Patient-Reported Outcomes Version Of The Common Terminology Criteria For Adverse Events Items Research Articles

Identifying symptomatic adverse events using the patient-reported outcomes version of the common terminology criteria for adverse events in patients with non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations.

Tolerability and safety of treatments are important in oncology trials and should be informed by patient assessments. We identified the most relevant patient-reported symptomatic adverse events (AEs) to measure in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. This study selected relevant symptomatic AEs from 78 AEs available in the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) measurement system. Initially, symptomatic AEs were selected based on literature and product labeling reviews, and then core sets of symptomatic AEs were identified by patient and clinician interviews. Qualitative and descriptive analyses were performed using the data collected from three iterative rounds of patient interviews. During concept elicitation interviews involving 29 patients, 12 symptomatic AEs were identified and were then adapted into a 25-item PRO-CTCAE form for use in future clinical trials along with commonly used PRO measures. Cognitive interviews showed that the PRO-CTCAE items were easy to answer and appropriate for assessing the patients' experience with symptomatic AEs. This study also assessed disease symptoms, impacts, and overall patient experience. The 25-item PRO-CTCAE form captures the most relevant symptomatic AEs in this patient population, and it is available for future studies. Baseline characterization of AEs associated with this distinct patient group contributes to our broader knowledge about NSCLC and through platforms like Project Patient Voice will expand our understanding of treatment tolerability and safety for NSCLC. Ultimately, this data collection will help inform decision-making for patients, caregivers, healthcare providers, and regulators.

Missing data strategies for the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in Alliance A091105 and COMET-2

PurposeMissing scores complicate analysis of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) because patients with and without missing scores may systematically differ. We focus on optimal analysis methods for incomplete PRO-CTCAE items, with application to two randomized, double-blind, placebo-controlled, phase III trials.MethodsIn Alliance A091105 and COMET-2, patients completed PRO-CTCAE items before randomization and several times post-randomization (N = 64 and 107, respectively). For each trial, we conducted between-arm comparisons on the PRO-CTCAE via complete-case two-sample t-tests, mixed modeling with contrast, and multiple imputation followed by two-sample t-tests. Because interest lies in whether CTCAE grades can inform missing PRO-CTCAE scores, we performed multiple imputation with and without CTCAE grades as auxiliary variables to assess the added benefit of including them in the imputation model relative to only including PRO-CTCAE scores across all cycles.ResultsPRO-CTCAE completion rates ranged from 100.0 to 71.4% and 100.0 to 77.1% across time in A091105 and COMET-2, respectively. In both trials, mixed modeling and multiple imputation provided the most similar estimates of the average treatment effects. Including CTCAE grades in the imputation model did not consistently narrow confidence intervals of the average treatment effects because correlations for the same PRO-CTCAE item between different cycles were generally stronger than correlations between each PRO-CTCAE item and its corresponding CTCAE grade at the same cycle.ConclusionFor between-arm comparisons, mixed modeling and multiple imputation are informative techniques for handling missing PRO-CTCAE scores. CTCAE grades do not provide added benefit for informing missing PRO-CTCAE scores. ClinicalTrials.gov Identifiers: NCT02066181 (Alliance A091105); NCT01522443 (COMET-2).

Validity and reliability of the simplified Chinese patient-reported outcomes version of the common terminology criteria for adverse events

BackgroundThe psychometric properties of the simplified Chinese version of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) have not been assessed. Therefore, we aimed to assess its validity, reliability, and responsiveness.Patients and methodsA Chinese version of the PRO-CTCAE and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30) were distributed to 1580 patients from four cancer hospitals in China. Validity assessments included construct validity, measured by Pearson’s correlations and confirmatory factor analysis (CFA), and known-groups validity, measured by t-tests. The assessment of reliability included internal consistency, measured by Cronbach’s ɑ, and test-retest reliability, measured by the intraclass correlation (ICC). Responsiveness was assessed by standardized response means (SRMs).ResultsData from 1555 patients who completed the instruments were analyzed. The correlations were high between PRO-CTCAE items and parallel QLQ-C30 symptom scales (r > 0.60, p < 0.001), except for fatigue (severity: r = 0.49). Moreover, CFA showed the PRO-CTCAE structure was a good fit with the data (Root Mean Square Error of Approximation = 0.046). Known-groups validity was also confirmed. Cronbach’s ɑ of all item clusters were greater than 0.9 and the median test-retest reliability coefficients of the 38 items were 0.85 (range = 0.71–0.91). In addition, the SRMs of PRO-CTCAE items were greater than 0.8, indicating strong responsiveness.ConclusionThe simplified Chinese version of the PRO-CTCAE showed good reliability, validity, and responsiveness.

