Unleashing patient voices: empowering adverse event assessment with complete patient-reported outcomes.

The 124-item patient reported-outcome common terminology criteria for adverse events (PRO-CTCAE) questionnaire, assessing 78 symptoms, is widely used in cancer clinical trials to identify side effects. However, its regular use in routine cancer care is rarely reported. We aimed to investigate the feasibility of weekly PRO-CTCAE completion over 9 weeks in a prospective study with 30 patients with cancer undergoing chemotherapy. Participants were asked to complete electronic surveys with reminders, but no feedback or incentives. Only 136 (50%) of the planned 270 time points at which a PRO-CTCAE self-report was expected were completed, with an additional 21 (8%) partially completed, and represents a failure to achieve the expected level of completion. Patients reported experiencing up to 51 and a median of 30 symptoms across all time points, highlighting the complexity of symptom assessment in acute cancer care. While weekly implementation of the PRO-CTCAE may not be feasible outside of clinical trial settings, this study highlights the breadth of symptoms experienced.

The Weighted Toxicity Score: Confirmation of a Simple Metric to Communicate Toxicity in Randomized Trials of Systemic Cancer Therapy.

INTRODUCTION: FDA's Project Optimus was developed in part to better identify appropriate dose and schedule of cancer therapeutics. The tabular method to summarize patients' maximum toxicity in a clinical trial does not allow for ready comparison to the treatment's benefit. In this manuscript, we apply a simple tool, the weighted toxicity score (WTS), to trials involving lung cancer immunotherapy and chemotherapy, as well as those cited in a recent publication as examples of trials that represent successful reduction of the appropriate dose of anti-cancer agents. METHODS: PubMed was queried for randomized controlled trials of therapy involving immune checkpoint inhibitors in lung cancer. Trial data from studies highlighting initial success with dose adjustments after FDA approval also were assembled and analyzed according to the WTS procedure described previously, compared to clinical outcomes data. RESULTS: The WTS provided, with the clinical outcome(s), a data pair that leads to easy interpretation of the expected benefit versus relative toxicity of studies involving immunotherapy or chemoimmunotherapy in lung cancers. The WTS was consistent with the conclusions of the primary studies, helping to quantitate the toxicity difference between treatments in a previously unavailable way. CONCLUSION: The WTS provides a tool to show the cost in toxicity of therapy in a randomized clinical trial, with applicability to studies involving chemotherapy, immunotherapy, or kinase-directed therapy. Inclusion of a running tally of WTS during conduct of a trial could serve as one means to adjust dosing or to provide feedback during data safety monitoring of a clinical trial.

Development and initial validation of the AL-PROfile patient-reported outcome measure in light chain (AL) amyloidosis.

OBJECTIVE: To evaluate the psychometric properties of the AL-PROfile, a patient-reported outcome measure combining the Patient-Reported Outcomes Measurement Information System (PROMIS)-29, two items from PROMIS Cognitive Function, and select Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) items. METHODS: Content validity was assessed through cognitive debriefing interviews of 20 patients who completed the AL-PROfile (Study 1). Study 2 involved 297 participants who completed the AL-PROfile and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Reliability (internal consistency and test-retest reliability) and validity (convergent and discriminant validity, known groups validity by stage/organ involvement) were calculated. RESULTS: Study 1 participants found the AL-PROfile straightforward confirming the relevance of the included content. Some felt that certain questions were not related to their amyloidosis experience. Study 2 demonstrated acceptable internal consistency for all domains/items except PROMIS Cognitive Function and acceptable test-retest reliability for all except PROMIS Cognitive Function and PRO-CTCAE nausea. Large correlations were seen for the same domain across measures while correlations for divergent domains within a measure and different domains across different measures were small. The PRO-CTCAE items showed small to medium correlations with each other and with PROMIS and SF-36 domains. Stage was associated with physical function, fatigue, social roles, swelling, and shortness of breath scores. CONCLUSION: The AL-PROfile has acceptable reliability and validity for use in systemic light chain amyloidosis patients.

