Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation.

BACKGROUND: Pharmacogenetic (PGx) testing for germline variants in the DPYD and UGT1A1 genes can be used to guide fluoropyrimidine and irinotecan dosing, respectively. Despite the known association between PGx variants and chemotherapy toxicity, preemptive testing prior to chemotherapy initiation is rarely performed in routine practice. METHODS: We conducted a qualitative study of oncology clinicians to identify barriers to using preemptive PGx testing to guide chemotherapy dosing in patients with gastrointestinal malignancies. Each participant completed a semi-structured interview informed by the Consolidated Framework for Implementation Research (CFIR). Interviews were analyzed using an inductive content analysis approach. RESULTS: Participants included sixteen medical oncologists and nine oncology pharmacists from one academic medical center and two community hospitals in Pennsylvania. Barriers to the use of preemptive PGx testing to guide chemotherapy dosing mapped to four CFIR domains: intervention characteristics, outer setting, inner setting, and characteristics of individuals. The most prominent themes included 1) a limited evidence base, 2) a cumbersome and lengthy testing process, and 3) a lack of insurance coverage for preemptive PGx testing. Additional barriers included clinician lack of knowledge, difficulty remembering to order PGx testing for eligible patients, challenges with PGx test interpretation, a questionable impact of preemptive PGx testing on clinical care, and a lack of alternative therapeutic options for some patients found to have actionable PGx variants. CONCLUSIONS: Successful adoption of preemptive PGx-guided chemotherapy dosing in patients with gastrointestinal malignancies will require a multifaceted effort to demonstrate clinical effectiveness while addressing the contextual factors identified in this study.

Barriers to Clinical Trial Implementation Among Community Care Centers.

Importance: While an overwhelming majority of patients diagnosed with cancer express willingness to participate in clinical trials, only a fraction will enroll onto a research protocol. Objective: To identify critical barriers to trial enrollment to translate findings into actionable practice changes that increase cancer clinical trial enrollment. Design, Setting, and Participants: This survey study included designated site contacts at oncology practices with teams who were highly involved with the Association of Community Cancer Centers (ACCC) Community Oncology Research Institute (ACORI) clinical trials activities, all American Society of Clinical Oncology (ASCO)-ACCC collaboration pilot sites, and/or sites providing care to at least 25% African American and Hispanic residents. To determine participation trends among health care practices in oncology-focused research, identify barriers to clinical trial implementation and operation, and establish unmet needs for cancer clinics interested in trial participation, a 34-question survey was designed. Survey questions were defined within 3 categories: cancer center demographic characteristics, clinical trial characteristics, and referral practices. The survey was distributed through email and was open from June 20 through October 5, 2022. Main Outcomes and Measures: Participation in and barriers to conducting oncology trials in different community oncology settings. Results: The survey was distributed to 100 cancer centers, with completion by 58 centers (58%) across 25 states. Fifty-two centers (88%) reported that they conduct therapeutic clinical trials, of which 33 (63%) were from urban settings, 11 (21%) were from suburban settings, and 8 (15%) were from rural settings. Only 25% of rural practices (2 of 8) offered phase 1 trials, compared with 67% of urban practices (22 of 33) (P = .01). Respondents noted challenges in conducting research, including patient recruitment (27 respondents [52%]), limited staffing (27 [52%]), and nonrelevant trials for their patient population (25 [48%]). Among sites not offering therapeutic trials, barriers to research conduct included limited infrastructure, funding, and staffing. Most centers (46 of 58 [79%]) referred patients to outside centers for clinical trial enrollment, particularly in the context of late-stage disease and/or disease progression. Only 17 of these sites (37%) had established protocols for patient follow-up subsequent to outside referral. Conclusions and Relevance: In this national survey study of barriers to clinical trial implementation, most sites offered therapeutic trials, but there were significant disparities in trial availability across care settings. Furthermore, fundamental deficiencies in trial support infrastructure limited research activity, including within programs currently conducting research as well as at sites interested in future clinical research opportunities. These results identify crucial unmet needs for oncology clinics to effectively offer clinical trials to patients seeking care.

