The Integration of Clinical Trials With the Practice of Medicine: Repairing a House Divided.

Importance: Optimal health care delivery, both now and in the future, requires a continuous loop of knowledge generation, dissemination, and uptake on how best to provide care, not just determining what interventions work but also how best to ensure they are provided to those who need them. The randomized clinical trial (RCT) is the most rigorous instrument to determine what works in health care. However, major issues with both the clinical trials enterprise and the lack of integration of clinical trials with health care delivery compromise medicine's ability to best serve society. Observations: In most resource-rich countries, the clinical trials and health care delivery enterprises function as separate entities, with siloed goals, infrastructure, and incentives. Consequently, RCTs are often poorly relevant and responsive to the needs of patients and those responsible for care delivery. At the same time, health care delivery systems are often disengaged from clinical trials and fail to rapidly incorporate knowledge generated from RCTs into practice. Though longstanding, these issues are more pressing given the lessons learned from the COVID-19 pandemic, heightened awareness of the disproportionate impact of poor access to optimal care on vulnerable populations, and the unprecedented opportunity for improvement offered by the digital revolution in health care. Four major areas must be improved. First, especially in the US, greater clarity is required to ensure appropriate regulation and oversight of implementation science, quality improvement, embedded clinical trials, and learning health systems. Second, greater adoption is required of study designs that improve statistical and logistical efficiency and lower the burden on participants and clinicians, allowing trials to be smarter, safer, and faster. Third, RCTs could be considerably more responsive and efficient if they were better integrated with electronic health records. However, this advance first requires greater adoption of standards and processes designed to ensure health data are adequately reliable and accurate and capable of being transferred responsibly and efficiently across platforms and organizations. Fourth, tackling the problems described above requires alignment of stakeholders in the clinical trials and health care delivery enterprises through financial and nonfinancial incentives, which could be enabled by new legislation. Solutions exist for each of these problems, and there are examples of success for each, but there is a failure to implement at adequate scale. Conclusions and Relevance: The gulf between current care and that which could be delivered has arguably never been wider. A key contributor is that the 2 limbs of knowledge generation and implementation-the clinical trials and health care delivery enterprises-operate as a house divided. Better integration of these 2 worlds is key to accelerated improvement in health care delivery.

Real-world progression, treatment, and survival outcomes during rapid adoption of immunotherapy for advanced non-small cell lung cancer.

BACKGROUND: Despite the rapid adoption of immunotherapies in advanced non-small cell lung cancer (advNSCLC), knowledge gaps remain about their real-world (rw) performance. METHODS: This retrospective, observational, multicenter analysis used the Flatiron Health deidentified electronic health record-derived database of rw patients with advNSCLC who received treatment with PD-1 and/or PD-L1 (PD-[L]1) inhibitors before July 1, 2017 (N = 5257) and had ≥6 months of follow-up. The authors investigated PD-(L)1 line of treatment and PD-L1 testing rates and the relationship between overall survival (OS) and rw intermediate endpoints: progression-free survival (rwPFS), rw time to progression (rwTTP), rw time to next treatment (rwTTNT), and rw time to discontinuation (rwTTD). RESULTS: First-line PD-(L)1 inhibitor use increased from 0% (in the third quarter of 2014 [Q3 2014]) to 42% (Q2 2017) over the study period. PD-L1 testing also increased (from 3% in Q3 2015 to 70% in Q2 2017). The estimated median OS was 9.3 months (95% CI, 8.9-9.8 months), and the estimated rwPFS was 3.2 months (95% CI, 3.1-3.3 months). Longer OS and rwPFS were associated with ≥50% PD-L1 percentage staining results. Correlations (⍴) between OS and intermediate endpoints were ⍴ = 0.75 (95% CI, 0.73-0.76) for rwPFS and ⍴ = 0.60 (95% CI, 0.57-0.63) for rwTTP, and, for treatment-based intermediate endpoints, correlations were ⍴ = 0.60 (95% CI, 0.56-0.64) for rwTTNT (N = 856) and ⍴ = 0.81 (95% CI, 0.80-0.82) for rwTTD. CONCLUSIONS: The use of first-line PD-(L)1 inhibitors and PD-L1 testing has substantially increased, with better outcomes for patients who have ≥50% PD-L1 percentage staining. Intermediate rw tumor-dynamics estimates were moderately correlated with OS in patients with advNSCLC who received immunotherapy, highlighting the need for optimizing and standardizing rw endpoints to enhance the understanding of patient outcomes outside clinical trials.

Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval.

BACKGROUND: Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval. MATERIALS AND METHODS: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded. RESULTS: Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4-9.0 months). Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS. CONCLUSION: This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies. IMPLICATIONS FOR PRACTICE: This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.

Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial.

Does sertraline provide symptomatic relief for chronic breathlessness in people with advanced disease whose underlying cause(s) are optimally treated?223 participants with chronic breathlessness (modified Medical Research Council breathlessness scale ≥2) who had optimal treatment of underlying cause(s) were randomised 1:1 to sertraline 25-100 mg (titrated upwards over 9 days) or placebo for 4 weeks. The primary outcome was the proportion who had an improvement in intensity of current breathlessness >15% from baseline on a 100-mm visual analogue scale.The proportion of people responding to sertraline was similar to placebo for current breathlessness on days 26-28 (OR 1.00, 95% CI 0.71-1.40) and for other measures of breathlessness. Quality of life in the sertraline arm had a higher likelihood of improving than in the placebo arm over the 4 weeks (OR 0.21, 95% CI 0.01-0.41; p=0.044). No differences in performance status, anxiety and depression, or survival were observed. Adverse event rates were similar between arms.Sertraline does not appear to provide any benefit over placebo in the symptomatic relief of chronic breathlessness in this patient population.

Associations Between Polypharmacy, Symptom Burden, and Quality of Life in Patients with Advanced, Life-Limiting Illness.

BACKGROUND: Polypharmacy may be particularly burdensome near the end of life, as patients "accumulate" medications to treat and prevent multiple diseases. OBJECTIVE: To evaluate associations between polypharmacy, symptom burden, and quality of life (QOL) in patients with advanced, life-limiting illness (clinician-estimated, 1 month-1 year). DESIGN: Secondary analysis of baseline data from a trial of statin discontinuation. PARTICIPANTS: Adults with advanced, life-limiting illness. MAIN MEASURES: Polypharmacy was assessed by summing the number of non-statin medications taken regularly or as needed. Symptom burden was assessed using the Edmonton Symptom Assessment Scale (range 0-90; higher scores indicating greater symptom burden) and QOL was assessed using the McGill QOL Questionnaire (range 0-10; higher scores indicating better QOL). Linear regression models assessed associations between polypharmacy, symptom burden, and QOL. KEY RESULTS: Among 372 participants, 47% were age 75 or older and 35% were enrolled in hospice. The mean symptom score was 27.0 (standard deviation (SD) 16.1) and the mean QOL score was 7.0 (SD 1.3). The average number of non-statin medications was 11.6 (SD 5.0); one-third of participants took ≥ 14 medications. In adjusted models, higher polypharmacy was associated with higher symptom burden (coefficient 0.81; p < .001) and lower QOL (coefficient - .06; p = .001). Adjusting for symptom burden weakened the association between polypharmacy and QOL (coefficient - .03; p = .045) without a significant interaction, suggesting that worse quality of life associated with polypharmacy may be related to medication-associated symptoms. CONCLUSIONS: Among adults with advanced illness, taking more medications is associated with higher symptom burden and lower QOL. Attention to medication-related symptoms and shared decision-making regarding deprescribing are warranted in this setting. NIH TRIAL REGISTRY NUMBER: ClinicalTrials.gov Identifier for Parent Study - NCT01415934.

A behavioral cancer pain intervention: A randomized noninferiority trial comparing in-person with videoconference delivery.

