Patterns of Social Needs Predict Quality-of-Life and Healthcare Utilization Outcomes in Patients from a Large Hospital System.

BACKGROUND: Unmet social needs (SNs) often coexist in distinct patterns within specific population subgroups, yet these patterns are understudied. OBJECTIVE: To identify patterns of social needs (PSNs) and characterize their associations with health-related quality-of-life (HRQoL) and healthcare utilization (HCU). DESIGN: Observational study using data on SNs screening, HRQoL (i.e., low mental and physical health), and 90-day HCU (i.e., emergency visits and hospital admission). Among patients with any SNs, latent class analysis was conducted to identify unique PSNs. For all patients and by race and age subgroups, compared with no SNs, we calculated the risks of poor HRQoL and time to first HCU following SNs screening for each PSN. PATIENTS: Adult patients undergoing SNs screening at the Mass General Brigham healthcare system in Massachusetts, United States, between March 2018 and January 2023. MAIN MEASURES: SNs included: education, employment, family care, food, housing, medication, transportation, and ability to pay for household utilities. HRQoL was assessed using the Patient-Reported Outcomes Measurement Information System Global-10. KEY RESULTS: Six unique PSNs were identified: "high number of social needs," "food and utility access," "employment needs," "interested in education," "housing instability," and "transportation barriers." In 14,230 patients with HRQoL data, PSNs increased the risks of poor mental health, with risk ratios ranging from 1.07(95%CI:1.01-1.13) to 1.80(95%CI:1.74-1.86). Analysis of poor physical health yielded similar findings, except that the "interested in education" showed a mild protective effect (0.97[95%CI:0.94-1.00]). In 105,110 patients, PSNs increased the risk of 90-day HCU, with hazard ratios ranging from 1.09(95%CI:0.99-1.21) to 1.70(95%CI:1.52-1.90). Findings were generally consistent in subgroup analyses by race and age. CONCLUSIONS: Certain SNs coexist in distinct patterns and result in poorer HRQoL and more HCU. Understanding PSNs allows policymakers, public health practitioners, and social workers to identify at-risk patients and implement integrated, system-wide, and community-based interventions.

Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders.

BACKGROUND: Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed. METHODS: This multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18). RESULTS: In the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder's TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response. CONCLUSIONS: Pembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab.

Social Determinants of Health Needs and Health-related Quality of Life Among Surgical Patients: A Retrospective Analysis of 8512 Patients.

OBJECTIVE: To assess associations between social determinants of health (SDOH) needs and health-related quality of life (HRQOL) among surgical patients. BACKGROUND: Despite the profound impact of SDOH on health outcomes, studies examining the effect of SDOH needs on HRQOL among surgical patients are limited. METHODS: A retrospective study was conducted using responses from the SDOH needs assessment and the Patient-Reported Outcomes Measurement Information Systems Global Health instrument of adults seen in surgical clinics at a single institution. Patient characteristics including socioeconomic status (insurance type, education level, and employment status) were extracted. Stepwise multivariable logistic regression analyses were performed to identify independent predictors of global health scores. RESULTS: A total of 8512 surgical patients (mean age: 55.6±15.8 years) were included. 25.2% of patients reported one or more SDOH needs. The likelihood of reporting at least one SDOH need varied by patient characteristics and socioeconomic status variables. In fully adjusted regression models, food insecurity [odds ratio (OR), 1.53; 95% CI, 1.38-1.70 and OR, 1.49; 95% CI, 1.22-1.81, respectively], housing instability (OR, 1.27; 95% CI, 1.12-1.43 and OR, 1.39; 95% CI, 1.13-1.70, respectively) lack of transportation (OR, 1.46; 95% CI, 1.27-1.68 and OR, 1.25; 95% CI, 1.00-1.57, respectively), and unmet medication needs (OR, 1.31; 95% CI, 1.13-1.52 and OR, 1.61; 95% CI, 1.28-2.03, respectively) were independent predictors of poor physical and mental health. CONCLUSIONS: SDOH needs are independent predictors of poor patient-reported physical and mental health among surgical patients. Assessing and addressing SDOH needs should be prioritized in health care settings and by policymakers to improve HRQOL.