Prospective analysis of patient-reported outcomes and physician-reported outcomes with gynecologic cancer chemotherapy.

OBJECTIVE: Gynecologic cancer chemotherapy impacts the quality of life (QOL) of patients, with lasting adverse events that may require treatment adjustments or discontinuation. Consequently, real-time symptom monitoring before outpatient visits has resulted in improved QOL for patients and extended survival times. This study investigated whether there are differences between electronic patient-reported outcomes (e-PRO-CTCAE) and physician-assessed outcomes (NCI-CTCAE) evaluated in an outpatient setting in gynecologic cancer chemotherapy. METHODS: The study was conducted on 50 patients who received their first chemotherapy treatment at St. Marianna University Hospital Obstetrics and Gynecology from July 1, 2021 to December 31, 2022. PRO-CTCAE and NCI-CTCAE were evaluated at each instance of chemotherapy and 2 weeks after. The PRO-CTCAE was additionally collected weekly using e-PRO. RESULTS: The values for "Joint Pain," "Nausea," "Taste Disturbance," "Constipation," "Insomnia," "Fatigue," "Limb Edema," and "Concentration Impairment" were consistently higher in PRO-CTCAE than in NCI-CTCAE, indicating that physicians underestimated the severity of adverse events. In contrast, there was no significant difference in "Peripheral Neuropathy," demonstrating that physicians had a good understanding of this condition in patients. The weekly responses obtained from e-PRO revealed that symptom exacerbations peaked outside of clinic visits. CONCLUSIONS: This study demonstrated physicians tend to underestimate most adverse events. Moreover, the responses using e-PRO revealed peak symptom deterioration occurred outside of outpatient visits. This suggested that e-PRO and actions taken in response to them can improve patients' QOL.

Developing tumor-specific PRO-CTCAE item sets: analysis of a cross-sectional survey in three German outpatient cancer centers.

BACKGROUND: To include the patient perspective in the assessment of adverse events in oncology, a patient-reported outcomes (PRO) version of the Common Terminology Criteria for Adverse Events (CTCAE) was developed by the US National Cancer Institute, the so called PRO-CTCAE. The objective of this study was the development of disease-specific PRO-CTCAE item sets for patients with breast cancer (BC), multiple myeloma (MM), and prostate cancer (PC). METHODS: The cross-sectional survey was conducted at three German outpatient cancer centers. Prevalence and importance of the 78 PRO-CTCAE symptoms were assessed using a patient questionnaire. To select the most relevant PRO-CTCAE items for each tumor entity, symptoms were ranked based on patient answers. RESULTS: 101 patients with BC, 107 with MM, and 66 with PC participated. The final item sets contained 21 symptoms (BC) or 19 symptoms (MM and PC), respectively. Eight symptoms (fatigue, muscle pain, insomnia, joint pain, general pain, dizziness, shortness of breath, and swelling) were represented in all three item sets. Fatigue was the symptom with the highest ranking across item sets followed by insomnia. Symptoms with the highest rankings represented in only one item set were symptoms affecting the urogenital system in the PC item set, blurred vision in the BC item set, and decreased appetite in the MM item set. CONCLUSIONS: Individual PRO-CTCAE item sets for a German patient population were developed for the three tumor entities on the basis of patients' differences in symptom profiles and perceptions. The quality and psychometric criteria of the newly compiled item sets should be evaluated in validation studies.

Patient-reported outcome measures for emotional functioning in cancer patients: Content comparison of the EORTC CAT Core, FACT-G, HADS, SF-36, PRO-CTCAE, and PROMIS instruments.