OBJECTIVE: Behavioral cancer pain interventions are efficacious for improving important pain outcomes; yet, traditional in-person delivery limits patient access. This study compared videoconference-delivered mobile health pain coping skills training (mPCST) to in-person pain coping skills training (PCST-traditional). METHODS: This study was a randomized, noninferiority trial with cancer patients. Participants (N = 178) were randomly assigned to four, 45-minute sessions of mPCST or PCST-traditional. Session content focused on evidence-based cognitive and behavioral pain management skills. Assessments were completed at baseline, posttreatment, and 3-month posttreatment, and included measures of primary intervention outcomes (ie, pain severity and pain interference) and secondary intervention outcomes (ie, physical symptoms, psychological distress, physical well-being, and self-efficacy). The main study aim tested whether mPCST was more accessible (defined as feasibility, acceptability, patient burden, and engagement) than PCST-traditional. The second aim tested whether mPCST was noninferior to PCST-traditional. RESULTS: mPCST demonstrated significantly greater feasibility (ie, attrition, adherence, and time to completion) than PCST-traditional. Both groups reported similar patient burden and engagement as well as a high degree of acceptability. All intervention outcomes demonstrated noninferiority at posttreatment and, with the exception of physical symptoms, 3-month posttreatment. Concerning the primary intervention outcomes, 95% CIs for the mean differences (d) were below the noninferiority margin of 1 for pain severity (posttreatment d = 0.09, 95% CI, -0.63-0.81; 3 months d = -0.43 95% CI, -1.22-0.36) and pain interference (posttreatment d = -0.11, 95% CI, -0.99-0.76; 3 months d = -0.26 95% CI, -1.14-0.62). CONCLUSION: mPCST is highly accessible and noninferior to PCST-traditional.

Treatment patterns and outcomes for patients with advanced melanoma in US oncology clinical practices.

AIM: To describe recent evolution in treatment patterns and outcomes for advanced melanoma (AMel). METHODS: This retrospective observational study analyzed de-identified electronic health record data from the Flatiron Health database for 1140 adult patients who initiated first-line therapy for AMel from 1 January 2014 to 30 June 2016 with follow-up through 28 February 2017. RESULTS: The most common first-line regimens were ipilimumab-based therapies (34%), anti-PD-1 monotherapy (26%) and BRAF/MEK inhibitor(s) (20%). First-line ipilimumab-based and BRAF inhibitor regimens decreased after the third quarter of 2014 (3Q2014), and by 2Q2016, 55 and 91% of BRAF-mutant and BRAF wild-type cohorts, respectively, received a first-line anti-PD-1 regimen. Median overall survival from first-line initiation for all patients was 18.8 months (95% CI: 16.3-23.3). CONCLUSION: Results illustrate changing paradigms of therapy and real-world patient outcomes for AMel.

Pruritus in patients with solid tumors: an overlooked supportive care need.

PURPOSE: Pruritus is a common symptom in cutaneous malignancies, but its impact on patients with solid tumors is unclear. We explored the impact and management of pruritus in patients with solid tumors, using patient-reported outcomes (PRO) data from a real-world registry. METHODS: From 2006 to 2011, patients seen in the Duke Cancer Institute reported their symptoms via the Patient Care Monitor v2.0, a validated PRO tool that includes a 0-10-point question about pruritus severity. From > 25,000 encounters, 203 patients reported severe pruritus (> 6/10) on at least one visit and 506 total visits were abstracted where patients reported either moderate or severe pruritus (> 3/10). From this cohort, we abstracted demographics, diagnosis, stage, cancer therapy, anti-pruritic therapy, and clinicians' responses. RESULTS: Mean age was 59.8 (SD 13.3), 134 (66%) were female, 125 (62%) were Caucasian, and 65 (32%) were African American. Breast cancer was the most common tumor (36.5%), followed by lung cancer (23.2%). Mean pruritus severity score was 6.8 (SD 1.8) for patients on chemotherapy, 6.9 (SD 1.8) for patients on targeted therapy alone or in combination, and 7.1(SD 1.8) for patients off treatment. Overall, 67% of patients reported at least two episodes of moderate-severe pruritus (mean # of visits 4.2 (SD 2.7)). Despite frequent report of severe and persistent pruritus, this was mentioned in just 28% of clinician notes and an intervention was recommended/prescribed in only 7% of visits. CONCLUSIONS: Pruritus is an under-addressed symptom in patients with solid tumors. Additional research is needed to understand the burden of pruritus in affected populations.

Association of Patient Characteristics and Tumor Genomics With Clinical Outcomes Among Patients With Non-Small Cell Lung Cancer Using a Clinicogenomic Database.