Feasibility of Weekly Electronic Health Record-Embedded Patient-Reported Outcomes for Patients Starting Oral Cancer-Directed Therapy.

PURPOSE: To examine the feasibility of integrating a symptom management platform into the electronic health record (EHR) using electronic patient-reported outcomes (ePROs) during oral cancer-directed therapy (OCDT) and explore the impact of prompting oncology nurse navigators (ONNs) to respond to severe symptomatic adverse events (SAEs). MATERIALS AND METHODS: Adults prescribed OCDT at Dana-Farber Cancer Institute were consecutively invited to participate. Participants received weekly messages to complete ePROs. The first half enrolled in a passive (P) group where ePROs responses could be viewed anytime, but outreach was not expected. The second half enrolled in an active (A) group where severe SAEs prompted emails to ONNs for outreach within 1 business day. Feasibility was the proportion of participants completing ≥2 ePROs during the first 30 days. Participants were followed for up to 90 days. RESULTS: From June 25, 2019, to August 18, 2021, 100 participants enrolled, and 96 remained enrolled for at least 30 days. Overall, average age was 59 years, 80% female, and 9% used the platform in Spanish. Twenty-two A (45%) and 27 P (57%) participants met the feasibility threshold (P = .26). ePROs returned at 30 days were similar (P = .50): 0 ePROs 17 A, 13 P; 1 ePRO 10 A, 7 P; 2 ePROs 3 A, 5 P; 3 ePROs 1 A, 4 P; 4 ePROs 7 A, 8 P; and 5 ePROs 11 A, 10 P. Documented telephone encounters at 30 days were similar (109 A, 101 P; P = .86). CONCLUSION: EHR-embedded ePROs administered weekly for people on OCDT was feasible, although many went incomplete. ePRO completion was not clearly affected by nursing calls for severe SAEs. Future efforts will investigate improving engagement and addressing symptoms proactively.

G-CSF rescue of FOLFIRINOX-induced neutropenia leads to systemic immune suppression in mice and humans.

BACKGROUND: Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes and neutrophils that contribute to both systemic and local immunosuppression in the tumor microenvironment. The effect of recombinant G-CSF (pegfilgrastim or filgrastim) on the production of myeloid-derived suppressive cells is unknown. Here we examined patients with pancreatic cancer, a disease known to induce myeloid-derived suppressor cells (MDSCs), and for which pegfilgrastim is routinely administered concurrently with FOLFIRINOX but not with gemcitabine-based chemotherapy regimens. METHODS: Serial blood was collected from patients with pancreatic ductal adenocarcinoma newly starting on FOLFIRINOX or gemcitabine/n(ab)paclitaxel combination chemotherapy regimens. Neutrophil and monocyte frequencies were determined by flow cytometry from whole blood and peripheral blood mononuclear cell fractions. Serum cytokines were evaluated pretreatment and on-treatment. Patient serum was used in vitro to differentiate healthy donor monocytes to MDSCs as measured by downregulation of major histocompatibility complex II (HLA-DR) and the ability to suppress T-cell proliferation in vitro. C57BL/6 female mice with pancreatic tumors were treated with FOLFIRINOX with or without recombinant G-CSF to directly assess the role of G-CSF on induction of immunosuppressive neutrophils. RESULTS: Patients receiving FOLFIRINOX with pegfilgrastim had increased serum G-CSF that correlated with an induction of granulocytic MDSCs. This increase was not observed in patients receiving gemcitabine/n(ab)paclitaxel without pegfilgrastim. Interleukin-18 also significantly increased in serum on FOLFIRINOX treatment. Patient serum could induce MDSCs as determined by in vitro functional assays, and this suppressive effect increased with on-treatment serum. Induction of MDSCs in vitro could be recapitulated by addition of recombinant G-CSF to healthy serum, indicating that G-CSF is sufficient for MDSC differentiation. In mice, neutrophils isolated from spleen of G-CSF-treated mice were significantly more capable of suppressing T-cell proliferation. CONCLUSIONS: Pegfilgrastim use contributes to immune suppression in both humans and mice with pancreatic cancer. These results suggest that use of recombinant G-CSF as supportive care, while critically important for mitigating neutropenia, may complicate efforts to induce antitumor immunity.