Using machine learning to identify older adults at high risk for hospitalization and mortality via the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

169 Background: PRO-CTCAE captures symptomatic adverse events (e.g. pain, fatigue) and may indicate poor treatment tolerability in older patients (pts) with advanced cancer. Using unsupervised machine learning which can detect unknown patterns in data, we aimed to evaluate if clusters identified based on PRO-CTCAE severity were associated with hospitalization and survival. Methods: We included pts randomized to the control arm of GAP 70+ (URCC 13059; PI: Mohile), which enrolled pts aged ≥70, with incurable solid tumors or lymphoma, and ≥1 geriatric assessment (GA) domain impairment starting a new treatment regimen. Measures included 24 PRO-CTCAE items (v1.0) with severity attributes (item 0-4; total score 0-96, higher score = greater severity). The unsupervised algorithm (K-means with Euclidean Distance) clustered pts at baseline based on similarities of severities of the 24 items. We examined if the clusters were associated with treatment-related hospitalization within 3 months and lower survival at 6 months using Logistic and Cox regressions. Results: Of the 369 control pts, 366 completed GA and PRO-CTCAE at baseline (mean age 77.2, 94.3% white, 30.9% with GI and 31.4% with lung cancer; mean number of impaired GA 4.4). By PRO-CTCAE, the most prevalent symptoms were fatigue (82.7%), pain (60.9%), and decreased appetite (58.7%). Greater GA impairment was associated with 20 PRO-CTCAE items (fatigue, pain, and decreased appetite having the strongest associations; all Pearson's r &gt; 0.33). Three clusters were identified: Low Severity (51.4%); Moderate Severity (34.4%), and High Severity (14.2%). Mean total severity score was 6.9 (low), 16.9 (moderate), and 28.7 (high), respectively (p &lt; 0.01). No difference in demographics was found among clusters. Percent of pts hospitalized were 21.3% (low), 36.5% (moderate), and 38.5% (high) (p &lt; 0.01); survival rates were 81.9% (low), 71.4% (moderate), and 55.3% (high) (p &lt; 0.01). Controlling for cancer type and GA, compared to pts in Low Severity cluster, pts in Moderate and High Severity were more likely to be hospitalized (odds ratio = 1.77, p = 0.03); pts in High Severity cluster were more likely to die (hazard ratio = 2.23, p = 0.01). Conclusions: Unsupervised machine learning was able to partition pts into different PRO-CTCAE severity clusters; pts with higher baseline severity were more likely to be hospitalized or die. PRO-CTCAE provides additional information to GA. Funding: R01CA177592, U01CA233167, UG1CA189961.

Patient-Reported Outcomes From Patients Receiving Immunotherapy or Chemoimmunotherapy for Metastatic Non–Small-Cell Lung Cancer in Clinical Practice

IntroductionImmunotherapy and chemoimmunotherapy clinical trials for metastatic non–small-cell lung cancer (mNSCLC) have generally excluded patients with poor performance status (PS) and have utilized patient-reported measures that could miss some symptoms associated with immunotherapy. The goals of this study were to describe quality of life and symptom burden among mNSCLC patients receiving immunotherapy in clinical practice, and to examine burden by Eastern Cooperative Oncology Group performance status (ECOG PS) and age. Patients and MethodsBetween 2017 and 2018, mNSCLC patients receiving immuno/chemoimmunotherapy at an academic medical center completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) and the National Cancer Institute Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Univariate and bivariate analyses described EORTC-QLQ-C30 subscales and the proportion reporting at least moderate PRO-CTCAE symptoms, and compared scores by ECOG PS (0/1 vs. 2/3) and age (< 70 vs. ≥ 70 years). ResultsSixty patients (60% female; 75% < 70 years old; 68% ECOG PS 0/1; 57% receiving single-agent immunotherapy) participated. The mean EORTC-QLQ-C30 global health score was 62.6; EORTC symptoms were highest for fatigue, insomnia, dyspnea, and financial concerns (all > 30). Global health and pain were worse in ECOG PS 2/3 patients. For PRO-CTCAE, 20% to 40% reported at least moderate gastrointestinal, respiratory, dermatologic, arthralgia, or myalgia symptoms. The PRO-CTCAE pain score was higher among ECOG PS 2/3 patients. ConclusionIn clinical practice, global health was largely comparable to published clinical trials, but PRO-CTCAE items indicated a higher symptom prevalence. Closer monitoring of symptoms is warranted in ECOG PS 2/3 patients.

