Diane St. Germain

Development of the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

The standard approach for documenting symptomatic adverse events (AEs) in cancer clinical trials involves investigator reporting using the National Cancer Institutes (NCIs) Common Terminology Criteria for Adverse Events (CTCAE). Because this approach underdetects symptomatic AEs, the NCI issued two contracts to create a patient-reported outcome (PRO) measurement system as a companion to the CTCAE, called the PRO-CTCAE. This Commentary describes development of the PRO-CTCAE by a group of multidisciplinary investigators and patient representatives and provides an overview of qualitative and quantitative studies of its measurement properties. A systematic evaluation of all 790 AEs listed in the CTCAE identified 78 appropriate for patient self-reporting. For each of these, a PRO-CTCAE plain language term in English and one to three items characterizing the frequency, severity, and/or activity interference of the AE were created, rendering a library of 124 PRO-CTCAE items. These items were refined in a cognitive interviewing study among patients on active cancer treatment with diverse educational, racial, and geographic backgrounds. Favorable measurement properties of the items, including construct validity, reliability, responsiveness, and between-mode equivalence, were determined prospectively in a demographically diverse population of patients receiving treatments for many different tumor types. A software platform was built to administer PRO-CTCAE items to clinical trial participants via the internet or telephone interactive voice response and was refined through usability testing. Work is ongoing to translate the PRO-CTCAE into multiple languages and to determine the optimal approach for integrating the PRO-CTCAE into clinical trial workflow and AE analyses. It is envisioned that the PRO-CTCAE will enhance the precision and patient-centeredness of adverse event reporting in cancer clinical research.

Racial/ethnic differences in clinical trial enrollment, refusal rates, ineligibility, and reasons for decline among patients at sites in the National Cancer Institute's Community Cancer Centers Program

This study examined racial/ethnic differences among patients in clinical trial (CT) enrollment, refusal rates, ineligibility, and desire to participate in research within the National Cancer Institutes Community Cancer Centers Program (NCCCP) Clinical Trial Screening and Accrual Log.

Quality of life and pain in premenopausal women with major depressive disorder: The POWER Study

BackgroundWhereas it is established that organic pain may induce depression, it is unclear whether pain is more common in healthy subjects with depression. We assessed the prevalence of pain in premenopausal women with major depression (MDD). Subjects were 21- to 45-year-old premenopausal women with MDD (N = 70; age: 35.4 +/- 6.6; mean +/- SD) and healthy matched controls (N = 36; age 35.4 +/- 6.4) participating in a study of bone turnover, the P.O.W.E.R. (P remenopausal, O steopenia/Osteoporosis, W omen, Ale ndronate, Depr ession) Study.MethodsPatients received a clinical assessment by a pain specialist, which included the administration of two standardized forms for pain, the Brief Pain Inventory – Short Form, and the Initial Pain Assessment Tool, and two scales of everyday stressors, the Hassles and Uplifts Scales. In addition, a quality-of-life instrument, the SF-36, was used. The diagnosis of MDD was established by a semi-structured interview, according to the DSM-IV criteria. Substance P (SP) and calcitonin-gene-related-peptide (CGRP), neuropeptides which are known mediators of pain, were measured every hour for 24 h in a subgroup of patients (N = 17) and controls (N = 14).ResultsApproximately one-half of the women with depression reported pain of mild intensity. Pain intensity was significantly correlated with the severity of depression (r2 = 0.076; P = 0.04) and tended to be correlated with the severity of anxiety, (r2 = 0.065; P = 0.07), and the number of depressive episodes (r2 = 0.072; P = 0.09). Women with MDD complained of fatigue, insomnia, and memory problems and experienced everyday negative stressors more frequently than controls. Quality of life was decreased in women with depression, as indicated by lower scores in the emotional and social well-being domains of the SF-36. SP (P < 0.0003) and CGRP (P < 0.0001) were higher in depressed subjects.ConclusionWomen with depression experienced pain more frequently than controls, had a lower quality of life, and complained more of daily stressors. Assessment of pain may be important in the clinical evaluation of women with MDD. SP and CGRP may be useful biological markers in women with MDD.