Protocol for a type 3 hybrid implementation cluster randomized clinical trial to evaluate the effect of patient and clinician nudges to advance the use of genomic medicine across a diverse health system.

BACKGROUND: Germline genetic testing is recommended for an increasing number of conditions with underlying genetic etiologies, the results of which impact medical management. However, genetic testing is underutilized in clinics due to system, clinician, and patient level barriers. Behavioral economics provides a framework to create implementation strategies, such as nudges, to address these multi-level barriers and increase the uptake of genetic testing for conditions where the results impact medical management. METHODS: Patients meeting eligibility for germline genetic testing for a group of conditions will be identified using electronic phenotyping algorithms. A pragmatic, type 3 hybrid cluster randomization study will test nudges to patients and/or clinicians, or neither. Clinicians who receive nudges will be prompted to either refer their patient to genetics or order genetic testing themselves. We will use rapid cycle approaches informed by clinician and patient experiences, health equity, and behavioral economics to optimize these nudges before trial initiation. The primary implementation outcome is uptake of germline genetic testing for the pre-selected health conditions. Patient data collected through the electronic health record (e.g. demographics, geocoded address) will be examined as moderators of the effect of nudges. DISCUSSION: This study will be one of the first randomized trials to examine the effects of patient- and clinician-directed nudges informed by behavioral economics on uptake of genetic testing. The pragmatic design will facilitate a large and diverse patient sample, allow for the assessment of genetic testing uptake, and provide comparison of the effect of different nudge combinations. This trial also involves optimization of patient identification, test selection, ordering, and result reporting in an electronic health record-based infrastructure to further address clinician-level barriers to utilizing genomic medicine. The findings may help determine the impact of low-cost, sustainable implementation strategies that can be integrated into health care systems to improve the use of genomic medicine. TRIAL REGISTRATION: ClinicalTrials.gov. NCT06377033. Registered on March 31, 2024. https://clinicaltrials.gov/study/NCT06377033?term=NCT06377033&rank=1.

Toward Predicting 30-Day Readmission Among Oncology Patients: Identifying Timely and Actionable Risk Factors.

PURPOSE: Predicting 30-day readmission risk is paramount to improving the quality of patient care. In this study, we compare sets of patient-, provider-, and community-level variables that are available at two different points of a patient's inpatient encounter (first 48 hours and the full encounter) to train readmission prediction models and identify possible targets for appropriate interventions that can potentially reduce avoidable readmissions. METHODS: Using electronic health record data from a retrospective cohort of 2,460 oncology patients and a comprehensive machine learning analysis pipeline, we trained and tested models predicting 30-day readmission on the basis of data available within the first 48 hours of admission and from the entire hospital encounter. RESULTS: Leveraging all features, the light gradient boosting model produced higher, but comparable performance (area under receiver operating characteristic curve [AUROC]: 0.711) with the Epic model (AUROC: 0.697). Given features in the first 48 hours, the random forest model produces higher AUROC (0.684) than the Epic model (AUROC: 0.676). Both models flagged patients with a similar distribution of race and sex; however, our light gradient boosting and random forest models were more inclusive, flagging more patients among younger age groups. The Epic models were more sensitive to identifying patients with an average lower zip income. Our 48-hour models were powered by novel features at various levels: patient (weight change over 365 days, depression symptoms, laboratory values, and cancer type), hospital (winter discharge and hospital admission type), and community (zip income and marital status of partner). CONCLUSION: We developed and validated models comparable with the existing Epic 30-day readmission models with several novel actionable insights that could create service interventions deployed by the case management or discharge planning teams that may decrease readmission rates over time.

An Assessment of the Feasibility and Utility of an ACCC-ASCO Implicit Bias Training Program to Enhance Racial and Ethnic Diversity in Cancer Clinical Trials.

