, Reeve BB, Mitchell SA, et al. Development ofthe National Cancer Institute’s patient-reported outcomesversion of the common terminology criteria for adverseevents (PRO-CTCAE). J Natl Cancer Inst 2014;106: dju244.4. Dueck AC, Mendoza TR, Mitchell SA, et al. Validity andreliability of the US National Cancer Institute’s Patient-Reported Outcomes Version of the Common TerminologyCriteria for Adverse Events (PRO-CTCAE). JAMA Oncol2015;1:1051e1059.5. Hay JL, Atkinson TM, Reeve BB, et al. Cognitive inter-viewing of the US National Cancer Institute’s Patient-Reported Outcomes version of the Common TerminologyCriteria for Adverse Events (PRO-CTCAE). Qual Life Res2014;23:257e269.6. Patrick DL, Burke LB, Gwaltney CJ, et al. Contentvalidity-establishing and reporting the evidence in newlydeveloped patient-reported outcomes (PRO) instrumentsfor medical product evaluation: ISPOR PRO goodresearch practices task force report: Part 1-eliciting con-cepts for a new PRO instrument. Value Health 2011;14:967e977.7. Patrick DL, Burke LB, Gwaltney CJ, et al. Contentvalidity-establishing and reporting the evidence in newlydeveloped patient-reported outcomes (PRO) instrumentsfor medical product evaluation: ISPOR PRO goodresearch practices task force report: Part 2-assessingrespondent understanding. Value Health 2011;14:978e988.8. Aaronson NK, Ahmedzai S, Bergman B, et al. The Euro-pean Organization for Research and Treatment of CancerQLQ-C30: a quality-of-life instrument for use in interna-tional clinical trials in oncology. J Natl Cancer Inst 1993;85:365e376.9. Giesinger JM, Kieffer JM, Fayers PM, et al. Replicationand validation of higher order models demonstrated that asummary score for the EORTC QLQ-C30 is robust. J ClinEpidemiol 2016;69:79e88.10. Jonckheere AR. A distribution-free k-sample test againstordered alternatives. Biometrika 1954;41:133.

What Do “None,” “Mild,” “Moderate,” “Severe,” and “Very Severe” Mean to Patients With Cancer? Content Validity of PRO-CTCAE™ Response Scales

What Do “None,” “Mild,” “Moderate,” “Severe,” and “Very Severe” Mean to Patients With Cancer? Content Validity of PRO-CTCAE™ Response Scales

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