Improved Outcomes in the Malnourished Patient: We’re Not There Yet

Malnutrition in the setting of cancer treatment is often foreboding and for good reasons, as it is an independent predictor of poor outcomes (ie, decreased survival, poor response to cancer therapies, increased symptomatology, and impaired functional abilities). Nor is the scope of the problem insignificant, as it has been estimated that when malnutrition progresses to cachexia, it accounts for approximately 30% of cancer-related deaths overall (1,2). Treating malnutrition and ideally preventing its unrelenting transition to cancer cachexia is a goal that clinicians have been seeking for decades. Despite the array of oral therapies available, not all patients will benefit, either in improved survival or improved quality of life (QOL). Several systematic reviews during the past decades have shown that a number of considerations must be taken into account when treating patients at risk for or suffering from cancer-related malnutrition (3–5). These include type and stage of disease, treatment modalities, patient comorbidities, functional performance, and psychosocial status. Research aimed at preventing and treating weight loss, and malnutrition must incorporate these factors, beginning with restrictive eligibility criteria and meaningful patient reported outcomes. With this approach, other endpoints that heretofore have eluded the research community, such as improved survival and weight gain or maintenance, might be achieved. Unfortunately, in this issue of the Journal, results from the meta-analysis of Baldwin et al. (6) suggest these changes and achievements have yet to occur. The authors are to be commended for their thorough and rigorous review and meta-analysis of oral nutritional interventions in malnourished cancer patients or those at risk for malnourishment. Thirteen randomized controlled studies were included in the analysis representing 1414 participants. Study participants were adults with cancer (all sites and stages) receiving active treatment, including palliative treatment, and an oral nutritional intervention consisting of dietary advice, oral nutritional supplements, or both. All studies compared one of these nutritional interventions with usual care. The outcomes included in the analyses were mortality, QOL, weight loss, and energy intake. QOL was measured using the European Organization for Research and Treatment of Cancer (EORTC) questionnaire, which consists of 30 items assessing five functions, eight symptoms, global QOL, and perceived financial impact. The number of studies used to analyze each outcome varied depending on clinical and statistical heterogeneity. Analyses of mortality (15 studies), QOL (five studies), weight (eight studies), and energy intake (10 studies) were done. Overall, the analyses revealed no effect on mortality, no statistically significant difference in body weight or energy intake, and improvement in global QOL, EORTC domain of emotional functioning, dyspnea, and loss of appetite. These results reflect reanalyzed data excluding studies responsible for heterogeneity. There are several limitations to the review that the authors carefully outline. With regard to nutritional status, the patient population was very heterogeneous, including those at risk for malnourishment, those who were malnourished, and those who were cachectic. These nutritional statuses are often used interchangeably; yet, they constitute very distinct entities, possibly requiring very different interventions. Experts agree that conventional nutritional support cannot fully reverse the process of cachexia (7). Might the results of the analysis have been more promising if the eligibility criterion for weight loss had been more restrictive? Patients also varied in terms of cancer type, stage, and treatment. Though the authors believe this is justified, Santarpia et al. (8) advocate a tailored/personalized nutritional approach dictated by the underlying etiology. Nutritional deficits resulting from cancer and its treatment vary widely, as do their interventions, which may account for the variation seen in the duration, nature, and intensity of the nutritional interventions in the meta-analyses, which the authors cite as a factor contributing to heterogeneity. The most important limitation is the inclusion of studies that were of poor quality because of inadequate blinding, high risk of bias, small sample sizes, and inadequate power. Regrettably, these limitations reduce the clinical applicability of the findings and underscore the inherent challenges in conducting a meta-analysis in this area of research. Moreover, it speaks to the need for further research in this area. By outlining the limitations, the authors provide direction for future researchers. A key point made by the authors is that despite the statistical significance of some aspects of QOL, it is unclear how meaningful these changes are to the patient. The challenge that researchers face is explaining how improved emotional well-being resulted from taking an oral nutritional supplement and/or receiving dietary counseling. Was the improvement from the nutritional counseling, the supplement, the combination, or the extra attention to and clinical involvement with the patient? Was the improvement seen in cachectic patients only? If the goal of nutritional clinical studies is to improve QOL, more work is needed to define what aspects of QOL are clinically significant and meaningful to the patient and most importantly, to gain a better understanding of the underlying mechanisms. Consideration must also be given to a uniform definition of malnourishment that should be an eligibility criterion. Future studies should use a common QOL scale so data can be analyzed across multiple EDITORIALS

Chapter 30 – Data Management in Clinical Trials

There are essential elements that need to be in place to conduct a clinical trial successfully. First is a knowledgeable, adequately staffed research team well versed in the conduct of clinical research. Second, a clearly written protocol document that provides the necessary background information, rules and all aspects of conducting the study is needed. It is during the development phase of a protocol that all facets of data collection and management should be established: what, how, when data are collected and by whom. Third, timely and accurate data collection and analysis is crucial as data reveal the trial’s progress, toxicities and determine the outcome of a trial. Lastly, each member of the research team must be knowledgeable of and comply with the legal and regulatory aspects of clinical research. Conducting clinical research is a significant commitment of time, resources, and money; hence it is vital to have these elements in place for the trial to succeed.