Importance: Data sets linking comprehensive genomic profiling (CGP) to clinical outcomes may accelerate precision medicine. Objective: To assess whether a database that combines EHR-derived clinical data with CGP can identify and extend associations in non-small cell lung cancer (NSCLC). Design, Setting, and Participants: Clinical data from EHRs were linked with CGP results for 28 998 patients from 275 US oncology practices. Among 4064 patients with NSCLC, exploratory associations between tumor genomics and patient characteristics with clinical outcomes were conducted, with data obtained between January 1, 2011, and January 1, 2018. Exposures: Tumor CGP, including presence of a driver alteration (a pathogenic or likely pathogenic alteration in a gene shown to drive tumor growth); tumor mutation burden (TMB), defined as the number of mutations per megabase; and clinical characteristics gathered from EHRs. Main Outcomes and Measures: Overall survival (OS), time receiving therapy, maximal therapy response (as documented by the treating physician in the EHR), and clinical benefit rate (fraction of patients with stable disease, partial response, or complete response) to therapy. Results: Among 4064 patients with NSCLC (median age, 66.0 years; 51.9% female), 3183 (78.3%) had a history of smoking, 3153 (77.6%) had nonsquamous cancer, and 871 (21.4%) had an alteration in EGFR, ALK, or ROS1 (701 [17.2%] with EGFR, 128 [3.1%] with ALK, and 42 [1.0%] with ROS1 alterations). There were 1946 deaths in 7 years. For patients with a driver alteration, improved OS was observed among those treated with (n = 575) vs not treated with (n = 560) targeted therapies (median, 18.6 months [95% CI, 15.2-21.7] vs 11.4 months [95% CI, 9.7-12.5] from advanced diagnosis; P < .001). TMB (in mutations/Mb) was significantly higher among smokers vs nonsmokers (8.7 [IQR, 4.4-14.8] vs 2.6 [IQR, 1.7-5.2]; P < .001) and significantly lower among patients with vs without an alteration in EGFR (3.5 [IQR, 1.76-6.1] vs 7.8 [IQR, 3.5-13.9]; P < .001), ALK (2.1 [IQR, 0.9-4.0] vs 7.0 [IQR, 3.5-13.0]; P < .001), RET (4.6 [IQR, 1.7-8.7] vs 7.0 [IQR, 2.6-13.0]; P = .004), or ROS1 (4.0 [IQR, 1.2-9.6] vs 7.0 [IQR, 2.6-13.0]; P = .03). In patients treated with anti-PD-1/PD-L1 therapies (n = 1290, 31.7%), TMB of 20 or more was significantly associated with improved OS from therapy initiation (16.8 months [95% CI, 11.6-24.9] vs 8.5 months [95% CI, 7.6-9.7]; P < .001), longer time receiving therapy (7.8 months [95% CI, 5.5-11.1] vs 3.3 months [95% CI, 2.8-3.7]; P < .001), and increased clinical benefit rate (80.7% vs 56.7%; P < .001) vs TMB less than 20. Conclusions and Relevance: Among patients with NSCLC included in a longitudinal database of clinical data linked to CGP results from routine care, exploratory analyses replicated previously described associations between clinical and genomic characteristics, between driver mutations and response to targeted therapy, and between TMB and response to immunotherapy. These findings demonstrate the feasibility of creating a clinicogenomic database derived from routine clinical experience and provide support for further research and discovery evaluating this approach in oncology.

Characteristics of Real-World Metastatic Non-Small Cell Lung Cancer Patients Treated with Nivolumab and Pembrolizumab During the Year Following Approval.