BACKGROUND: Cancer and its treatment can have substantial impact on patients' emotional functioning. Several patient-reported outcome measures (PROMs) assessing emotional functioning are available, but differences in content limit the comparability of results. To better understand conceptual (dis)similarities, we conducted a content comparison of commonly used PROMs. METHODS: We included emotional functioning items, scales, and item banks from the EORTC CAT Core, EORTC QLQ-C30, FACT-G, Hospital anxiety and depression scale (HADS), SF-36, PRO-CTCAE, and PROMIS (item banks for anxiety, depression, and anger). Item content was linked to the International Classification of Functioning, Disability, and Health (ICF) and a hierarchical framework established for PROMIS. Single items could be coded with more than one ICF category but were solely assigned to one facet within the PROMIS framework. RESULTS: The measures comprise 132 unique items covering the ICF components 'Body functions' (136/153 codings, 88.9%) and 'Activities and participation' (15/153, 9.8%). Most ICF codings (112/153, 73.2%) referred to the third-level category 'b1528 Emotional functions, other specified'. According to the PROMIS framework 48.5% of the items assessed depression (64/132 items), followed by anxiety (41/132, 31.1%) and anger (26/132, 19.7%). The EORTC measures covered depression, anxiety, and anger in a single measure, while the PROMIS inventory provides separate item banks for these concepts. The FACT-G, SF-36, PRO-CTCAE and HADS covered depression and anxiety, but not anger. CONCLUSION: Our results provide an in-depth conceptual understanding of selected PROMs and important qualitative information going beyond psychometric evidence. Such information supports the identification of PROMs for which scores can be meaningfully linked with quantitative methods.

Efficacy of the PRO-CTCAE mobile application for improving patient participation in symptom management during cancer treatment: a randomized controlled trial.

PURPOSE: Although mobile-based symptom monitoring is expected to improve patient participation in symptom management during anticancer therapy, previous trials have not evaluated its effectiveness. Therefore, this study aims to evaluate the impact of a symptom monitoring mobile application on improving patient participation in symptom management during anticancer therapy. METHODS: We conducted a single-center, open-label, randomized controlled trial that enrolled patients with breast, lung, head and neck, esophageal, or gynecologic cancer who were scheduled to receive anticancer therapy (oral or intravenous) between October 2020 and March 2021. We excluded patients with physical or psychological problems. The intervention group received a symptom monitoring application for 8 weeks, and the control group received the usual clinical practice. At 8 weeks, the improvement in patient participation in symptom management was assessed, and additionally quality of life and unplanned clinical visits were assessed. RESULTS: A total of 222 patients were included in the analysis, of whom 142 were randomly assigned to the intervention group and 71 to the control group. The intervention group reported better outcome in patient participation in symptom management than the control group at 8 weeks (mean scores of 8.5 vs. 8.0; P = 0.01). There were no significant differences between the groups in Quality of life (P = 0.88) and unplanned clinical visits (P = 0.39-0.76). CONCLUSIONS: This study is meaningful in figuring out that the mobile-based symptom monitoring made them more engaged in their management. Future research should continue to evaluate the effects of patient participation as mediators of clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04568278.

Reliability and validity of PRO-CTCAE® daily reporting with a 24-hour recall period.