Programmatic Precision Oncology Decision Support for Patients With Gastrointestinal Cancer.

PURPOSE: With the growing number of available targeted therapeutics and molecular biomarkers, the optimal care of patients with cancer now depends on a comprehensive understanding of the rapidly evolving landscape of precision oncology, which can be challenging for oncologists to navigate alone. METHODS: We developed and implemented a precision oncology decision support system, GI TARGET, (Gastrointestinal Treatment Assistance Regarding Genomic Evaluation of Tumors) within the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute. With a multidisciplinary team, we systematically reviewed tumor molecular profiling for GI tumors and provided molecularly informed clinical recommendations, which included identifying appropriate clinical trials aided by the computational matching platform MatchMiner, suggesting targeted therapy options on or off the US Food and Drug Administration-approved label, and consideration of additional or orthogonal molecular testing. RESULTS: We reviewed genomic data and provided clinical recommendations for 506 patients with GI cancer who underwent tumor molecular profiling between January and June 2019 and determined follow-up using the electronic health record. Summary reports were provided to 19 medical oncologists for patients with colorectal (n = 198, 39%), pancreatic (n = 124, 24%), esophagogastric (n = 67, 13%), biliary (n = 40, 8%), and other GI cancers. We recommended ≥ 1 precision medicine clinical trial for 80% (406 of 506) of patients, leading to 24 enrollments. We recommended on-label and off-label targeted therapies for 6% (28 of 506) and 25% (125 of 506) of patients, respectively. Recommendations for additional or orthogonal testing were made for 42% (211 of 506) of patients. CONCLUSION: The integration of precision medicine in routine cancer care through a dedicated multidisciplinary molecular tumor board is scalable and sustainable, and implementation of precision oncology recommendations has clinical utility for patients with cancer.

Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial.

While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAFV600E CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431.

Infrastructure to Support Accrual of Older Adults to National Cancer Institute Clinical Trials.

As part of ongoing efforts to meaningfully improve recruitment, enrollment, and accrual of older adults into cancer clinical trials, the National Cancer Institute (NCI) sponsored a workshop with experts across the country entitled Engaging Older Adults in the NCI Clinical Trials Network: Challenges and Opportunities. Three working groups, including Study Design, Infrastructure, and Stakeholders, were formed, who worked together to offer synergistic improvements in the system. Here, we summarize the workshop discussions of the Infrastructure Working Group, whose goal was to address infrastructural challenges, identify underlying resources, and offer solutions to facilitate accrual of older adults into cancer clinical trials. Based on preconference work and workshop discussions, four key recommendations to strengthen NCI infrastructure were proposed: 1) further centralize resources and expertise; 2) provide training for clinical research staff; (3) develop common data elements; and 4) evaluate what works and does not work. These recommendations provide a strategy to improve the infrastructure to enroll more older adults in cancer clinical trials.

Framework for integrating electronic patient-reported data in routine cancer care: an Oncology Intake Questionnaire.

Objective: As part of ongoing implementation of electronic patient-reported outcome tools at the Dana-Farber Cancer Institute, here we describe the development of the electronic New Patient Intake Questionnaire. Materials and Methods: The original New Patient Intake Questionnaire includes a review of symptoms, oncology history, family history, health behaviors, health and social status, health literacy and numeracy, which was modified for integration into the EHR using content determination, build and configuration, implementation, analytics, and interventions. The engagement of key stakeholders, including patients, clinical staff, and providers, throughout the development and deployment of the electronic Questionnaire was crucial to producing a successful tool. Continual modifications based on input of stakeholders (such as mode of tool deployment) were made to ensure the utility and usability of the tool for both patients and providers. Results: Implementation of the EHR-integrated electronic New Patient Intake Questionnaire improved collection of the PRD by increasing questionnaire accessibility for patients, while also providing all available data to clinicians and researchers. Careful consideration of the content and configuration of the questionnaire allowed for a successful, institute-wide implementation of the tool. Discussion: This effort demonstrates the feasibility of implementation of a system-wide electronic questionnaire, emphasizing the importance of iterative refinement to create a tool that is both patient-centric and usable for clinicians. Conclusions: The electronic New Patient Intake Questionnaire allows for systematic collection of the PRD, which should benefit cancer care outcomes through innovative care delivery and healthcare interventions.

