Enrolling Older Adults Onto National Cancer Institute-Funded Clinical Trials in Community Oncology Clinics: Barriers and Solutions.

In April 2021, the National Cancer Institute (NCI) Division of Cancer Prevention collaborated with the NCI Division of Cancer Treatment and Diagnosis to produce a virtual workshop that developed recommendations for enhancing NCI-sponsored clinical trial accrual of older adults. Prior to the workshop, a multidisciplinary group of stakeholders (eg, community oncologists, advanced practice practitioners, clinic and research staff, and patient advocates) gathered information related to accrual of older adults to clinical trials from the literature. Subsequently, a survey was conducted to detail NCI Community Oncology Research Program members' perspective on accrual barriers for this population; 305 individuals responded to the survey. Barriers to clinical trial accruals included comorbidity-attributed trial ineligibility, transportation and time issues, concern that the proposed regimen is too toxic for older adults, patient or family caregiver declined participation, and lack of trials relevant to older patients. Identified solutions included broadening clinical trial inclusion criteria, increasing the number of clinical trials specifically designed for older adults, simplifying consent forms, improving recruitment materials for older adults and their families, and facilitating transportation vouchers. At the workshop, participants, including stakeholders, used prior literature and survey results to develop recommendations, including interventions to address clinician bias, implement geriatric assessment, and promote clinician and staff engagement as mechanisms to improve accrual of older adults to clinical trials.

Use of a clinical trial screening tool to enhance patient accrual.

BACKGROUND: Clinical trial patient accrual continues to be challenging despite the identification of multiple physician, patient, and system barriers. Expanded collection of demographic data, including socioeconomic status (employment, income, education) and comorbidities, can enhance our understanding of the identified barriers, inform the development of interventions to overcome these barriers, and recognize their impact on treatment outcomes. A clinical trials screening tool was developed to collect expanded demographic data and barriers to trial enrollment; it has been implemented in the National Cancer Institute Clinical Oncology Research Program. The purpose of this article is to describe the development and implementation of the tool and to share information obtained during the first 43 months of its use. METHODS: There were 19,373 entries collected; 74% of those screened enrolled in a clinical trial. Demographic characteristics were compared between those screened and those enrolled. They varied significantly between the groups. RESULTS: Reasons for nonenrollment included ineligibility (50%), eligible but declined (47%), eligible but physician declined to offer participation (2%), and eligible but the study was suspended (1%). The most common reasons for ineligibility were failure to meet the protocol-specific stage of cancer, the presence of comorbidities, and the symptom-eligibility score was not met. The most common reason for eligible patients declining participation was that they had no desire to participate in research. CONCLUSIONS: The tool provides valuable information about the characteristics of individuals who are screened and enrolled in National Cancer Institute-sponsored trials, as well as about barriers to enrollment in trials. The data also inform protocol development and interventions at the patient, provider, and institutional level.

Chemotherapy-induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design.

BACKGROUND: To the authors' knowledge, the empiric identification of agents and interventions to mitigate chemotherapy-induced peripheral neuropathy (CIPN) has resulted in only 1 agent that modestly mitigates it and no agents or interventions that prevent its development. This speaks to the need for a mechanistic understanding of CIPN to develop effective interventions. METHODS: To understand the extent to which mechanistic understanding of CIPN is being translated into the development of interventions, the National Cancer Institute conducted a review of the National Institutes of Health (NIH)'s portfolio of investigator-initiated grants, the literature regarding CIPN mechanisms, and the clinical trials listed in the ClinicalTrials.gov database from January 1, 2011, to May 22, 2019. RESULTS: A total of 69 NIH-supported grants and 95 published articles were identified that evaluated mechanistic pathways of 7 different chemotherapy agents that cause CIPN. The review also identified 35 clinical trials that investigated agents or devices with which to treat CIPN. Only 3 trials incorporated a mechanistic rationale to support the choice of the intervention. CONCLUSIONS: To the authors' knowledge, very little of the mechanistic understanding of the development of CIPN is being translated into intervention rationale in clinical trials that evaluate interventions to mitigate CIPN. Efforts to incentivize this translation are needed.