PURPOSE: The standard recall period for the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE®) is the past 7 days, but there are contexts where a 24-hour recall may be desirable. The purpose of this analysis was to investigate the reliability and validity of a subset of PRO-CTCAE items captured using a 24-hour recall. METHODS: 27 PRO-CTCAE items representing 14 symptomatic adverse events (AEs) were collected using both a 24-hour recall (24 h) and the standard 7 day recall (7d) in a sample of patients receiving active cancer treatment (n = 113). Using data captured with a PRO-CTCAE-24h on days 6 and 7, and 20 and 21, we computed intra-class correlation coefficients (ICC); an ICC ≥ 0.70 was interpreted as demonstrating high test-retest reliability. Correlations between PRO-CTCAE-24h items on day 7 and conceptually relevant EORTC QLQ-C30 domains were examined. In responsiveness analysis, patients were deemed changed if they had a one-point or greater change in the corresponding PRO-CTCAE-7d item (from week 0 to week 1). RESULTS: PRO-CTCAE-24h captured on two consecutive days demonstrated that 21 of 27 items (78%) had ICCs ≥ 0.70 (day 6/7 median ICC 0.76), (day 20/21 median ICC 0.84). Median correlation between attributes within a common AE was 0.75, and the median correlation between conceptually relevant EORTC QLQ-C30 domains and PRO-CTCAE-24 h items captured on day 7 was 0.44. In the analysis of responsiveness to change, the median standardized response mean (SRM) for patients with improvement was - 0.52 and that for patients with worsening was 0.71. CONCLUSION: A 24-hour recall period for PRO-CTCAE items has acceptable measurement properties and can inform day-to-day variations in symptomatic AEs when daily PRO-CTCAE administration is implemented in a clinical trial.

Identifying meaningful change on PROMIS short forms in cancer patients: a comparison of item response theory and classic test theory frameworks.

BACKGROUND: This study compares classical test theory and item response theory frameworks to determine reliable change. Reliable change followed by anchoring to the change in categorically distinct responses on a criterion measure is a useful method to detect meaningful change on a target measure. METHODS: Adult cancer patients were recruited from five cancer centers. Baseline and follow-up assessments at 6 weeks were administered. We investigated short forms derived from PROMIS® item banks on anxiety, depression, fatigue, pain intensity, pain interference, and sleep disturbance. We detected reliable change using reliable change index (RCI). We derived the T-scores corresponding to the RCI calculated under IRT and CTT frameworks using PROMIS® short forms. For changes that were reliable, meaningful change was identified using patient-reported change in PRO-CTCAE by at least one level. For both CTT and IRT approaches, we applied one-sided tests to detect reliable improvement or worsening using RCI. We compared the percentages of patients with reliable change and reliable/meaningful change. RESULTS: The amount of change in T score corresponding to RCICTT of 1.65 ranged from 5.1 to 9.2 depending on domains. The amount of change corresponding to RCIIRT of 1.65 varied across the score range, and the minimum change ranged from 3.0 to 8.2 depending on domains. Across domains, the RCICTT and RCIIRT classified 80% to 98% of the patients consistently. When there was disagreement, the RCIIRT tended to identify more patients as having reliably changed compared to RCICTT if scores at both timepoints were in the range of 43 to 78 in anxiety, 45 to 70 in depression, 38 to 80 in fatigue, 35 to 78 in sleep disturbance, and 48 to 74 in pain interference, due to smaller standard errors in these ranges using the IRT method. The CTT method found more changes compared to IRT for the pain intensity domain that was shorter in length. Using RCICTT, 22% to 66% had reliable change in either direction depending on domains, and among these patients, 62% to 83% had meaningful change. Using RCIIRT, 37% to 68% had reliable change in either direction, and among these patients, 62% to 81% had meaningful change. CONCLUSION: Applying the two-step criteria demonstrated in this study, we determined how much change is needed to declare reliable change at different levels of baseline scores. We offer reference values for percentage of patients who meaningfully change for investigators using the PROMIS instruments in oncology.

Simulation study comparing analytical methods for single-item longitudinal patient-reported outcomes data.

PURPOSE: Efficient analytical methods are necessary to make reproducible inferences on single-item longitudinal ordinal patient-reported outcome (PRO) data. A thorough simulation study was performed to compare the performance of the semiparametric probabilistic index models (PIM) with a longitudinal analysis using parametric cumulative logit mixed models (CLMM). METHODS: In the setting of a control and intervention arm, we compared the power of the PIM and CLMM to detect differences in PRO adverse event (AE) between these groups using several existing and novel summary scores of PROs. For each scenario, PRO data were simulated using copula multinomial models. Comparisons were also exemplified using clinical trial data. RESULTS: On average, CLMM provided substantially greater power than the PIM to detect differences in PRO-AEs between the groups when the baseline-adjusted method was used, and a small advantage in power when using the baseline symptom as a covariate. CONCLUSION: Although the CLMM showed the best performance among analytical methods, it relies on assumptions difficult to verify and that might not be fulfilled in the real world, therefore our recommendation is the use of PIM models with baseline symptom as a covariate.