Barriers to Electronic Patient-Reported Outcome Measurement Among Patients with Cancer and Limited English Proficiency.

Importance: Often electronic tools are built with English proficient (EP) patients in mind. Cancer patients with limited English proficiency (LEP) experience gaps in care and are at risk for excess toxic effects if they are unable to effectively communicate with their care team. Objective: To evaluate whether electronic patient-reported outcome tools (ePROs) built to improve health outcomes for EP patients might also be acceptable for LEP patients in the context of oral cancer-directed therapies (OCDT). Design, Setting, and Participants: This qualitative study was conducted at a single National Cancer Institute-designated comprehensive cancer center. In 2019, English-speaking and Spanish-speaking LEP patients with cancer receiving oral chemotherapies were recruited to participate in a qualitative focus group examining patient attitudes toward ePROs and electronic tools that are used to manage adherence and symptoms related to oral therapies. Six focus groups were held for EP patients and 1 for Spanish-speaking LEP patients. LEP was defined as patients who self-identified as needing an interpreter to navigate the health care system. Data analysis was performed April through June of 2019. Exposures: Enrolled patients participated in a focus group lasting approximately 90 minutes. Main Outcomes and Measures: The perspectives of patients with cancer treated with oral chemotherapies on integrating ePROs into their care management. Results: Among the 46 participants included in the study, 46 (100%) were White, 10 (22%) were Latinx Spanish-speaking, 43 (93%) were female, and 37 (80%) were aged at least 50 years or older. Among the 6 focus groups with 6 to 8 EP patients (ranging from 6 to 8 participants) and 1 focus group with 10 Spanish-speaking LEP patients, this qualitative study found that EP and LEP patients had different levels of acceptability of using technology and ePRO tools to manage their OCDT. EP patients felt generally positive toward OCDT and were not generally interested in using electronic tools to manage their care. LEP patients generally disliked OCDT and welcomed the use of technology for health management, particularly when addressing gaps in symptom management by their oncology clinicians. Conclusions and Relevance: Although most electronic interventions target EP patients, these findings reveal the willingness of LEP patients to participate in technology-based interventions. Expanding ePROs to LEP patients may help to manage gaps in communication about treatment and potential adverse events because of the willingness of LEP patients to use ePRO tools to manage their health. This qualitative assessment is a strategic step in determining the resources needed to narrow the digital health gap and extend the value of PROs to the LEP oncology population.

Physical activity in older adults with metastatic gastrointestinal cancer: a pilot and feasibility study.

Objectives: This study determined the feasibility of delivering a 12-week structured physical activity programme during chemotherapy to older adults recently diagnosed with metastatic gastrointestinal (GI) cancer. Methods: This study used a single-cohort design. Older adults (aged ≥65 years) diagnosed with metastatic oesophageal, gastric, pancreatic or colorectal cancer who planned to initiate chemotherapy were enrolled. The physical activity programme included a combination of aerobic, flexibility, strength and balance modalities delivered by a certified cancer exercise trainer during chemotherapy infusion appointments, then translated and sustained at home by participants. The co-primary endpoints included: (1) accrual of 20 participants in 12 months and (2) physical activity adherence of ≥50%. Results: Between March and October 2018, 29 participants were screened, and 20 were enrolled within 12 months (recruitment rate: 69% (90% CI: 55% to 83%); p<0.001), meeting the first co-primary endpoint. The median age of participants was 73.3 years (IQR: 69.3-77.2). At week 12, 67% (90% CI: 48% to 85%) of participants adhered to ≥50% of the prescribed physical activity (p=0.079 (statistically significant)), meeting the second co-primary endpoint. From baseline to week 12, accelerometer-measured light-intensity and moderate-intensity to vigorous-intensity physical activity increased by 307.4 (95% CI: 152.6 to 462.2; p<0.001) and 25.0 min per week (95% CI: 9.9 to 40.1; p=0.001), respectively. There were no serious or unexpected adverse events. The median overall survival was 16.2 months (8.4-22.4). Conclusion: These results establish the feasibility of a larger scale randomised controlled trial that enrols older adults with metastatic GI cancer and delivers a structured physical activity programme during chemotherapy. Trial registration number: NCT03331406.