PURPOSE: Cancer trial participants do not reflect the racial and ethnic diversity in the population of people with cancer in the United States. As a result of multiple system-, patient-, and provider-level factors, including implicit bias, cancer clinical trials are not consistently offered to all potentially eligible patients. MATERIALS AND METHODS: ASCO and ACCC evaluated the utility (pre- and post-test knowledge changes) and feasibility (completion rates, curriculum satisfaction metrics, survey questions, and interviews) of a customized online training program combined with facilitated peer-to-peer discussion designed to help research teams identify their own implicit biases and develop strategies to mitigate them. Discussion focused on (1) specific elements of the training modules; (2) how to apply lessons learned; and (3) key considerations for developing a facilitation guide to support peer-to-peer discussions in cancer clinical research settings. We evaluated discussion via a qualitative assessment. RESULTS: Participant completion rate was high: 49 of 50 participating cancer programs completed training; 126 of 129 participating individuals completed the training (98% response rate); and 119 completed the training and evaluations (92% response rate). Training increased the mean percentage change in knowledge scores by 19%-45% across key concepts (eg, causes of health disparities) and increased the mean percentage change in knowledge scores by 10%-31% about strategies/actions to address implicit bias and diversity concerns in cancer clinical trials. Knowledge increases were sustained at 6 weeks. Qualitative evaluation validated the utility and feasibility of facilitated peer-to-peer discussion. CONCLUSION: The pilot implementation of the training program demonstrated excellent utility and feasibility. Our evaluation affirms that an online training designed to raise awareness about implicit bias and develop strategies to mitigate biases among cancer research teams is feasible and can be readily implemented in cancer research settings.

Increasing Racial and Ethnic Equity, Diversity, and Inclusion in Cancer Treatment Trials: Evaluation of an ASCO-Association of Community Cancer Centers Site Self-Assessment.

Clinical trial participants do not reflect the racial and ethnic diversity of people with cancer. ASCO and the Association of Community Cancer Centers collaborated on a quality improvement study to enhance racial and ethnic equity, diversity, and inclusion (EDI) in cancer clinical trials. The groups conducted a pilot study to examine the feasibility, utility, and face validity of a two-part clinical trial site self-assessment to enable diverse types of research sites in the United States to (1) review internal data to assess racial and ethnic disparities in screening and enrollment and (2) review their policies, programs, procedures to identify opportunities and strategies to improve EDI. Overall, 81% of 62 participating sites were satisfied with the assessment; 82% identified opportunities for improvement; and 63% identified specific strategies and 74% thought the assessment had potential to help their site increase EDI. The assessment increased awareness about performance (82%) and helped identify specific strategies (63%) to increase EDI in trials. Although most sites (65%) were able to provide some data on the number of patients that consented, only two sites were able to provide all requested trial screening, offering, and enrollment data by race and ethnicity. Documenting and evaluating such data are critical steps toward improving EDI and are key to identifying and addressing disparities more broadly. ASCO and Association of Community Cancer Centers will partner with sites to better understand their processes and the feasibility of collecting screening, offering, and enrollment data in systematic and automated ways.

Role of Oncology Advanced Practitioners to Enhance Clinical Research.

Background: Oncology advanced practitioners (APs), including nurse practitioners, clinical nurse specialists, physician assistants, and clinical pharmacists contribute significantly to quality cancer care. Advanced practitioners enhance value across the spectrum of cancer care. Research is an underdeveloped component of quality care, as well as an underdeveloped component of AP practice. Understanding research-related attitudes and roles of APs could lead to enhanced clinical trial accrual, conduct, and protocol development. Methods: A nationwide survey addressing attitudes, beliefs, and roles of APs regarding clinical research was distributed by the Association of Community Cancer Centers (ACCC) and Harborside in early 2020. Results: 408 oncology APs completed the survey. Thirty-five percent practice in an academic setting and 62% in the community. Nearly all respondents believe clinical trials are important to improve care, and over 90% report clinical trials are available at their practice. About 80% report being comfortable discussing the topic of clinical trials with patients and are involved in the care of trial participants. Sixty percent are comfortable discussing available trials, and 38% routinely explore available trials with patients. While 70% report approaching eligible patients about trials, only 20% report doing so "a great deal" or "a lot." Ninety percent report that APs should play a role in clinical research, and 73% want to be more involved. Barriers identified to greater AP clinical trial involvement include lack of time, inadequate awareness of trial specifics, and a lack of a formal role in protocol development and leadership. Conclusions: Advanced practitioners are engaged and interested in clinical trials and believe clinical research is important to improve cancer care. Multidisciplinary team integration, trials-related education, and policy change are needed to employ APs to their full potential within cancer clinical trials.