Reporting of health-related quality of life endpoints in National Cancer Institute-supported cancer treatment trials.

BACKGROUND: The importance of capturing and reporting health-related quality of life (HRQOL) in clinical trials has been increasingly recognized in the oncology field. As a result, the National Cancer Institute (NCI) began to provide support for correlative HRQOL studies in cancer treatment trials. The current study was conducted to assess the publication rate of HRQOL correlative studies in NCI-supported treatment trials and to identify potential factors positively or negatively associated with publication rates. METHODS: The NCI conducted a retrospective review of existing NCI databases to identify cancer treatment trials that had obtained additional NCI funding for the assessment of HRQOL and to determine the extent to which funded HRQOL studies have been completed and published in a peer-reviewed journal. RESULTS: Of the 108 included trials, 58 (54%) had a parent trial (PT) publication; of these, 36 trials (62%) had a published HRQOL result: 20 as an independent publication and 16 that were included and/or reported in the PT publication. The length of time between trial activation and closure, as well as the specific cancer, appeared to be associated with the publication rates. CONCLUSIONS: The results of the current study demonstrated that approximately 45% of the PT publications were followed by a HRQOL publication within 1 year, to allow the knowledge to be used in patient treatment decision making. The authors believe the current analysis is an important first step toward a better understand of the challenges that researchers face when reporting HRQOL endpoints.

Patient free text reporting of symptomatic adverse events in cancer clinical research using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

OBJECTIVE: The study sought to describe patient-entered supplemental information on symptomatic adverse events (AEs) in cancer clinical research reported via a National Cancer Institute software system and examine the feasibility of mapping these entries to established terminologies. MATERIALS AND METHODS: Patients in 3 multicenter trials electronically completed surveys during cancer treatment. Each survey included a prespecified subset of items from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Upon completion of the survey items, patients could add supplemental symptomatic AE information in a free text box. As patients typed into the box, structured dropdown terms could be selected from the PRO-CTCAE item library or Medical Dictionary for Regulatory Activities (MedDRA), or patients could type unstructured free text for submission. RESULTS: Data were pooled from 1760 participants (48% women; 78% White) who completed 8892 surveys, of which 2387 (26.8%) included supplemental symptomatic AE information. Overall, 1024 (58%) patients entered supplemental information at least once, with an average of 2.3 per patient per study. This encompassed 1474 of 8892 (16.6%) dropdowns and 913 of 8892 (10.3%) unstructured free text entries. One-third of the unstructured free text entries (32%) could be mapped post hoc to a PRO-CTCAE term and 68% to a MedDRA term. DISCUSSION: Participants frequently added supplemental information beyond study-specific survey items. Almost half selected a structured dropdown term, although many opted to submit unstructured free text entries. Most free text entries could be mapped post hoc to PRO-CTCAE or MedDRA terms, suggesting opportunities to enhance the system to perform real-time mapping for AE reporting. CONCLUSIONS: Patient reporting of symptomatic AEs using a text box functionality with mapping to existing terminologies is both feasible and informative.

Cancer Clinical Trials: Improving Awareness and Access for Minority and Medically Underserved Communities.

Cancer clinical trials offer patients an opportunity to receive new and innovative treatment, as well as contribute to the future of cancer care. Enrollment onto clinical trials also may lead to better care and outcomes; however, few adult patients with cancer and even fewer ethnic and racial minority patients participate.

The National Cancer Institute Clinical Trials Planning Meeting for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy.