Correlation Between Remote Symptom Reporting by Caregivers and Adverse Clinical Outcomes: Mixed Methods Study.

BACKGROUND: Timely collection of patient-reported outcomes (PROs) decreases emergency department visits and hospitalizations and increases survival. However, little is known about the outcome predictivity of unpaid informal caregivers' reporting using similar clinical outcome assessments. OBJECTIVE: The aim of this study is to assess whether caregivers and adults with cancer adhered to a planned schedule for electronically collecting patient-reported outcomes (PROs) and if PROs were associated with future clinical events. METHODS: We developed 2 iPhone apps to collect PROs, one for patients with cancer and another for caregivers. We enrolled 52 patient-caregiver dyads from Kaiser Permanente Northern California in a nonrandomized study. Participants used the apps independently for 4 weeks. Specific clinical events were obtained from the patients' electronic health records up to 6 months following the study. We used logistic and quasi-Poisson regression analyses to test associations between PROs and clinical events. RESULTS: Participants completed 97% (251/260) of the planned Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) surveys and 98% (254/260) of the Patient-Reported Outcomes Measurement Information System (PROMIS) surveys. PRO-CTCAE surveys completed by caregivers were associated with patients' hospitalizations or emergency department visits, grade 3-4 treatment-related adverse events, dose reductions (P<.05), and hospice referrals (P=.03). PROMIS surveys completed by caregivers were associated with hospice referrals (P=.02). PRO-CTCAE surveys completed by patients were not associated with any clinical events, but their baseline PROMIS surveys were associated with mortality (P=.03), while their antecedent or final PROMIS surveys were associated with all clinical events examined except for total days of treatment breaks. CONCLUSIONS: In this study, caregivers and patients completed PROs using smartphone apps as requested. The association of caregiver PRO-CTCAE surveys with patient clinical events suggests that this is a feasible approach to reducing patient burden in clinical trial data collection and may help provide early information about increasing symptom severity.

Patient self-reporting of tolerability using PRO-CTCAE in a randomized double-blind, placebo-controlled phase II trial comparing gemcitabine in combination with adavosertib or placebo in patients with platinum resistant or refractory epithelial ovarian carcinoma.

BACKGROUND: A double-blind, randomized, placebo-controlled, phase 2 trial assessed gemcitabine in combination with the wee1 inhibitor adavosertib or placebo in platinum resistant or refractory high grade serous ovarian cancer (HGSOC), demonstrating improved progression free and overall survival favouring the adavosertib/gemcitabine arm. An exploratory objective of the study included the PRO-CTCAE assessment, to capture self-reporting of frequency, severity and/or interference of symptomatic adverse events (syAEs). METHODS: PRO-CTCAE items at baseline, days 1 and 15 of each cycle and off treatment, were completed in two centres, with the objective of characterizing syAEs in the first three months of therapy. The maximum post-baseline score proportion for each syAE was tabulated per patient. The 12-week area under the curve (AUC12w) as a measure of syAE over-time and incremental AUC12w (iAUC12w) for adjustment to baseline syAEs. RESULTS: Sixty-one patients were approached for PRO-CTCAE surveys and 55 were evaluable. Among patients with HGSOC, 28 received gemcitabine/adavosertib (arm A) and 19 gemcitabine/placebo (arm B). Survey completion rates were high. The proportion of participants with positive (≥1) PRO-CTCAE scores was higher for difficulty swallowing with gemcitabine/adavosertib (arm A 35.7% vs arm B 5.3%, p = 0.02). The high score (≥3) syAEs showed more frequent diarrhea with gemcitabine/adavosertib (arm A 25% vs arm B 0%, p = 0.03). The proportions of worsening syAEs over time were higher in patients receiving gemcitabine/adavosertib for difficulty swallowing (arm A 35.7% vs arm B 5.3%; p = 0.03) and fatigue severity (arm A 71.43% vs arm B 42.1%; p = 0.04). CONCLUSIONS: The longitudinal assessment of patient self-reported tolerability showed greater difficulty swallowing and fatigue severity in patients receiving gemcitabine/adavosertib, compared to gemcitabine/placebo. PRO-CTCAE provides complementary and objective assessment of drug tolerability from a patient's perspective.