Incorporating Patient-Reported Outcomes Into Early-Phase Trials

Abstract Early-phase cancer trials are designed to evaluate the safety, tolerability, and preliminary efficacy signals of a new therapeutic agent or combination. In a phase 1 trial the maximal tolerated dose is determined based on clinician assessment of toxicity during the first cycle of treatment. However, this may not always reflect the patient’s experience of tolerability over time. With more anticancer agents receiving accelerated approval based on early-phase trial data, and an expanding array of orally administered agents, the need to incorporate the patient’s perspective in early-phase trials has become more essential. The value of patient-reported outcomes (PROs) in later-phase trials can be extended and modified for the inclusion of PROs in the early drug development. This chapter traces the history of PRO inclusion in clinical trials, highlights selected PRO assessment tools, and outlines the important study design issues to consider when measuring, analyzing, and reporting PROs in early-phase clinical trials.

Software for Administering the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events: Usability Study

Background The US National Cancer Institute (NCI) developed software to gather symptomatic adverse events directly from patients participating in clinical trials. The software administers surveys to patients using items from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) through Web-based or automated telephone interfaces and facilitates the management of survey administration and the resultant data by professionals (clinicians and research associates). Objective The purpose of this study was to iteratively evaluate and improve the usability of the PRO-CTCAE software. Methods Heuristic evaluation of the software functionality was followed by semiscripted, think-aloud protocols in two consecutive rounds of usability testing among patients with cancer, clinicians, and research associates at 3 cancer centers. We conducted testing with patients both in clinics and at home (remotely) for both Web-based and telephone interfaces. Furthermore, we refined the software between rounds and retested. Results Heuristic evaluation identified deviations from the best practices across 10 standardized categories, which informed initial software improvement. Subsequently, we conducted user-based testing among 169 patients and 47 professionals. Software modifications between rounds addressed identified issues, including difficulty using radio buttons, absence of survey progress indicators, and login problems (for patients) as well as scheduling of patient surveys (for professionals). The initial System Usability Scale (SUS) score for the patient Web-based interface was 86 and 82 (P=.22) before and after modifications, respectively, whereas the task completion score was 4.47, which improved to 4.58 (P=.39) after modifications. Following modifications for professional users, the SUS scores improved from 71 to 75 (P=.47), and the mean task performance improved significantly (4.40 vs 4.02; P=.001). Conclusions Software modifications, informed by rigorous assessment, rendered a usable system, which is currently used in multiple NCI-sponsored multicenter cancer clinical trials. Trial Registration ClinicalTrials.gov NCT01031641; https://clinicaltrials.gov/ct2/show/NCT01031641 (Archived by WebCite at http://www.webcitation.org/708hTjlTl)

ReCAP: Clinical Trial Assessment of Infrastructure Matrix Tool to Improve the Quality of Research Conduct in the Community

PURPOSE Several publications have described minimum standards and exemplary attributes for clinical trial sites to improve research quality. The National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) developed the clinical trial Best Practice Matrix tool to facilitate research program improvements through annual self-assessments and benchmarking. The tool identified nine attributes, each with three progressive levels, to score clinical trial infrastructural elements from less to more exemplary. The NCCCP sites correlated tool use with research program improvements, and the NCI pursued a formative evaluation to refine the interpretability and measurability of the tool. METHODS From 2011 to 2013, 21 NCCCP sites self-assessed their programs with the tool annually. During 2013 to 2014, NCI collaborators conducted a five-step formative evaluation of the matrix tool. RESULTS Sites reported significant increases in level-three scores across the original nine attributes combined (P<.001). Two specific attributes exhibited significant change: clinical trial portfolio diversity and management (P=.0228) and clinical trial communication (P=.0281). The formative evaluation led to revisions, including renaming the Best Practice Matrix as the Clinical Trial Assessment of Infrastructure Matrix (CT AIM), expanding infrastructural attributes from nine to 11, clarifying metrics, and developing a new scoring tool. CONCLUSION Broad community input, cognitive interviews, and pilot testing improved the usability and functionality of the tool. Research programs are encouraged to use the CT AIM to assess and improve site infrastructure. Experience within the NCCCP suggests that the CT AIM is useful for improving quality, benchmarking research performance, reporting progress, and communicating program needs with institutional leaders. The tool model may also be useful in disciplines beyond oncology.