Clinician vs Patient Reporting of Baseline and Postbaseline Symptoms for Adverse Event Assessment in Cancer Clinical Trials

Many patients enter cancer clinical trials with baseline symptoms. Notably, the current clinician reporting mechanism for symptomatic adverse events (AEs) via the Common Terminology Criteria for Adverse Events (CTCAE) does not formally distinguish between symptoms present at baseline vs those that develop during a trial. Therefore, AE estimation in clinical trials may include symptoms that predate trial entry. This raises concern that the cumulative incidence of patient-reported AEs may be high, particularly if preexisting symptoms related to other causes (eg, comorbidities, prior treatment) are attributed to study drugs

An Exploratory Analysis of the “Was It Worth It?” Questionnaire as a Novel Metric to Capture Patient Perceptions of Cancer Treatment

Objectives: Asking “Was it worth it?” (WIWI) potentially captures the patient perception of a treatment's benefit weighed against its harms. This exploratory analysis evaluates the WIWI questionnaire as a metric of patients’ perspectives on the worthwhileness of cancer treatment. Methods: A 3-item WIWI questionnaire was assessed at end of treatment in patients with cancer on the COMET-2 trial (NCT01522443). WIWI items were evaluated to determine their association with quality of life (QOL), treatment duration, end-of-treatment reason, patient-reported adverse events (AEs), and disease response. Results: A total of 65 patients completed the questionnaire; 40 (62%), 16 (25%), and 9 (14%) patients replied yes, uncertain, and no to “Was it worthwhile for you to receive the cancer treatment given in this study?” (item 1), respectively; 39 (60%), 12 (18%), and 14 (22%) to “If you had to do it over again, would you choose to have this cancer treatment?”; and 40 (62%), 14 (22%), and 11 (17%) to “Would you recommend this cancer treatment to others?” Patients responding yes to item 1 remained on treatment longer than those responding uncertain or no (mean 23.0 vs 11.3 weeks, P<.001). Patients responding uncertain/no to item 1 discontinued treatment because of AEs more frequently than those responding yes (36% vs 7.5%, P=.004) and demonstrated meaningful decline in QOL from baseline (−2.5 vs −0.2 mean change, P<.001). Associations between WIWI responses and most patient-reported AEs or treatment efficacy did not reach statistical significance. Conclusions: Patients who responded affirmatively on WIWI items remained on therapy longer, were less likely to stop treatment because of AEs, and demonstrated superior QOL. The WIWI may inform clinical practice, oncology research, and value frameworks

Composite grading algorithm for the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Background: The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events is an item library designed for eliciting patient-reported adverse events in oncology. For each adverse event, up to three individual items are scored for frequency, severity, and interference with daily activities. To align the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events with other standardized tools for adverse event assessment including the Common Terminology Criteria for Adverse Events, an algorithm for mapping individual items for any given adverse event to a single composite numerical grade was developed and tested. Methods: A five-step process was used: (1) All 179 possible Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events score combinations were presented to 20 clinical investigators to subjectively map combinations to single numerical grades ranging from 0 to 3. (2) Combinations with <75% agreement were presented to investigator committees at a National Clinical Trials Network cooperative group meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability, and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating adverse events between study arms was measured in two Phase III clinical trials (NCT02066181 and NCT01522443). Results: In Step 1, 12/179 score combinations had <75% initial agreement. In Step 2, majority consensus was reached for all combinations. In Step 3, five grades were adjusted to assure directional consistency. In Steps 4 and 5, composite grades performed well and comparably to individual item scores on validity, reliability, sensitivity, and between-arm delineation. Conclusion: A composite grading algorithm has been developed and yields single numerical grades for adverse events assessed via the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, and can be useful in analyses and reporting

Evaluating Treatment Tolerability Using the Toxicity Index With Patient-Reported Outcomes Data