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.

PURPOSE: Missing 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. METHODS: In 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. RESULTS: PRO-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. CONCLUSION: For 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).

Effects of patient-reported outcome assessment order.

BACKGROUND: In clinical trials and clinical practice, patient-reported outcomes are almost always assessed using multiple patient-reported outcome measures at the same time. This raises concerns about whether patient responses are affected by the order in which the patient-reported outcome measures are administered. METHODS: This questionnaire-based study of order effects included adult cancer patients from five cancer centers. Patients were randomly assigned to complete questionnaires via paper booklets, interactive voice response system, or tablet web survey. Linear Analogue Self-Assessment, Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events, and Patient-Reported Outcomes Measurement Information System assessment tools were each used to measure general health, physical function, social function, emotional distress/anxiety, emotional distress/depression, fatigue, sleep, and pain. The order in which the three tools, and domains within tools, were presented to patients was randomized. Rates of missing data, scale scores, and Cronbach's alpha coefficients were compared by the order in which they were assessed. Analyses included Cochran-Armitage trend tests and mixed models adjusted for performance score, age, sex, cancer type, and curative intent. RESULTS: A total of 1830 patients provided baseline patient-reported outcome assessments. There were no significant trends in rates of missing values by whether a scale was assessed earlier or later. The largest order effect for scale scores was due to a large mean score at one assessment time point. The largest difference in Cronbach's alpha between the versions for the Patient-Reported Outcomes Measurement Information System scales was 0.106. CONCLUSION: The well-being of a cancer patient has many different aspects such as pain, fatigue, depression, and anxiety. These are assessed using a variety of surveys often collected at the same time. This study shows that the order in which the different aspects are collected from the patient is not important.

Timing is everything: The importance of patient-reported outcome assessment frequency when characterizing symptomatic adverse events.

OBJECTIVE: Although patient-reported symptoms and side effects are increasingly measured in cancer clinical trials, an appropriate assessment frequency has not yet been established. To determine whether differences in assessment frequency affect the apparent incidence and severity of patient-reported symptoms using two well-established patient-reported outcome measures used within the same clinical trial. METHODS: We examined patient-reported outcome results from AURA3 (NCT02151981), a randomized open-label study comparing Tagrisso (osimertinib) with platinum-based chemotherapy in patients with previously treated estimated glomerular filtration rate/T790M mutation-positive metastatic non-small cell lung cancer. The outcome of interest was the proportion of patients in each arm that reported worsening of nausea, vomiting, fatigue, diarrhea, constipation, and appetite loss from baseline measured using the patient-reported outcome-common terminology criteria for adverse event (weekly) or European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (every 6 weeks). RESULTS: Similar trends were observed for all six symptoms investigated. Using nausea in the chemotherapy arm as an example, 76% of patients reported any worsening from baseline based on weekly patient-reported outcome-common terminology criteria for adverse event assessments. When using an every 6-week assessment of Quality of Life Questionnaire Core 30 nausea and restricting analysis to an every 6-week assessment for patient-reported outcome-common terminology criteria for adverse event nausea, the proportion of chemotherapy arm patients reporting any worsening of nausea was 40% for both measures. Across the six patient-reported symptomatic adverse events, we observed differential proportions when comparing frequent versus sparse assessment. CONCLUSION: This analysis demonstrates that more frequent assessment of patient-reported symptomatic adverse events will lead to improved detection, and therefore a more complete understanding of the tolerability of experimental anti-cancer therapies.

