This consensus document is intended to serve 3 functions. First, it standardizes the criteria for diagnosis of chronic graft-versus-host disease (GVHD). Second, it proposes a new clinical scoring system (0-3) that describes the extent and severity of chronic GVHD for each organ or site at any given time, taking functional impact into account. Third, it proposes new guidelines for global assessment of chronic GVHD severity that are based on the number of organs or sites involved and the degree of involvement in affected organs (mild, moderate, or severe). Diagnosis of chronic GVHD requires the presence of at least 1 diagnostic clinical sign of chronic GVHD (e.g., poikiloderma or esophageal web) or the presence of at least 1 distinctive manifestation (e.g., keratoconjunctivitis sicca) confirmed by pertinent biopsy or other relevant tests (e.g., Schirmer test) in the same or another organ. Furthermore, other possible diagnoses for clinical symptoms must be excluded. No time limit is set for the diagnosis of chronic GVHD. The Working Group recognized 2 main categories of GVHD, each with 2 subcategories. The acute GVHD category is defined in the absence of diagnostic or distinctive features of chronic GVHD and includes (1) classic acute GVHD occurring within 100 days after transplantation and (2) persistent, recurrent, or late acute GVHD (features of acute GVHD occurring beyond 100 days, often during withdrawal of immune suppression). The broad category of chronic GVHD includes (1) classic chronic GVHD (without features or characteristics of acute GVHD) and (2) an overlap syndrome in which diagnostic or distinctive features of chronic GVHD and acute GVHD appear together. It is currently recommended that systemic therapy be considered for patients who meet criteria for chronic GVHD of moderate to severe global severity.

The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic 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, more accurately measures the global burden of disease attributed to GVHD, and will facilitate biomarker association studies.

The standard approach for documenting symptomatic adverse events (AEs) in cancer clinical trials involves investigator reporting using the National Cancer Institute's (NCI's) 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.

The SPIRIT-PRO guidelines provide recommendations for items that should be addressed and included in clinical trial protocols in which PROs are a primary or key secondary outcome. Improved design of clinical trials including PROs could help ensure high-quality data that may inform patient-centered care.

Importance Symptomatic adverse events (AEs) in cancer trials are currently reported by clinicians using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE). To integrate the patient perspective, the NCI developed a patient-reported outcomes version of the CTCAE (PRO-CTCAE) to capture symptomatic AEs directly from patients. Objective To assess the construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items. Design Participants completed PRO-CTCAE items on tablet computers in clinic waiting rooms at two visits 1-6 weeks apart. A subset completed PRO-CTCAE items during an additional visit one business day after the first visit. Setting Nine U.S. cancer centers and community oncology practices. Participants 975 adult cancer patients undergoing outpatient chemotherapy and/or radiation enrolled between January 2011 and February 2012. Eligibility required participants to read English and be without clinically significant cognitive impairment. Main Outcome(s) and Measure(s) Primary comparators were clinician-reported Eastern Cooperative Oncology Group Performance Status (ECOG PS) and the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30). Results 940/975 (96%) and 852/940 (91%) participants completed PRO-CTCAE items at each visit. 938/940 (99.8%) participants (53% female, median age 59, 32% high school education or less, 17% ECOG PS 2-4) reported having at least one symptom. All PRO-CTCAE items had at least one correlation in the expected direction with a QLQ-C30 scale (111/124 P<.05). Stronger correlations were seen between PRO-CTCAE items and conceptually-related QLQ-C30 domains. Scores for 94/124 PRO-CTCAE items were higher in the ECOG PS 2-4 versus 0-1 group (58/124 P<.05). Overall, 119/124 items met at least one construct validity criterion. Test-retest reliability was acceptable for 36/49 pre-specified items (median intra-class correlation coefficient .76; range .53-.96). Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes reached statistical significance for 27 pre-specified items (median r=.43, range .10-.56; all P≤.006). Conclusions and Relevance Evidence demonstrates favorable validity, reliability, and responsiveness of PRO-CTCAE in a large, heterogeneous U.S. sample of patients undergoing cancer treatment. Studies evaluating other measurement properties of PRO-CTCAE are underway to inform further development of PRO-CTCAE and its inclusion in cancer trials.