BACKGROUND: Evidence from cancer clinical trials can be difficult to generalize to real-world patient populations, but can be complemented by real-world evidence to optimize personalization of care. Further, real-world usage patterns of programmed cell death protein 1 (PD-1) inhibitors following approval can inform future studies of subpopulations underrepresented in clinical trials. MATERIALS AND METHODS: We performed a multicenter analysis using electronic health record data collected during routine care of patients treated in community cancer care clinics in the Flatiron Health network. Real-world metastatic non-small cell lung cancer (NSCLC) patients who received nivolumab or pembrolizumab in the metastatic setting (n = 1,344) were selected from a starting random sample of 55,969 NSCLC patients with two or more documented visits from January 1, 2011, through March 31, 2016. The primary study outcome measurement was demographic and treatment characteristics of the cohort. RESULTS: Median age at PD-1 inhibitor initiation was 69 years (interquartile range 61-75). Patients were 56% male, 88% smokers, 65% nonsquamous histology, and 64% diagnosed at stage IV. Of 1,344 patients, 112 (8%) were tested for programmed death-ligand 1 expression. Overall, 50% received nivolumab or pembrolizumab in the second line, with a substantial proportion of third and later line use that began to decline in Q4 2015. CONCLUSION: During the year following U.S. regulatory approval of PD-1 inhibitors for treatment of NSCLC, real-world patients receiving nivolumab or pembrolizumab were older at treatment initiation and more had smoking history relative to clinical trial cohorts. Studies of outcomes in underrepresented subgroups are needed to inform real-world treatment decisions. IMPLICATIONS FOR PRACTICE: Evidence gathered in conventional clinical trials used to assess safety and efficacy of new therapies is not necessarily generalizable to real-world patients receiving these drugs following regulatory approval. Real-world evidence derived from electronic health record data can yield complementary evidence to enable optimal clinical decisions. Examined here is a cohort of programmed cell death protein 1 inhibitor-treated metastatic non-small cell lung cancer patients in the first year following regulatory approval of these therapies in this indication. The analysis revealed how the real-world cohort differed from the clinical trial cohorts, which will inform which patients are underrepresented and warrant additional studies.

Patient-Reported Distress in Myelodysplastic Syndromes and Its Association With Clinical Outcomes: A Retrospective Cohort Study.

Background: NCCN defines distress as a multifactorial, unpleasant emotional experience of a psychological nature that may interfere with patients' ability to cope with cancer symptoms and treatment. Patients with myelodysplastic syndromes (MDS) are at risk for distress due to the largely incurable nature of this hematopoietic malignancy and its symptom burden, yet associations with clinical outcomes are unknown. Methods: We retrospectively reviewed patient-reported distress data from adult ambulatory patients with MDS visiting a single, tertiary care medical center from July 2013 to September 2015. Demographic, diagnostic, treatment, and comorbidity information were abstracted from records along with NCCN Distress Thermometer (DT) and Problem List (PL) scores. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression. Results: We abstracted 376 DT scores (median, 1; range, 0-10) from 606 visits and 110 patients (median, 2 DT scores/patient; range, 1-16). NCCN Guidelines suggest that patients with DT scores ≥4 should be evaluated for referral to specialty services to address unmet needs. A total of 54 patients (49%) had at least 1 DT score ≥4 and 20 (18%) had 2 or more DT scores ≥4; 98 patients (89.1%) reported 1,379 problems during 23,613 person-days of follow-up (median, 4 problems/patient/visit; range, 1-23). The 5 most frequently reported problems were fatigue (181 times; 78 patients), pain (95 times; 46 patients), worry (80 times; 45 patients), sleep (78 times; 41 patients), and tingling hands/feet (68 times; 33 patients). After adjustment for risk stratification at diagnosis, a single point increase on the DT was associated with an increased risk of death (hazard ratio, 1.18; 95% CI, 1.01-1.36). Conclusions: Patients with MDS experience a high burden of distress, and patient-reported distress is associated with clinical outcomes. Distress should be further studied as a prognostic variable and a marker of unmet needs in MDS.

Treatment dynamics of bone-targeting agents among men with bone metastases from prostate cancer in the United States.

PURPOSE: To examine the dynamics of treatment with 2 bone-targeting agents (BTAs)-denosumab and zoledronic acid-among men with bone metastases from prostate cancer. METHODS: Using electronic health record data from oncology practices across the US, we identified prostate cancer patients diagnosed with bone metastasis in 2012/2013 without evidence of BTA use within 6 months prior to diagnosis. We examined the risk and predictors of BTA initiation, interruption, and re-initiation. RESULTS: Among 897 men diagnosed with prostate cancer, the cumulative incidence of BTA initiation after bone metastasis diagnosis was 34% (95% confidence interval [CI], 31-37%) at 30 days, 64% (95% CI, 61-68%) at 180 days, and 88% (95% CI, 85-91%) at 2 years. Denosumab was initiated more frequently than zoledronic acid. Men with diabetes, more bone lesions, history of androgen deprivation therapy, or no hospice enrollment were more likely to initiate treatment. Following initiation, the cumulative incidence of treatment interruption was 17% (95% CI, 14-19%) at 60 days and 70% (95% CI, 66-74%) at 2 years, with interruption more likely among patients receiving emerging therapies for prostate cancer or enrolling in hospice. The cumulative incidence of re-initiation following interruption was 36.3% (95% CI, 32.7-40.2%) at 15 days, 49.8% (95% CI, 45.9-54.1%) at 30 days, and 81.0% (95% CI, 77.5-84.7%) at 1 year. CONCLUSIONS: Bone-targeting agent therapy is initiated by the majority of men living with bone metastases following a prostate cancer diagnosis; however, the timing of initiation is highly variable. Once on treatment, gaps or interruptions in therapy are common.