Context: Summarizing longitudinal symptomatic adverse events during clinical trials is necessary for understanding treatment tolerability. The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) provides insight for capturing treatment tolerability within trials. Tolerability summary measures, such as the maximum score, are often used to communicate the potential negative symptoms both in the medical literature and directly to patients. Commonly, the proportions of present and severe symptomatic adverse events are used and reported between treatment arms among adverse event types. The toxicity index is also a summary measure previously applied to clinician-reported CTCAE data. Objectives: Apply the toxicity index to PRO-CTCAE data from the COMET-2 trial alongside the maximum score, then present and discuss considerations for using the toxicity index as a summary measure for communicating tolerability to patients and clinicians. Methods: Proportions of maximum PRO-CTCAE severity levels and median toxicity index were computed by arm using all trial data and adjusting for baseline symptoms. Results: Group-wise statistical differences were similar whether using severity level proportions or the toxicity index. The impact of adjusting for baseline symptoms was equivalently seen when comparing arms using severity rates or the toxicity index. Conclusion: The toxicity index is a useful method when ranking patients from those with the least to most symptomatic adverse event burden. This study showed the toxicity index can be applied to PRO-CTCAE data. Though as a tolerability summary measure, further study is needed to provide a clear clinical or patient-facing interpretation of the toxicity index

Electronic Patient Reporting of Adverse Events and Quality of Life: A Prospective Feasibility Study in General Oncology

PURPOSE: Adverse event (AE) reporting is essential in clinical trials. Clinician interpretation can result in under-reporting; therefore, the value of patient self-reporting has been recognized. The National Cancer Institute has developed a Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for direct patient AE reporting. A nonrandomized prospective cohort feasibility study aimed to explore the compliance and acceptability of an electronic (Internet or telephone) system for collecting patient self-reported AEs and quality of life (QOL). METHODS: Oncology patients undergoing treatment (chemotherapy, targeted agents, hormone therapy, radiotherapy, and/or surgery) at 2 hospitals were sent automated weekly reminders to complete PRO-CTCAE once a week and QOL (for a maximum of 12 weeks). Patients had to speak/understand English and have access to the Internet or a touch-tone telephone. Primary outcome was compliance (proportion of expected questionnaires), and recruitment rate, attrition, and patient/staff feedback were also explored. RESULTS: Of 520 patients, 249 consented (47.9%)—mean age was 62 years, 51% were male, and 70% were married—and 230 remained on the study at week 12. PRO-CTCAE was completed at 2,301 (74.9%) of 3,074 timepoints and QOL at 749 (79.1%) of 947 timepoints. Individual weekly/once every 4 weeks compliance reduced over time but was more than 60% throughout. Of 230 patients, 106 (46.1%) completed 13 or more PRO-CTCAE, and 136 (59.1%) of 230 patients completed 4 QOL questionnaires. Most were completed on the Internet (82.3%; mean age, 60.8 years), which was quicker, but older patients preferred the telephone option (mean age, 70.0 years). Positive feedback was received from patients and staff. CONCLUSION: Self-reporting of AEs and QOL using an electronic home-based system is feasible and acceptable. Implementation of this approach in cancer clinical trials may improve the precision and accuracy of AE reporting

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)

Overcoming the barriers of teaching physical examination at the bedside: More than just curriculum design