A dynamic portrait of adverse events for breast cancer patients: results from a phase II clinical trial of eribulin in advanced HER2-negative breast cancer.

PURPOSE: Adverse events (AE) during oncology clinical trials are typically reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), which provides information about the frequency and severity of AEs from the provider's perspective. Instruments that track patient-reported outcomes (PRO) complement the CTCAE and provide additional patient-centered information about the toxicity profile of an anti-cancer drug. METHODS: We conducted a single-arm, open-label phase II study of eribulin as first- or second-line therapy for metastatic hormone receptor-positive/HER2-negative (HR+/HER2-) or triple-negative breast cancer (TNBC). Patients were recruited simultaneously into each cohort by tumor subtype. The primary endpoint was overall response rate (ORR). Secondary endpoints included evaluation of toxicity by CTCAE and PRO instruments and agreement between CTCAE and PRO. The study also investigated single-nucleotide polymorphisms (SNPs) associated with treatment-induced neurotoxicity. RESULTS: 83 patients were enrolled: 45 into the HR+/HER2- cohort and 38 into the TNBC cohort. The ORR was 35.6% (90% CI 24-39%) in the HR+/HER2- cohort and 13.2% (90% CI 5-26%) in the TNBC cohort. Stable disease as the best response was recorded in 55.1% of patients with HR+/HER2- disease and 60.5% with TNBC. Toxicity analysis revealed a discordance between CTCAE and PRO assessment in many patients, with a focus on fatigue, alopecia, and neuropathy. Pharmacogenomic analysis identified SNPs associated with treatment-induced peripheral neuropathy. CONCLUSIONS: Eribulin is active in HER2- breast cancer. This study reveals that provider-assessed AEs can vary greatly from patient experiences. Future studies should incorporate CTCAE and PRO instruments to improve reporting of treatment-related AEs. ClinicalTrials.gov Registration: NCT01827787.

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

BACKGROUND: The 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 METHODS: A 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). RESULTS: Data 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. CONCLUSION: The simplified Chinese version of the PRO-CTCAE showed good reliability, validity, and responsiveness.

Linguistic validation of the simplified Chinese version of the US National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE™).

BACKGROUND: The aim of this study was to translate and linguistically validate the U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) into Simplified Chinese for use in Singapore. METHODS: All 124 items of the English source PRO-CTCAE item library were translated into Simplified Chinese using internationally established translation procedures. Two rounds of cognitive interviews were conducted with 96 cancer patients undergoing adjuvant treatment to determine if the translations adequately captured the PRO-CTCAE source concepts, and to evaluate comprehension, clarity and ease of judgement. Interview probes addressed the 78 PRO-CTCAE symptom terms (e.g. fatigue), as well as the attributes (e.g. severity), response choices, and phrasing of 'at its worst'. Items that met the a priori threshold of ≥20% of participants with comprehension difficulties were considered for rephrasing and retesting. Items where < 20% of the sample experienced comprehension difficulties were also considered for rephrasing if better phrasing options were available. RESULTS: A majority of PRO-CTCAE-Simplified Chinese items were well comprehended by participants in Round 1. One item posed difficulties in ≥20% and was revised. Two items presented difficulties in < 20% but were revised as there were preferred alternative phrasings. Twenty-four items presented difficulties in < 10% of respondents. Of these, eleven items were revised to an alternative preferred phrasing, four items were revised to include synonyms. Revised items were tested in Round 2 and demonstrated satisfactory comprehension. CONCLUSIONS: PRO-CTCAE-Simplified Chinese has been successfully developed and linguistically validated in a sample of cancer patients residing in Singapore.