Moving on: Factors associated with caregivers' bereavement adjustment using a random population-based face-to-face survey.

BACKGROUND: Providing care at end of life has consequences for caregivers' bereavement experience. 'Difficulty moving on with life' is an informative and unbiased symptom of prolonged grief disorder. Predictors of bereaved caregivers' ability to 'move on' have not been examined across the population. AIM: To identify the characteristics of bereaved hands-on caregivers who were, and were not, able to 'move on' 13-60 months after the 'expected' death of someone close. DESIGN: The South Australian Health Omnibus is an annual, random, cross-sectional community survey. From 2000 to 2007, respondents were asked about providing care for someone terminally ill and their subsequent ability to 'move on'. Multivariable logistic regression models explored the characteristics moving on and not moving on. SETTING: Respondents were aged ⩾15 years and lived in households within South Australia. They had provided care to someone who had died of terminal illness in the preceding 5 years. RESULTS: A total of 922 people provided hands-on care. In all, 80% of caregivers (745) had been able to 'move on'. Closeness of relationship to the deceased, increasing caregiver age, caregiver report of needs met, increasing time since loss, sex and English-speaking background were significantly associated with 'moving on'. A closer relationship to the deceased, socioeconomic disadvantage and being male were significantly associated with not 'moving on'. CONCLUSION: These results support the relevance of 'moving on' as an indicator of caregivers' bereavement adjustment. Following the outcomes of bereaved caregivers longitudinally is essential if effective interventions are to be developed to minimise the risk of prolonged grief disorder.

Association of Broad-Based Genomic Sequencing With Survival Among Patients With Advanced Non-Small Cell Lung Cancer in the Community Oncology Setting.

Importance: Broad-based genomic sequencing is being used more frequently for patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the association between broad-based genomic sequencing and treatment selection or survival among patients with advanced NSCLC in a community oncology setting. Objective: To compare clinical outcomes between patients with advanced NSCLC who received broad-based genomic sequencing vs a control group of patients who received routine testing for EGFR mutations and/or ALK rearrangements alone. Design, Setting, and Participants: Retrospective cohort study of patients with chart-confirmed advanced NSCLC between January 1, 2011, and July 31, 2016, and who received care at 1 of 191 oncology practices across the United States using the Flatiron Health Database. Patients were diagnosed with stage IIIB/IV or unresectable nonsquamous NSCLC who received at least 1 line of antineoplastic treatment. Exposures: Receipt of either broad-based genomic sequencing or routine testing (EGFR and/or ALK only). Broad-based genomic sequencing included any multigene panel sequencing assay examining more than 30 genes prior to third-line treatment. Main Outcomes and Measures: Primary outcomes were 12-month mortality and overall survival from the start of first-line treatment. Secondary outcomes included frequency of genetic alterations and treatments received. Results: Among 5688 individuals with advanced NSCLC (median age, 67 years [interquartile range, 41-85], 63.6% white, 80% with a history of smoking); 875 (15.4%) received broad-based genomic sequencing and 4813 (84.6%) received routine testing. Among patients who received broad-based genomic sequencing, 4.5% received targeted treatment based on testing results, 9.8% received routine EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. Unadjusted mortality rates at 12 months were 49.2% for patients undergoing broad-based genomic sequencing and 35.9% for patients undergoing routine testing. Using an instrumental variable analysis, there was no significant association between broad-based genomic sequencing and 12-month mortality (predicted probability of death at 12 months, 41.1% for broad-based genomic sequencing vs 44.4% for routine testing; difference -3.6% [95% CI, -18.4% to 11.1%]; P = .63). The results were consistent in the propensity score-matched survival analysis (42.0% vs 45.1%; hazard ratio, 0.92 [95% CI, 0.73 to 1.11]; P = .40) vs unmatched cohort (hazard ratio, 0.69 [95% CI, 0.62 to 0.77]; log-rank P < .001). Conclusions and Relevance: Among patients with advanced non-small cell lung cancer receiving care in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.

