Sandra A. Mitchell

National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.

The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.

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.

Recommended Patient-Reported Core Set of Symptoms to Measure in Adult Cancer Treatment Trials

BACKGROUND The National Cancer Institutes Symptom Management and Health-Related Quality of Life Steering Committee held a clinical trials planning meeting (September 2011) to identify a core symptom set to be assessed across oncology trials for the purposes of better understanding treatment efficacy and toxicity and to facilitate cross-study comparisons. We report the results of an evidence-synthesis and consensus-building effort that culminated in recommendations for core symptoms to be measured in adult cancer clinical trials that include a patient-reported outcome (PRO). METHODS We used a data-driven, consensus-building process. A panel of experts, including patient representatives, conducted a systematic review of the literature (2001-2011) and analyzed six large datasets. Results were reviewed at a multistakeholder meeting, and a final set was derived emphasizing symptom prevalence across diverse cancer populations, impact on health outcomes and quality of life, and attribution to either disease or anticancer treatment. RESULTS We recommend that a core set of 12 symptoms--specifically fatigue, insomnia, pain, anorexia (appetite loss), dyspnea, cognitive problems, anxiety (includes worry), nausea, depression (includes sadness), sensory neuropathy, constipation, and diarrhea--be considered for inclusion in clinical trials where a PRO is measured. Inclusion of symptoms and other patient-reported endpoints should be well justified, hypothesis driven, and meaningful to patients. CONCLUSIONS This core set will promote consistent assessment of common and clinically relevant disease- and treatment-related symptoms across cancer trials. As such, it provides a foundation to support data harmonization and continued efforts to enhance measurement of patient-centered outcomes in cancer clinical trials and observational studies.

Cancer-Related Fatigue: State of the Science

Cancer‐related fatigue (CRF) is a disabling and distressing symptom that is highly prevalent across the cancer continuum from a patients diagnosis and treatment through survivorship and end of life. It has a multifactorial etiology and significant individual variability in its clinical expression, determinants, and sequelae. Despite the significance of CRF, it is often underdiagnosed, and management is frequently suboptimal. This review synthesizes the state of the science concerning the features, possible mechanisms, and predictors of CRF; offers recommendations for the evaluation of CRF; and appraises the strength of the evidence for a wide range of pharmacologic and nonpharmacologic interventions to prevent and manage fatigue during and after cancer and its treatment. There is evidence from methodologically rigorous controlled trials that exercise, psycho‐educational interventions, and cognitive‐behavioral therapy for insomnia are effective in the treatment of CRF, and a wide range of pharmacologic and nonpharmacologic interventions has shown initial promise in single‐arm pilot studies with small, heterogeneous samples. Rigorously designed and adequately powered randomized trials are warranted to (1) determine the effectiveness of promising approaches and (2) identify the interventions that are most effective in treating CRF in specific subpopulations (eg, stem cell transplant recipients, older adults, patients with lung or colorectal cancers, survivors, and those at the end of life). Studies to elucidate the biologic expression profiles of CRF, to explicate the mechanisms through which particular interventions impact CRF, and to identify the mediators and moderators of fatigue outcomes will ultimately permit individually tailored approaches for the treatment of CRF.

Cancer‐related fatigue and its impact on functioning

This article presents the contrasting European and American perspectives on cancer‐related fatigue (CRF) and its impact on functioning in cancer survivors. The content is presented in 3 sections: state of the art, intervention studies, and future areas of research, followed by a discussion. Gaps identified include a lack of understanding of the etiology, definition, and measurement of CRF. Models to guide the study of CRF, selection of biomarkers, and design of interventions are needed. There is overlap between Europe and the United States concerning the future directions for research and collaboration related to CRF. The authors suggest the need for international consensus regarding the defining features of CRF in cancer survivors to identify phenotypes, a harmonized measurement of CRF outcomes using instruments that have demonstrated measurement equivalence across languages and cultures, and interventions (including exercise, rehabilitation, and psychoeducational) that have been manualized to permit intervention fidelity across diverse contexts. Coordinated intercontinental efforts would increase understanding of the biological, psychological, and social mechanisms underlying CRF and assist in the design of future intervention studies as well as revisions to clinical guidelines. Cancer 2013;119(11 suppl):2124‐30.

Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

In 2005, the National Institutes of Health (NIH) Chronic Graft-versus-Host Disease (GVHD) Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for overall outcome. Based on publications over the last 9 years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include elimination of several clinical parameters from the determination of response, updates to or addition of new organ scales to assess response, and the recognition that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance reliability and practical utility of these measures in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population.

A thematic analysis of theoretical models for translational science in nursing: Mapping the field

The quantity and diversity of conceptual models in translational science may complicate rather than advance the use of theory. This paper offers a comparative thematic analysis of the models available to inform knowledge development, transfer, and utilization. Literature searches identified 47 models for knowledge translation. Four thematic areas emerged: (1) evidence-based practice and knowledge transformation processes, (2) strategic change to promote adoption of new knowledge, (3) knowledge exchange and synthesis for application and inquiry, and (4) designing and interpreting dissemination research. This analysis distinguishes the contributions made by leaders and researchers at each phase in the process of discovery, development, and service delivery. It also informs the selection of models to guide activities in knowledge translation. A flexible theoretical stance is essential to simultaneously develop new knowledge and accelerate the translation of that knowledge into practice behaviors and programs of care that support optimal patient outcomes.

Determinants of functional performance in long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease (cGVHD)

This study examined factors accounting for functional performance limitations in 100 long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease (cGVHD). Functional performance, measured by the SF-36 physical component summary score, was substantially lower (mean=36.8±10.7) than the US population norm of 50 (P<0.001). The most severe decrements were in physical function (mean=38.8±10.9) and physical role function (mean=37.88±11.88); 68% of respondents exceeded the five-point threshold of minimum clinically important difference below the norm on these subscales. Controlling for age and gender, six variables explained 56% of the variance in functional performance: time since cGVHD diagnosis, cGVHD severity, intensity of immunosuppression, comorbidity, functional capacity (distance walked in 2 min, grip strength, and range of motion), and cGVHD symptom bother (F=11.26; P<0.001). Significant independent predictors of impaired performance were intensive systemic immunosuppression, reduced capacity for ambulation, and greater cGVHD symptom bother (P<0.05). Symptom bother had a direct effect on functional performance, as well as an indirect effect partially mediated by functional capacity (Sobel test, P=0.004). Results suggest two possible mechanisms underlying impaired functional performance in survivors with cGVHD and underscore the importance of testing interventions to enhance functional capacity and reduce symptom bother.

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Salivary Gland Involvement in Chronic Graft-Versus-Host Disease: Prevalence, Clinical Significance, and Recommendations for Evaluation

Although xerostomia is a commonly reported complaint in patients with chronic graft-versus-host disease (cGVHD), criteria for evaluating the prevalence and characteristics of salivary gland involvement have not been well defined in this patient population. Previous studies also have made no distinction between salivary and mucosal oral cGVHD. We systematically evaluated signs and symptoms of sicca in a large cohort of patients with cGVHD (n = 101) using instruments widely used to study Sjogrens syndrome. Xerostomia was reported in 60 (77%) patients reporting ocular and 52 (67%) patients reporting oral complaints [corrected]. The salivary flow rate was < or =0.2 mL/min in 27%, and < or =0.1 mL/min in 16%. Histopathological changes, consisting of mononuclear infiltration and/or fibrosis/atrophy, were present in all patients with salivary dysfunction. Importantly, there was no correlation of salivary and oral mucosal involvement in cGVHD. Patients with cGVHD-associated salivary gland involvement had diminished oral cavity-specific quality of life and lower body mass index. Salivary gland involvement is a common and clinically distinct manifestation of cGVHD. Formal evaluation of salivary function using standardized criteria is needed, and this could be incorporated as an outcome measure in clinical trials of cGVHD.