Metastatic Colorectal Cancer Outcomes by Age Among ARCAD First- and Second-Line Clinical Trials.

BACKGROUND: We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. METHODS: Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. RESULTS: Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). CONCLUSIONS: Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy.

Age and comorbidity association with survival outcomes in metastatic colorectal cancer: CALGB 80405 analysis.

BACKGROUND: Little is known about the interaction of comorbidities and age on survival outcomes in colorectal cancer (mCRC), nor how comorbidities impact treatment tolerance. METHODS: We utilized a cohort of 1345 mCRC patients enrolled in CALGB/SWOG 80405, a multicenter phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) plus bevacizumab, cetuximab or both. Endpoints were overall survival (OS), progression-free survival (PFS), and grade ≥ 3 toxicities assessed using NCI CTCAE v.3.0. Participants completed a questionnaire, including a modified Charlson Comorbidity Index. Adjusted Cox and logistic regression models tested associations of comorbidities and age on the endpoints. RESULTS: In CALGB/SWOG 80405, 1095 (81%) subjects were < 70 years and >70 250 (19%). Presence of ≥1 comorbidity was not significantly associated with either OS (HR 1.10, 95% CI 0.96-1.25) or PFS (HR 1.03, 95% CI 0.91-1.16). Compared to subjects <70 with no comorbidities, OS was non-significantly inferior for ≥70 with no comorbidities (HR 1.21, 95% CI 0.98-1.49) and significantly inferior for ≥70 with at least one comorbidity (HR 1.51, 95% CI 1.22-1.86). There were no significant associations or interactions between age or comorbidity with PFS. Comorbidities were not associated with treatment-related toxicities. Age ≥ 70 was associated with greater risk of grade ≥ 3 toxicities (OR 2.15, 95% CI 1.50-3.09, p < 0.001). CONCLUSIONS: Among participants in a clinical trial of combination chemotherapy for mCRC, presence of older age with comorbidities was associated with worse OS but not PFS. The association of age with toxicity suggests additional factors of care should be measured in clinical trials.

Adoption of Patient-Generated Health Data in Oncology: A Report From the NCCN EHR Oncology Advisory Group.

BACKGROUND: Collecting, monitoring, and responding to patient-generated health data (PGHD) are associated with improved quality of life and patient satisfaction, and possibly with improved patient survival in oncology. However, the current state of adoption, types of PGHD collected, and degree of integration into electronic health records (EHRs) is unknown. METHODS: The NCCN EHR Oncology Advisory Group formed a Patient-Reported Outcomes (PRO) Workgroup to perform an assessment and provide recommendations for cancer centers, researchers, and EHR vendors to advance the collection and use of PGHD in oncology. The issues were evaluated via a survey of NCCN Member Institutions. Questions were designed to assess the current state of PGHD collection, including how, what, and where PGHD are collected. Additionally, detailed questions about governance and data integration into EHRs were asked. RESULTS: Of 28 Member Institutions surveyed, 23 responded. The collection and use of PGHD is widespread among NCCN Members Institutions (96%). Most centers (90%) embed at least some PGHD into the EHR, although challenges remain, as evidenced by 88% of respondents reporting the use of instruments not integrated. Forty-seven percent of respondents are leveraging PGHD for process automation and adherence to best evidence. Content type and integration touchpoints vary among the members, as well as governance maturity. CONCLUSIONS: The reported variability regarding PGHD suggests that it may not yet have reached its full potential for oncology care delivery. As the adoption of PGHD in oncology continues to expand, opportunities exist to enhance their utility. Among the recommendations for cancer centers is establishment of a governance process that includes patients. Researchers should consider determining which PGHD instruments confer the highest value. It is recommended that EHR vendors collaborate with cancer centers to develop solutions for the collection, interpretation, visualization, and use of PGHD.

Patterns of Adjuvant Chemotherapy Use and Association With Survival in Adults 80 Years and Older With Pancreatic Adenocarcinoma.