Digital Health Applications in Oncology: An Opportunity to Seize.

Digital health advances have transformed many clinical areas including psychiatric and cardiovascular care. However, digital health innovation is relatively nascent in cancer care, which represents the fastest growing area of health-care spending. Opportunities for digital health innovation in oncology include patient-facing technologies that improve patient experience, safety, and patient-clinician interactions; clinician-facing technologies that improve their ability to diagnose pathology and predict adverse events; and quality of care and research infrastructure to improve clinical workflows, documentation, decision support, and clinical trial monitoring. The COVID-19 pandemic and associated shifts of care to the home and community dramatically accelerated the integration of digital health technologies into virtually every aspect of oncology care. However, the pandemic has also exposed potential flaws in the digital health ecosystem, namely in clinical integration strategies; data access, quality, and security; and regulatory oversight and reimbursement for digital health technologies. Stemming from the proceedings of a 2020 workshop convened by the National Cancer Policy Forum of the National Academies of Sciences, Engineering, and Medicine, this article summarizes the current state of digital health technologies in medical practice and strategies to improve clinical utility and integration. These recommendations, with calls to action for clinicians, health systems, technology innovators, and policy makers, will facilitate efficient yet safe integration of digital health technologies into cancer care.

Implementing Pharmacogenetic Testing in Gastrointestinal Cancers (IMPACT-GI): Study Protocol for a Pragmatic Implementation Trial for Establishing DPYD and UGT1A1 Screening to Guide Chemotherapy Dosing.

Background: Fluoropyrimidines (fluorouracil [5-FU], capecitabine) and irinotecan are commonly prescribed chemotherapy agents for gastrointestinal (GI) malignancies. Pharmacogenetic (PGx) testing for germline DPYD and UGT1A1 variants associated with reduced enzyme activity holds the potential to identify patients at high risk for severe chemotherapy-induced toxicity. Slow adoption of PGx testing in routine clinical care is due to implementation barriers, including long test turnaround times, lack of integration in the electronic health record (EHR), and ambiguity in test cost coverage. We sought to establish PGx testing in our health system following the Exploration, Preparation, Implementation, Sustainment (EPIS) framework as a guide. Our implementation study aims to address barriers to PGx testing. Methods: The Implementing Pharmacogenetic Testing in Gastrointestinal Cancers (IMPACT-GI) study is a non-randomized, pragmatic, open-label implementation study at three sites within a major academic health system. Eligible patients with a GI malignancy indicated for treatment with 5-FU, capecitabine, or irinotecan will undergo PGx testing prior to chemotherapy initiation. Specimens will be sent to an academic clinical laboratory followed by return of results in the EHR with appropriate clinical decision support for the care team. We hypothesize that the availability of a rapid turnaround PGx test with specific dosing recommendations will increase PGx test utilization to guide pharmacotherapy decisions and improve patient safety outcomes. Primary implementation endpoints are feasibility, fidelity, and penetrance. Exploratory analyses for clinical effectiveness of genotyping will include assessing grade ≥3 treatment-related toxicity using available clinical data, patient-reported outcomes, and quality of life measures. Conclusion: We describe the formative work conducted to prepare our health system for DPYD and UGT1A1 testing. Our prospective implementation study will evaluate the clinical implementation of this testing program and create the infrastructure necessary to ensure sustainability of PGx testing in our health system. The results of this study may help other institutions interested in implementing PGx testing in oncology care. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04736472, identifier [NCT04736472].

Increasing Racial and Ethnic Diversity in Cancer Clinical Trials: An American Society of Clinical Oncology and Association of Community Cancer Centers Joint Research Statement.