Although recent scientific advances have improved our understanding of basic biological mechanisms underlying chemotherapy-induced peripheral neuropathy (CIPN), few interventions are available to prevent or treat CIPN. Although some biological targets from preclinical studies show promise in nonhuman animal models, few targets have been translated to successful clinical trials. To address this problem, the National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee convened a meeting of experts in the CIPN and oncology symptom management fields to participate in a Clinical Trials Planning Meeting (CTPM). Investigators presented data from preclinical and translational studies for possible CIPN interventions; these were evaluated for readiness of randomized clinical trial testing by experts, and recommendations were provided. Breakout sessions were convened to discuss and develop future studies. The CTPM experts concluded that there is compelling evidence to move forward with selected pharmacological and nonpharmacological clinical trials for the prevention and treatment of CIPN. Several key feasibility issues need to be addressed, however. These include identification of optimal outcome measures to define the CIPN phenotype, establishment of parameters that guide the evaluation of clinically meaningful effects, and adoption of approaches for inclusion of translational and biomarker and/or genetic measures. The results of the CTPM provide support for conducting clinical trials that include both pharmacological and nonpharmacological approaches, alone or in combination, with biomarkers, genetics, or other measures designed to inform underlying CIPN mechanisms. Several working groups were formed to design rigorous CIPN clinical trials, the results of which are ongoing.

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).

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.

Creating a "culture of research" in a community hospital: Strategies and tools from the National Cancer Institute Community Cancer Centers Program.

BACKGROUND: The value of community-based cancer research has long been recognized. In addition to the National Cancer Institute's Community Clinical and Minority-Based Oncology Programs established in 1983, and 1991 respectively, the National Cancer Institute established the National Cancer Institute Community Cancer Centers Program in 2007 with an aim of enhancing access to high-quality cancer care and clinical research in the community setting where most cancer patients receive their treatment. This article discusses strategies utilized by the National Cancer Institute Community Cancer Centers Program to build research capacity and create a more entrenched culture of research at the community hospitals participating in the program over a 7-year period. METHODS: To facilitate development of a research culture at the community hospitals, the National Cancer Institute Community Cancer Centers Program required leadership or chief executive officer engagement; utilized a collaborative learning structure where best practices, successes, and challenges could be shared; promoted site-to-site mentoring to foster faster learning within and between sites; required research program assessments that spanned clinical trial portfolio, accrual barriers, and outreach; increased identification and use of metrics; and, finally, encouraged research team engagement across hospital departments (navigation, multidisciplinary care, pathology, and disparities) to replace the traditionally siloed approach to clinical trials. LIMITATIONS: The health-care environment is rapidly changing while complexity in research increases. Successful research efforts are impacted by numerous factors (e.g. institutional review board reviews, physician interest, and trial availability). The National Cancer Institute Community Cancer Centers Program sites, as program participants, had access to the required resources and support to develop and implement the strategies described. Metrics are an important component yet often challenging to identify and collect. The model requires a strong emphasis on outreach that challenges hospitals to improve and expand their reach, particularly into underrepresented populations and catchment areas. These efforts build on trust and a referral pipeline within the community which take time and significant commitment to establish. CONCLUSION: The National Cancer Institute Community Cancer Centers Program experience provides a relevant model to broadly address creating a culture of research in community hospitals that are increasingly networked via systems and consortiums. The strategies used align well with the National Cancer Institute-American Society of Clinical Oncology Accrual Symposium recommendations for patient-/community-, physician-/provider-, and site-/organizational-level approaches to clinical trials; they helped sites achieve organizational culture shifts that enhanced their cancer research programs. The National Cancer Institute Community Cancer Centers Program hospitals reported that the strategies were challenging to implement yet proved valuable as they provided useful metrics for programmatic assessment, planning, reporting, and growth. While focused on oncology trials, these concepts may be useful within other disease-focused research as well.

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 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.

Use of the National Cancer Institute Community Cancer Centers Program screening and accrual log to address cancer clinical trial accrual.