Japanese translation and linguistic validation of the US National Cancer Institute\u2019s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

BackgroundThe US National Cancer Institute (NCI) has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to capture patients’ self-reported symptomatic adverse events in cancer clinical trials. The aim of this study was to develop and linguistically validate a Japanese translation of PRO-CTCAE. Forward- and back-translations were produced, and an independent review was performed by the Japan Clinical Oncology Group (JCOG) Executive Committee and the US NCI. We then conducted cognitive interviews with 21 patients undergoing cancer treatment. Participants were asked to complete the PRO-CTCAE and were interviewed using semi-structured scripts and predetermined probes to investigate whether any items were difficult to understand or answer. The interviews were recorded and transcribed, and a thematic analysis was performed. The data were split into two categories: 1) remarks on the items and 2) remarks on the questionnaire in general.ResultsTwenty-one cancer patients undergoing chemotherapy or hormone therapy were interviewed at the University of Tokyo Hospital and the Kansai Medical University Hirakata Hospital during 2011 and 2012. Thirty-three PRO-CTCAE items were evaluated as “difficult to understand,” and 65 items were evaluated as “difficult to answer” by at least one respondent. However, on further investigation, only 24 remarks were categorized as “comprehension difficulties” or “clarity” issues. Most of these remarks concerned patients’ difficulties with rating their experience of individual symptomatic events.ConclusionsThe study provides preliminary evidence supporting the linguistic validity of the Japanese version of PRO-CTCAE. Further cognitive interviewing is warranted for PRO-CTCAE items relating to sexuality and anxiety and for response options on severity attribute items.

A pilot study of the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in a phase I clinical trial.

6587 Background: Recently the Patient-Reported Outcomes version of the CTCAE was developed to augment clinically graded adverse events with information reported directly by patients on clinical trials (Basch, 2009). The validation and potential application of PRO-CTCAE in phase I clinical trials are of great interest as toxicity is the primary endpoint. Methods: Selected PRO-CTCAE items (21 items measuring 12 symptomatic adverse events) corresponding to the major adverse events required to be graded clinically were collected in an ongoing phase I clinical trial of weekly cilengitide and paclitaxel in patients with advanced solid malignancies (NCT01276496). PRO-CTCAE was administered in a paper booklet by a clinical research associate prior to treatment on days 1, 8 and 15 of their regular visits. These PRO-CTCAE items were summarized descriptively in comparison to clinician-assessed CTCAE ver 4.0 (NCI, 2009) during the first cycle. As a pilot study to assess feasibility of PRO-CTCAE in phase I trials, PRO-CTCAE was not intended for determination of dose-limiting toxicity. Results: Twelve patients were accrued to two separate doses of cilengitide and paclitaxel. The median age was 56 (range 36—67) and half of patients were female. All patients had an ECOG performance score &lt;= 1. Over 90% of patients had received prior surgery and chemotherapy. All but one patient completed weekly PRO-CTCAE during the first cycle, the only patient refused to complete weeks 2 and 3 did not give a reason. PRO-CTCAE captured most of the symptomatic adverse events reflected in clinician-assessed CTCAE. Some symptomatic adverse events were not reported clinically by CTCAE but were reported by patients by PRO-CTCAE. Overall, PRO-CTCAE items indicated slightly more severe degree of symptoms experienced by patients than those reported in CTCAE. Conclusions: This is the first study that PRO-CTCAE items were integrated within regular study visits in a phase I trial. The administration of PRO-CTCAE has been proved feasible and fruitful, providing consistent and enhanced symptomatic toxicity from the patient point of view. The addition of PRO-CTCAE did not significantly increase patient burden. Clinical trial information: NCT01276496.