A concerted commitment across research stakeholders is necessary to increase equity, diversity, and inclusion (EDI) and address barriers to cancer clinical trial recruitment and participation. Racial and ethnic diversity among trial participants is key to understanding intrinsic and extrinsic factors that may affect patient response to cancer treatments. This ASCO and Association of Community Cancer Centers (ACCC) Research Statement presents specific recommendations and strategies for the research community to improve EDI in cancer clinical trials. There are six overarching recommendations: (1) clinical trials are an integral component of high-quality cancer care, and every person with cancer should have the opportunity to participate; (2) trial sponsors and investigators should design and implement trials with a focus on reducing barriers and enhancing EDI, and work with sites to conduct trials in ways that increase participation of under-represented populations; (3) trial sponsors, researchers, and sites should form long-standing partnerships with patients, patient advocacy groups, and community leaders and groups; (4) anyone designing or conducting trials should complete recurring education, training, and evaluation to demonstrate and maintain cross-cultural competencies, mitigation of bias, effective communication, and a commitment to achieving EDI; (5) research stakeholders should invest in programs and policies that increase EDI in trials and in the research workforce; and (6) research stakeholders should collect and publish aggregate data on racial and ethnic diversity of trial participants when reporting results of trials, programs, and interventions to increase EDI. The recommendations are intended to serve as a guide for the research community to improve participation rates among people from racial and ethnic minority populations historically under-represented in cancer clinical trials. ASCO and ACCC will work at all levels to advance the recommendations in this publication.

Anticancer Therapy at the End of Life: Lessons From a Community Cancer Institute.

INTRODUCTION: Studies have shown aggressive cancer care at the end of life is associated with decreased quality of life, decreased median survival, and increased cost of care. This study describes the patients most likely to receive systemic anticancer therapy at the end of life in a community cancer institute. MATERIALS AND METHODS: We performed a retrospective cohort study of 201 patients who received systemic anticancer therapy in our institution and died between July 2016 and April 2017. Data collected included primary malignancy, hospice enrollment, healthcare utilization, Oncology Care Model (OCM) enrollment, and clinical assessments at last office visit prior to a treatment decision before death. We defined our outcome variable as the receipt of anticancer treatment in the last 14 days of a patient's life. We evaluated 20 clinical exposure variables with respect to the outcome classes. Risk ratios along with their associated confidence intervals and P values were calculated. Significance was determined using the Benjamini-Hochberg procedure to account for multiple testing. RESULTS: Of the 201 patients who died of cancer, 36 (17%) received anticancer therapy within the last 14 days of life. Several risk factors were significantly positively associated with receiving anticancer therapy at the end of life including hospitalization within 30 days of end of life, number of hospitalizations per patient (≥2), death in hospital, enrollment in OCM, and a diagnosis of hematologic malignancy. CONCLUSION: Our findings demonstrate those enrolled in the OCM and those with hematologic malignancies have a higher risk of receiving anticancer therapy in the last 14 days of life. These observations highlight the need for better identifying the needs of high-risk patients and providing good quality care throughout the disease trajectory to better align end-of-life care with patients' wishes.

Secret Sauce-How Diverse Practices Succeed in Centers for Medicare & Medicaid Services Oncology Care Model.

PURPOSE: CMS' Oncology Care Model (OCM) is an episode-based alternative payment model designed to incent high-value care through the use of monthly payments for enhanced services and performance-based payments on the basis of decreases in spending compared with risk-adjusted historical benchmarks. Transitioning from a fee-for-service model to a value-based, alternative payment model in oncology can be difficult; some practices will perform better than others. We present detailed experiences of four successful OCM practices, each operating under diverse business models and in different geographic areas. METHODS: Practices that achieved success in OCM, on the basis of financial metrics, describe pathways to success. The practices represent distinct business models: a medium-sized community oncology practice, a large statewide community oncology practice, a hospital-affiliated practice, and a large academic medical center. RESULTS: Practices describe effective changes in practice culture such as new administrative flexibilities, physician champions, improved communication, changes in physician compensation, and increased physician-level transparency. New or improved clinical services include acute care clinics, care coordination, phone triage, end-of-life care programs, and adoption of treatment pathways that identify high-value drug use, including better use of supportive care drugs. CONCLUSION: There is no one thing that will ensure success in OCM. Success requires whole practice transformation, encompassing both administrative and clinical changes. Communication between administrative and clinical teams is vital, along with improved data sharing and transparency. Clinical support services must expand to manage problems and symptoms in a timely way to prevent costly emergency department visits and hospitalizations, while constant attention must be paid to making high-value therapeutic choices in both oncolytic and supportive drug categories.