Clinicians versus patients subjective adverse events assessment: based on patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE).

PURPOSE: Adverse events (AEs) assessment by clinicians is a standard practice in a clinical setting. However, studies have found clinicians tend to report fewer AEs, especially subjective AEs. We aimed to explore the difference of subjective AEs assessment between clinicians and patients based on PRO-CTCAE, and to discuss the necessity of incorporating patient into the evaluation of AEs. METHODS: Between April and July 2019, two different questionnaires with the same subjective AEs were given to patients and clinicians in the Day Chemotherapy ward of Breast Center in the Fourth Hospital of HeBei Medical University. Patients completed a Simplified Chinese version of PRO-CTCAE, including six common subjective AEs of chemotherapy: nausea, vomiting, diarrhea, fatigue, pain, and constipation. Clinicians completed the common terminology criteria for adverse events (CTCAE) with the same AEs. General information of enrolled patients and results from the questionnaires were collected and analyzed. RESULTS: 384 paired questionnaires were collected. Clinicians reported less subjective AEs than patients, and the general agreement between patients and clinicians was poor. When considering the grade difference, we utilize weighted kappa coefficient to analysis, and agreement between patients and clinicians was poor (k < 0.4) regardless of the frequency, the severity and interfering with daily life of AEs, and the most discrepancies were within one point. Patients tended to grade severer than the clinician. CONCLUSIONS: The results of this study showed that there were differences between clinicians and patients in subjective adverse events evaluation. Patient reporting of symptoms can be used as a supplementary method to incorporate the current approach to monitor subjective AEs, to improve the timeliness and accuracy of clinical evaluation of subjective AEs.

Patient-Reported Outcomes During Immunotherapy for Metastatic Melanoma: Mixed Methods Study of Patients' and Clinicians' Experiences.

BACKGROUND: The benefits of electronic patient reported outcomes (PRO) questionnaires have been demonstrated in many settings, including in hospitals and patient homes. However, it remains to be investigated how melanoma patients and their treating clinicians experience the electronic self-reporting of side effects and the derived communication. OBJECTIVE: The primary objective of this study was to examine patients' and clinicians' experiences with an eHealth intervention for weekly monitoring of side effects during treatment with immunotherapy. METHODS: An eHealth intervention based on questions from the PRO-Common Terminology Criteria for Adverse Events (CTCAE) library was used and tested in a randomized clinical trial with patients receiving immunotherapy for malignant melanoma and clinicians at a university hospital in Denmark. On a weekly basis, patients reported their symptoms from home during the treatment via a provided tablet. The electronic patient reports were available to clinicians in the outpatient clinic. A mixed methods approach was applied to investigate the patients' and clinicians' experiences with the intervention. Data from patient experiences were collected in a short survey, the Patient Feedback Form. Moreover, a subset of the patients participating in the survey was interviewed about their experience. Furthermore, one focus group interview with clinicians was carried out to elucidate their views. RESULTS: A total of 57 patients completed the Patient Feedback Form, and 14 patients were interviewed. The focus group interview included 5 clinicians. Overall, patients and clinicians were satisfied with the tool. They believed it enhanced patients' awareness of side effects and increased their feeling of involvement. The patients reported that it was easy to fill out the questionnaire and that it made sense to do so. However, a minority of the patients expressed in the interviews that they did not believe that the health care professionals had seen their reports when they came to the clinic, and that the reporting did not lead to increased contact with the department. CONCLUSIONS: Overall, satisfaction with the eHealth intervention was high among patients and their treating clinicians. The tool was easy to use and contributed to greater symptom awareness and patient involvement. Thus, in terms of patient and clinician satisfaction with the tool, it makes sense to continue using the tool beyond the project period. TRIAL REGISTRATION: ClinicalTrials.gov NCT03073031; https://tinyurl.com/tjx3gtu.