Background: Physicians in training must achieve a high degree of proficiency in performing physical examinations and must strive to become experts in the field. Concerns are emerging about physicians' abilities to perform these basic skills, essential for clinical decision making. Learning at the bedside has the potential to support skill acquisition through deliberate practice. Previous skills improvement programs, targeted at teaching physical examinations, have been successful at increasing the frequency of performing and teaching physical examinations. It remains unclear what barriers might persist after such program implementation. This study explores residents' and physicians' perceptions of physical examinations teaching at the bedside following the implementation of a new structured bedside curriculum: What are the potentially persisting barriers and proposed solutions for improvement? Methods: The study used a constructivist approach using a qualitative inductive thematic analysis that was oriented to construct an understanding of the barriers and facilitators of physical examination teaching in the context of a new bedside curriculum. Participants took part in individual interviews and subsequently focus groups. Transcripts were coded and themes were identified. Results: Data analyses yielded three main themes: (1) the culture of teaching physical examination at the bedside is shaped and threatened by the lack of hospital support, physicians' motivation and expertise, residents' attitudes and dependence on technology, (2) the hospital environment makes bedside teaching difficult because of its chaotic nature, time constraints and conflicting responsibilities, and finally (3) structured physical examination curricula create missed opportunities in being restrictive and pose difficulties in identifying patients with findings. Conclusions: Despite the implementation of a structured bedside curriculum for physical examination teaching, our study suggests that cultural, environmental and curriculum-related barriers remain important issues to be addressed. Institutions wishing to develop and implement similar bedside curricula should prioritize recruitment of expert clinical teachers, recognizing their time and efforts. Teaching should be delivered in a protected environment, away from clinical duties, and with patients with real findings. Physicians must value teaching and learning of physical examination skills, with multiple hands-on opportunities for direct role modeling, coaching, observation and deliberate practice. Ideally, clinical teachers should master the art of combining both patient care and educational activities

Clinical Utility and User Perceptions of a Digital System for Electronic Patient-Reported Symptom Monitoring during Routine Cancer Care: Findings from the PRO-TECT Trial

PURPOSE There is increasing interest in implementing digital systems for remote monitoring of patients’ symptoms during routine oncology practice. Information is limited about the clinical utility and user perceptions of these systems. METHODS PRO-TECT is a multicenter trial evaluating implementation of electronic patient-reported outcomes (ePROs) among adults with advanced and metastatic cancers receiving treatment at US community oncology practices (ClinicalTrials.gov identifier: NCT03249090). Questions derived from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) are administered weekly by web or automated telephone system, with alerts to nurses for severe or worsening symptoms. To elicit user feedback, surveys were administered to participating patients and clinicians. RESULTS Among 496 patients across 26 practices, the majority found the system and questions easy to understand (95%), easy to use (93%), and relevant to their care (91%). Most patients reported that PRO information was used by their clinicians for care (70%), improved discussions with clinicians (73%), made them feel more in control of their own care (77%), and would recommend the system to other patients (89%). Scores for most patient feedback questions were significantly positively correlated with weekly PRO completion rates in both univariate and multivariable analyses. Among 57 nurses, most reported that PRO information was helpful for clinical documentation (79%), increased efficiency of patient discussions (84%), and was useful for patient care (75%). Among 39 oncologists, most found PRO information useful (91%), with 65% using PROs to guide patient discussions sometimes or often and 65% using PROs to make treatment decisions sometimes or often. CONCLUSION These findings support the clinical utility and value of implementing digital systems for monitoring PROs, including the PRO-CTCAE, in routine cancer care

Informing the Tolerability of Cancer Treatments Using Patient-Reported Outcome Measures: Summary of an FDA and Critical Path Institute Workshop

The US Food and Drug Administration and the Critical Path Institute’s Patient-Reported Outcome (PRO) Consortium convened a cosponsored workshop on the use of PRO measures to inform the assessment of safety and tolerability in cancer clinical trials. A broad array of international stakeholders involved in oncology drug development and PRO measurement science provided perspectives on the role of PRO measures to provide complementary clinical data on the symptomatic side effects of anticancer agents. Speakers and panelists explored the utility of information derived from existing and emerging PRO measures, focusing on the PRO version of the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Panelists and speakers discussed potential ways to improve the collection, analysis, and presentation of PRO data describing symptomatic adverse events to support drug development and better inform regulatory and treatment decisions. Workshop participants concluded the day with a discussion of possible approaches to the patient-reported assessment of an investigational drug’s overall side effect burden as a potential clinical trial end point. The Food and Drug Administration reiterated its commitment to collaborate with international drug development stakeholders to identify rigorous methods to incorporate the patient perspective into the development of cancer therapeutics