CD8+ T cells contribute to survival in patients with COVID-19 and hematologic cancer.

Patients with cancer have high mortality from coronavirus disease 2019 (COVID-19), and the immune parameters that dictate clinical outcomes remain unknown. In a cohort of 100 patients with cancer who were hospitalized for COVID-19, patients with hematologic cancer had higher mortality relative to patients with solid cancer. In two additional cohorts, flow cytometric and serologic analyses demonstrated that patients with solid cancer and patients without cancer had a similar immune phenotype during acute COVID-19, whereas patients with hematologic cancer had impairment of B cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses. Despite the impaired humoral immunity and high mortality in patients with hematologic cancer who also have COVID-19, those with a greater number of CD8 T cells had improved survival, including those treated with anti-CD20 therapy. Furthermore, 77% of patients with hematologic cancer had detectable SARS-CoV-2-specific T cell responses. Thus, CD8 T cells might influence recovery from COVID-19 when humoral immunity is deficient. These observations suggest that CD8 T cell responses to vaccination might provide protection in patients with hematologic cancer even in the setting of limited humoral responses.

CD8 T cells compensate for impaired humoral immunity in COVID-19 patients with hematologic cancer.

Cancer patients have increased morbidity and mortality from Coronavirus Disease 2019 (COVID-19), but the underlying immune mechanisms are unknown. In a cohort of 100 cancer patients hospitalized for COVID-19 at the University of Pennsylvania Health System, we found that patients with hematologic cancers had a significantly higher mortality relative to patients with solid cancers after accounting for confounders including ECOG performance status and active cancer status. We performed flow cytometric and serologic analyses of 106 cancer patients and 113 non-cancer controls from two additional cohorts at Penn and Memorial Sloan Kettering Cancer Center. Patients with solid cancers exhibited an immune phenotype similar to non-cancer patients during acute COVID-19 whereas patients with hematologic cancers had significant impairment of B cells and SARS-CoV-2-specific antibody responses. High dimensional analysis of flow cytometric data revealed 5 distinct immune phenotypes. An immune phenotype characterized by CD8 T cell depletion was associated with a high viral load and the highest mortality of 71%, among all cancer patients. In contrast, despite impaired B cell responses, patients with hematologic cancers and preserved CD8 T cells had a lower viral load and mortality. These data highlight the importance of CD8 T cells in acute COVID-19, particularly in the setting of impaired humoral immunity. Further, depletion of B cells with anti-CD20 therapy resulted in almost complete abrogation of SARS-CoV-2-specific IgG and IgM antibodies, but was not associated with increased mortality compared to other hematologic cancers, when adequate CD8 T cells were present. Finally, higher CD8 T cell counts were associated with improved overall survival in patients with hematologic cancers. Thus, CD8 T cells likely compensate for deficient humoral immunity and influence clinical recovery of COVID-19. These observations have important implications for cancer and COVID-19-directed treatments, immunosuppressive therapies, and for understanding the role of B and T cells in acute COVID-19.

Developing and Sustaining an Effective and Resilient Oncology Careforce: Opportunities for Action.

Advances in cancer care have led to improved survival, which, coupled with demographic trends, have contributed to rapid growth in the number of patients needing cancer care services. However, with increasing caseload, care complexity, and administrative burden, the current workforce is ill equipped to meet these burgeoning new demands. These trends have contributed to clinician burnout, compounding a widening workforce shortage. Moreover, family caregivers, who have unique knowledge of patient preferences, symptoms, and goals of care, are infrequently appreciated and supported as integral members of the oncology "careforce." A crisis is looming, which will hinder access to timely, high-quality cancer care if left unchecked. Stemming from the proceedings of a 2019 workshop convened by the National Cancer Policy Forum of the National Academies of Sciences, Engineering, and Medicine, this commentary characterizes the factors contributing to an increasingly strained oncology careforce and presents multilevel strategies to improve its efficiency, effectiveness, and resilience. Together, these will enable today's oncology careforce to provide high-quality care to more patients while improving the patient, caregiver, and clinician experience.