Usability testing of the PRO-CTCAE measurement system in patients with cancer.

e17560 Background: Use of electronic Patient-Reported Outcomes (ePROs) are increasingly employed in patient care and oncology research. However, these systems can be difficult to use, preventing adoption and deployment. The objective is to evaluate the patient usability of the National Cancer Institute’s (NCI) Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Measurement System. Methods: PRO-CTCAE is an item bank of 124 questions evaluating 78 symptomatic adverse events, as well as a software system that includes a web-based and interactive voice response system [IVRS] to administer these items to patients, and electronic features to customize survey creation, schedule survey administration, export data, and generate alerts and reports. A protocol was developed for two rounds of usability testing to evaluate understanding and ease of navigation reported by patients undergoing cancer treatment. Software was refined between rounds and retested. Patients were asked to login and complete PRO-CTCAE items either in clinic or at home, then were immediately debriefed (semi-scripted) by a trained interviewer. Results: 173 patients at 3 cancer centers and affiliated community network sites were enrolled in the study between 1/11-5/12 (45% male; 32% non-white; 26% high school or less). Usability issues identified in Round 1 (N=37) included difficulty in using radio buttons, absence of survey progress indicators, and problems with system login. Modifications included increasing size of buttons, improving the progress bar feature, and simplifying the interface to focus users on survey questions. In Round 2 (N=136), remaining issues were related to general difficulty with Internet use, such as navigating to the URL. IVRS testing indicated high scores of ease of use and completion of items, but users had difficulty adding unique symptoms to the system. Conclusions: Iterative usability testing identified improvements to web-based and IVRS for patient self-reporting and achieved a more favorable user experience. The feasibility of integrating PRO-CTCAE into trials to gather symptomatic adverse events directly from patients is currently being evaluated in the cancer cooperative groups.

Validity and reliability of the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE).

9047 Background: Symptomatic adverse events (AE) in cancer trials are reported by clinicians using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE). To integrate the patient perspective into AE reporting, NCI contracted (HHSN261201000043C) to create a patient-reported outcomes companion tool (PRO-CTCAE). We report the validity and reliability of PRO-CTCAE’s 124 items reflecting 78 symptomatic AEs. Methods: English-speaking subjects (n=869; 44% male; median [mdn] age 59; 32% racial/ethnic minority; 34% high school or less; 17% ECOG Performance Status [PS] 2-4) receiving treatment for a range of cancers at 4 NCI-designated cancer centers and 5 sites in NCI's Community Cancer Centers Program completed a web-based survey in clinic including PRO-CTCAE and EORTC QLQ-C30. Pearson correlations were computed between PRO-CTCAE items and QLQ-C30 scales. Differences in PRO-CTCAE item scores between clinician-reported ECOG PS (0-1 vs 2-4) groups were computed. Test-retest reliability of 48 prespecified items was evaluated in a subset (n=79). Results: Correlations in the expected direction were observed for 116/124 PRO-CTCAE items with the QLQ-C30 global health scale (mdn r=-.21; range .08 to -.57). Stronger correlations were seen for PRO-CTCAE items with conceptually related QLQ-C30 domains: fatigue with physical, role and social functioning (-.54 to -.66); anxiety and depression with emotional functioning (-.54 to -.70); and concentration and memory problems with cognitive functioning (-.62 to -.72) [all p &lt;0.001]. Fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea items strongly correlated with corresponding QLQ-C30 symptom scales (.69 to .79, all p &lt;0.001). Scores for 98/124 PRO-CTCAE items were higher in the ECOG PS 2-4 vs 0-1 group (mdn effect size .3). Test-retest reliability was observed across all tested items (mdn intraclass correlation coeff .77; range .53 to .96). Conclusions: Results demonstrate favorable validity and reliability of PRO-CTCAE in a large, heterogeneous sample of patients undergoing cancer treatment. Further testing in multicenter treatment trials is underway.