Centralized patient-reported outcome data collection in transplantation is feasible and clinically meaningful.

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) cures many patients, but often with the risk of late effects and impaired quality of life. The value of quantifying patient-reported outcomes (PROs) is increasingly being recognized, but the routine collection of PROs is uncommon. This study evaluated the feasibility of prospective PRO collection by an outcome registry at multiple time points from unselected HCT patients undergoing transplantation at centers contributing clinical data to the Center for International Blood and Marrow Transplant Research (CIBMTR), and then it correlated the PRO data with clinical and demographic data. METHODS: The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), 36-Item Short Form Health Survey (SF-36), and Pediatric Quality of Life Inventory measures were administered before HCT, on day 100, and at 6 and 12 months. Patients were recruited by the transplant center, but posttransplant PRO collection was managed centrally by the CIBMTR. RESULTS: There were 580 eligible patients, and 390 (67%) enrolled. Feasibility was shown by high time-specific retention rates (176 of 238 at 1 year or 74%) and participant satisfaction. Factors associated with higher response rates were an age > 50 years (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.03-2.41; P = .0355), white race (OR, 4.61; 95% CI, 2.66-7.99; P < .0001), and being married (OR, 2.28; 95% CI, 1.42-3.65; P = .0006) for adults and a higher family income for children (OR, 4.99; 95% CI, 2.12-11.75; P = .0002). Importantly, pre-HCT PRO scores independently predicted survival after adjustments for patient-, disease-, and transplant-related factors. The adjusted probabilities of 1-year survival were 56%, 67%, 75%, and 76% by increasing quartiles of the pre-HCT FACT-BMT score and 58%, 72%, 62%, and 82% by increasing quartiles of the pre-HCT SF-36 physical component score. CONCLUSIONS: A hybrid model of local consent for centralized PRO collection is feasible, and pretransplant PROs provide critical prognostic information for HCT outcomes. Cancer 2017;123:4687-4700. © 2017 American Cancer Society.

Design and Rationale of the Metastatic Renal Cell Carcinoma (MaRCC) Registry: A Prospective Academic and Community-Based Study of Patients With Metastatic Renal Cell Cancer.

The Metastatic Renal Cell Cancer Registry, a large, nationally representative, prospective registry of patients with metastatic renal cell carcinoma (mRCC), aims to understand real-world treatment patterns and outcomes of patients with mRCC in routine clinical practice across the United States. This observational study is designed to enroll 500 patients with previously untreated mRCC from approximately 60 academic and community treatment sites; as of December 7, 2016, 500 patients have enrolled at 54 sites. Key endpoints include real-world data on reasons for treatment initiation and discontinuation; treatment regimens; disease progression; patient-reported outcomes; and healthcare resource utilization in this patient population.

Caregiver characteristics and bereavement needs: Findings from a population study.

BACKGROUND: Globally, most care for people with life-limiting illnesses is provided by informal caregivers. Identifying characteristics of caregivers that may have unmet needs and negative outcomes can help provide better support to facilitate adjustment. AIM: We compared characteristics, expressed unmet needs and outcomes for spousal caregivers, with other caregivers at the end of life, by gender and age. DESIGN: The South Australian Health Omnibus is an annual, random, face-to-face, cross-sectional survey wherein respondents are asked about end-of-life care. SETTING/PARTICIPANTS: Participants were aged over 15 years, resided in households in South Australia and had someone close to them die from a terminal illness in the last 5 years. RESULTS: Of the 1540 respondents who provided hands-on care for someone close at the end of life, 155 were widows/widowers. Bereaved spousal caregivers were more likely to be older, female, better educated, have lower incomes, less full-time work, English as second language, sought help with grief and provided more day-to-day care for longer periods. Spousal caregivers were less likely to be willing to take on caregiving again, less able to 'move on' with life and needed greater emotional support and information about illness and services. The only difference between widows and widowers was older age of spouse in women. Younger spousal caregivers perceived greater unmet emotional needs and were significantly less likely to be able to 'move on'. CONCLUSION: Spousal caregivers are different from other caregivers, with more intense needs that are not fully met. These have implications for bereavement, health and social services.