PURPOSE: Screening logs have the potential to help oncology clinical trial programs at the site level, as well as trial leaders, address enrollment in real time. Such an approach could be especially helpful in improving representation of racial/ethnic minority and other underrepresented populations in clinical trials. METHODS: The National Cancer Institute Community Cancer Centers Program (NCCCP) developed a screening log. Log data collected from March 2009 through May 2012 were analyzed for number of patients screened versus enrolled, including for demographic subgroups; screening methods; and enrollment barriers, including reasons for ineligibility and provider and patient reasons for declining to offer or participate in a trial. User feedback was obtained to better understand perceptions of log utility. RESULTS: Of 4,483 patients screened, 18.4% enrolled onto NCCCP log trials. Reasons for nonenrollment were ineligibility (51.6%), patient declined (25.8%), physician declined (15.6%), urgent need for treatment (6.6%), and trial suspension (0.4%). Major reasons for patients declining were no desire to participate in trials (43.2%) and preference for standard of care (39%). Major reasons for physicians declining to offer trials were preference for standard of care (53%) and concerns about tolerability (29.3%). Enrollment rates onto log trials did not differ between white and black (P = .15) or between Hispanic and non-Hispanic patients (P = .73). Other races had lower enrollment rates than whites and blacks. Sites valued the ready access to log data on enrollment barriers, with some sites changing practices to address those barriers. CONCLUSION: Use of screening logs to document enrollment barriers at the local level can facilitate development of strategies to enhance clinical trial accrual.

Palliative care outcomes in surgical oncology patients with advanced malignancies: a mixed methods approach.

PURPOSE: To prospectively compare outcomes and processes of hospital-based early palliative care with standard care in surgical oncology patients (N = 152). METHODS: A randomized, mixed methods, longitudinal study evaluated the effectiveness of a hospital-based Pain and Palliative Care Service (PPCS). Interviews were conducted presurgically and at follow-up visits up to 1 year. Primary outcome measures included the Gracely Pain Intensity and Unpleasantness Scales and the Symptom Distress Scale. Qualitative interviews assessed social support, satisfaction with care, and communication with providers. Survival analysis methods explored factors related to treatment crossover and study discontinuation. Models for repeated measures within subjects over time explored treatment and covariate effects on patient-reported pain and symptom distress. RESULTS: None of the estimated differences achieved statistical significance; however, for those who remained on study for 12 months, the PPCS group performed better than their standard of care counterparts. Patients identified consistent communication, emotional support, and pain and symptom management as positive contributions delivered by the PPCS. CONCLUSIONS: It is unclear whether lower pain perceptions despite greater symptom distress were clinically meaningful; however, when coupled with the patients' perceptions of their increased resources and alternatives for pain control, one begins to see the value of an integrated PPCS.

Challenges to and lessons learned from conducting palliative care research.

In response to a 2005 solicitation from the U.S. National Institutes of Health, 16 investigators received funding to test interventions that would reduce the barriers that prevent cancer patients from receiving adequate and appropriate symptom management therapies. Since the awards have been issued, the investigators have met two times and have identified a number of challenges to implementing their respective studies. A survey was conducted that focused on their experiences with hiring and retaining study personnel, gaining Institutional Review Board approval, incurring unexpected costs, challenges to accruing participants, and a listing of standard measures used in the study. The survey was completed online by the Principal Investigator for each project in late 2006 and the initial results were confirmed one year later by resending the initial survey and by a follow-up telephone call. All but one Principal Investigator completed the survey. Obtaining Institutional Review Board approval, hiring and recruiting research personnel, establishing subcontracts, and accruing research subjects were the primary challenges experienced by the investigators. This palliative care solicitation achieved more than its original intent of stimulating research in overcoming barriers to delivering cancer symptom management, palliative care and end-of-life care. From a survey on the challenges and issues that emerged from their projects, grantees were able to identify specific hurdles and their unique solutions that may help other investigators as they plan their program of research.

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

BACKGROUND: Whereas 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. (Premenopausal, Osteopenia/Osteoporosis, Women, Alendronate, Depression) Study. METHODS: Patients 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). RESULTS: Approximately 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. CONCLUSION: Women 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.