Acceptability of the NCI patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in women with metastatic breast cancer (MBC).

e19633 Background: NCI PRO-CTCAE is a new patient-reported outcome measure designed to enhance adverse event (AE) reporting in clinical trials by integrating the patient experience. The PRO-CTCAE item bank includes items representing the frequency (F), severity (S) and interference (I) with usual activities of 78 symptomatic AEs. The aim of this study was to examine the acceptability of a subset of PRO-CTCAE items to women receiving treatment for HER2+ MBC. Methods: 207 women on active treatment for HER2+ MBC (median 47 months since MBC diagnosis) were recruited from 6 U.S. breast cancer support groups and completed a web survey that included 18 PRO-CTCAE symptoms. Respondents were aged 45-64 years (71%), white (94%), college-educated (72%), with health-related quality of life rated good to excellent (61%) and median EQ5D utility score of 0.8. To explore PRO-CTCAE acceptability and data quality, we examined item level missingness, endorsement frequencies and binary and free-text responses about the comprehensibility of PRO-CTCAE items. Results: Item level missingness across all symptoms for each PRO-CTCAE dimension (F, S and I) ranged from 1.0% to 5.3%, with a median of 2.9%; interference associated with decreased appetite had the greatest missingness (5.3%). Excluding this outlier, maximum missingness was 3.9%. Endorsement frequencies of response choices for S of insomnia, constipation, fatigue, pain, anxiety/worry and sad/unhappy feelings support acceptable instrument sensitivity (all adjacent response points endorsed by &gt;7% of respondents). Most respondents (92%) thought the items were easy to understand; a few were uncertain about how to rate symptoms such as anxiety, depression, insomnia and nausea if they were present but partially controlled with medication. Conclusions: These findings confirm and extend those of other studies demonstrating the acceptability of PRO-CTCAE. Evaluation in a more heterogeneous sample, particularly with respect to education and cancer site, is underway.

Validation of the NCI patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in women receiving treatment for metastatic breast cancer.

9144 Background: NCI PRO-CTCAE is designed to enhance adverse event reporting by integrating patients’ self-report of the frequency (F), severity (S) and interference (I) with usual activities of 78 symptomatic treatment toxicities. This study examined the construct validity of a subset of PRO-CTCAE items in women with metastatic breast cancer (MBC). Methods: 207 women (70% aged 45-59 years; 94% White;71% college-educated) with HER2+ MBC who had received treatment in the past month were recruited from 6 U.S. breast cancer support groups and completed a web survey that collected 18 PRO-CTCAE symptoms, and the Rotterdam Symptom Checklist (RSC). Pairwise concordance among PRO-CTCAE symptom dimensions was examined using weighted Kappa and Bowker’s test for symmetry. Results: Respondents were a median of 47 months since MBC diagnosis and 61% rated their health-related quality of life (HRQL) as good to excellent. Symptom prevalence was similar for PRO-CTCAE and RSC, with respondents more likely to endorse mood disturbance on PRO-CTCAE (Anxiety/Worry 90%; Sad/Unhappy Feelings 86%) vs. RSC (Anxiety 63%; Depressed Mood 61%). There was parallel rank-ordering of fatigue, anxiety, insomnia, depression, difficulty concentrating and neuropathy as the symptoms that were most severe, interfered most and caused the greatest bother. Within PRO-CTCAE, pairwise agreement among F, S and I was moderate for most symptoms (κw=.42 to .54). Agreement between F and S was highest for pain, nausea and arm/leg swelling (κw=.61 to .80), and lowest for anxiety/worry and sad/unhappy feelings (κw= .27-.37). Except for arm/leg swelling, endorsement patterns by the dimensions of F, S and I were distinct (Bowker’s p all &lt;.002). Across PRO-CTCAE symptoms, S was consistently higher than I (mean differences .12 to .72, all p&lt;.01]). Means for S were consistently and significantly higher for those with impaired versus preserved HRQL, providing evidence of construct validity. Conclusions: This study supports the construct validity of PRO-CTCAE, and suggests that F, S and I dimensions offer non-overlapping information relative to 17 /18 PRO-CTCAE symptomatic toxicities.