IMPORTANCE: Patients 80 years and older with pancreatic ductal adenocarcinoma (PDAC) have not consistently received treatments that have established benefits in younger older adults (aged 60-79 years), yet patients 80 years and older are increasingly being offered surgery. Whether adjuvant chemotherapy (AC) provides additional benefit among patients 80 years and older with PDAC following surgery is not well understood. OBJECTIVE: To describe patterns of AC use in patients 80 years and older following surgical resection of PDAC and to compare overall survival between patients who received AC and those who did not. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study among patients 80 years or older diagnosed with PDAC (stage I-III) between 2004 to 2016 who underwent a pancreaticoduodenectomy at hospitals across the US reporting to the National Cancer Database. EXPOSURES: AC vs no AC 90 days following diagnosis of PDAC. MAIN OUTCOMES AND MEASURES: The proportion of patients who received AC was assessed over the study period. Overall survival was compared between patients who received AC and those who did not using Kaplan-Meier estimates and multivariable Cox proportional hazards regression. A landmark analysis was performed to address immortal time bias. A propensity score analysis was performed to address indication bias. Subgroup analyses were conducted in node-negative, margin-negative, clinically complex, node-positive, and margin-positive cohorts. RESULTS: Between 2004 and 2016, 2569 patients 80 years and older (median [IQR] age, 82 [81-84] years; 1427 were women [55.5%]) underwent surgery for PDAC. Of these patients, 1217 (47.4%) received AC. Findings showed an 18.6% (95% CI, 8.0%-29.0%; P = .001) absolute increase in the use of AC among older adults who underwent a pancreaticoduodenectomy comparing rates in 2004 vs 2016. Receipt of AC was associated with a longer median survival (17.2 months; 95% CI, 16.1-19.0) compared with those who did not receive AC (12.7 months; 95% CI, 11.8-13.6). This association was consistent in propensity and subgroup analyses. In multivariable analysis, receipt of AC (hazard ratio [HR], 0.72; 95% CI, 0.65-0.79; P < .001), female sex (HR, 0.88; 95% CI, 0.80-0.96; P < .001), and surgery in the more recent time period (≥2011) (HR, 0.90; 95% CI, 0.82-0.99; P = .02) were associated with a decreased hazard of death. An increased hazard of death was associated with higher pathologic stage (stage II: HR, 1.68; 95% CI, 1.43-1.97; P < .001; stage III: HR, 2.39; 95% CI, 1.88-3.04; P < .001), positive surgical margins (HR, 1.49; 95% CI, 1.34-1.65; P < .001), length of stay greater than median (10 days) (HR, 1.17; 95% CI, 1.07-1.28; P < .001), and receipt of oncologic care at a nonacademic facilities (Community Cancer Program: HR, 1.20; 95% CI, 1.07-1.35; P < .001; Integrated Network Cancer Program: HR, 1.25; 95% CI, 1.07-1.46; P < .001). CONCLUSIONS AND RELEVANCE: In this cohort study, the use of AC among patients who underwent resection for PDAC increased over the study period, yet it still was administered to fewer than 50% of patients. Receipt of AC was associated with a longer median survival.

Phase II study of pembrolizumab in refractory esophageal cancer with correlates of response and survival.

BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment, but the benefits in refractory patients with esophageal cancer have been modest. Predictors of response as well as new targets for novel therapeutic combinations are needed. In this phase 2 clinical trial, we tested single-agent pembrolizumab in patients with advanced esophageal cancer, who received at least one prior line of therapy. METHODS: Pembrolizumab 200 mg every 3 weeks was tested in 49 patients with refractory esophageal cancer: 39 with adenocarcinoma and 10 with esophageal squamous cell carcinoma. Major endpoints were radiological response by Immune-related Response Evaluation Criteria In Solid Tumors and survival. Tumor samples were evaluated for programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and immune contexture by both NanoString mRNA expression analysis and flow cytometry. Peripheral blood mononuclear cells and a panel of circulating chemokines were also analyzed. RESULTS: The overall response rate (ORR) was 8% (4 of 49 patients; 95% CI 2.3% to 19.6%). Median overall survival (OS) was 5.8 months (95% CI 4.0 to 9.5). ORR and OS were not associated with histology. For PD-L1-positive patients, ORR was 13.3% (95% CI 1.7% to 40.5%) and median OS was 7.9 months (95% CI 4.7 to 15.5). A trend toward improved OS was observed in seven patients with a TMB ≥10 mut/Mb (p=0.086). Tumors with a PD-L1 Combined Positive Score ≥1 showed enrichment of LAG3 (p=0.005) and IDO1 (p=0.04) gene expression. Baseline levels of circulating CXCL10, interleukin 2 (IL2) receptor α (IL2RA) and IL6 were associated with survival: CXCL10 favorably, (HR 0.37, p=0.002 (progression-free survival); HR 0.55, p=0.018 (OS)); IL2RA and IL6 unfavorably (HR 1.57, p=0.020 for IL6 (OS); HR 2.36, p=0.025 for IL2RA (OS)). CONCLUSIONS: Pembrolizumab monotherapy was modestly effective in refractory esophageal cancer. Circulating CXCL10 at baseline appeared to be a robust predictor of response. Other T cell exhaustion markers are upregulated in PD-L1-positive patients, suggesting that immunotherapy combinations such as anti-LAG3/programmed cell death protein 1 (PD-1) or anti-IDO1/PD-1 may be of promise in refractory esophageal cancer.

Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Body Composition among Patients with Advanced or Metastatic Colorectal Cancer: A Randomized Trial.

Skeletal muscle and adipose tissue express the vitamin D receptor and may be a mechanism through which vitamin D supplementation slows cancer progression and reduces cancer death. In this exploratory analysis of a double-blind, multicenter, randomized phase II clinical trial, 105 patients with advanced or metastatic colorectal cancer who were receiving chemotherapy were randomized to either high-dose vitamin D3 (4000 IU) or standard-dose (400 IU) vitamin D3. Body composition was measured with abdominal computed tomography at enrollment (baseline) and after cycle 8 of chemotherapy (16 weeks). As compared with standard-dose vitamin D3, high-dose vitamin D3 did not significantly change body weight [-0.7 kg; (95% CI: -3.5, 2.0)], body mass index [-0.2 kg/m2; (95% CI: -1.2, 0.7)], muscle area [-1.7 cm2; (95% CI: -9.6, 6.3)], muscle attenuation [-0.4 HU; (95% CI: -4.2, 3.2)], visceral adipose tissue area [-7.5 cm2; (95% CI: -24.5, 9.6)], or subcutaneous adipose tissue area [-8.3 cm2; (95% CI: -35.5, 18.9)] over the first 8 cycles of chemotherapy. Among patients with advanced or metastatic colorectal cancer, the addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy did not result in any changes in body composition.

Translation of Patient-Reported Outcomes in Oncology Clinical Trials to Everyday Practice.

PURPOSE: Clinical trials in oncology evaluating the effects of patient-reported outcomes (PRO) collection have found that monitoring of symptoms with PROs is associated with improved clinical care through reduced acute care utilization and decreased patient symptom burden. This educational review will evaluate strategies for systematic PRO integration into everyday oncology clinical practice. METHODS: We outline key considerations for using PROs in clinical practice, highlighting evidence from published studies. We also discuss the benefits and challenges of PRO implementation in oncology. RESULTS: Implementing PRO collection in clinical practice can improve care delivery and facilitate patient-centered clinical research. Considerations for using PROs in clinical practice include choice of instrument, method of delivery, and frequency of query. Challenges with implementing systematic PRO collection include the costs and resources needed for implementation, impact on clinical workflow, and controlling/monitoring physician burnout. CONCLUSIONS: While challenges exist in terms of financial resources and staff participation/burnout, patient-reported outcomes in clinical practice provide a number of benefits, including symptom monitoring, clinical research, and potential real-time personalized clinical-decision support.

Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial.

Importance: In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC). Objective: To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with metastatic CRC. Design, Setting, and Participants: Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018). Interventions: mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level. Results: Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, -5% [95% CI, -20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, -2.6 ng/mL [95% CI, -6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]). Conclusions and Relevance: Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01516216.