The Digital Drag and Drop Pillbox: Design and Feasibility of a Skill-based Education Model to Improve Medication Management.

OBJECTIVE: We present the design and feasibility testing for the "Digital Drag and Drop Pillbox" (D-3 Pillbox), a skill-based educational approach that engages patients and providers, measures performance, and generates reports of medication management skills. METHODS: A single-cohort convenience sample of patients hospitalized with heart failure was taught pill management skills using a tablet-based D-3 Pillbox. Medication reconciliation was conducted, and aptitude, performance (% completed), accuracy (% correct), and feasibility were measured. RESULTS: The mean age of the sample (n = 25) was 59 (36-89) years, 50% were women, 62% were black, 46% were uninsured, 46% had seventh-grade education or lower, and 31% scored very low for health literacy. However, most reported that the D-3 Pillbox was easy to read (78%), easy to repeat-demonstrate (78%), and comfortable to use (tablet weight) (75%). Accurate medication recognition was achieved by discharge in 98%, but only 25% reported having a "good understanding of my responsibilities." CONCLUSIONS: The D-3 Pillbox is a feasible approach for teaching medication management skills and can be used across clinical settings to reinforce skills and medication list accuracy.

Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials.

BACKGROUND: Patients with advanced cancer frequently experience anorexia and cachexia, which are associated with reduced food intake, altered body composition, and decreased functionality. We assessed anamorelin, a novel ghrelin-receptor agonist, on cachexia in patients with advanced non-small-cell lung cancer and cachexia. METHODS: ROMANA 1 and ROMANA 2 were randomised, double-blind, placebo-controlled phase 3 trials done at 93 sites in 19 countries. Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia (defined as ≥5% weight loss within 6 months or body-mass index <20 kg/m(2)) were randomly assigned 2:1 to anamorelin 100 mg orally once daily or placebo, with a computer-generated randomisation algorithm stratified by geographical region, cancer treatment status, and weight loss over the previous 6 months. Co-primary efficacy endpoints were the median change in lean body mass and handgrip strength over 12 weeks and were measured in all study participants (intention-to-treat population). Both trials are now completed and are registered with ClinicalTrials.gov, numbers NCT01387269 and NCT01387282. FINDINGS: From July 8, 2011, to Jan 28, 2014, 484 patients were enrolled in ROMANA 1 (323 to anamorelin, 161 to placebo), and from July 14, 2011, to Oct 31, 2013, 495 patients were enrolled in ROMANA 2 (330 to anamorelin, 165 to placebo). Over 12 weeks, lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 (median increase 0·99 kg [95% CI 0·61 to 1·36] vs -0·47 kg [-1·00 to 0·21], p<0·0001) and ROMANA 2 (0·65 kg [0·38 to 0·91] vs -0·98 kg [-1·49 to -0·41], p<0·0001). We noted no difference in handgrip strength in ROMANA 1 (-1·10 kg [-1·69 to -0·40] vs -1·58 kg [-2·99 to -1·14], p=0·15) or ROMANA 2 (-1·49 kg [-2·06 to -0·58] vs -0·95 kg [-1·56 to 0·04], p=0·65). There were no differences in grade 3-4 treatment-related adverse events between study groups; the most common grade 3-4 adverse event was hyperglycaemia, occurring in one (<1%) of 320 patients given anamorelin in ROMANA 1 and in four (1%) of 330 patients given anamorelin in ROMANA 2. INTERPRETATION: Anamorelin significantly increased lean body mass, but not handgrip, strength in patients with advanced non-small-cell lung cancer. Considering the unmet medical need for safe and effective treatments for cachexia, anamorelin might be a treatment option for patients with cancer anorexia and cachexia. FUNDING: Helsinn Therapeutics.

Emerging Issues and Opportunities in Health Information Technology.

When used effectively, health information technology (HIT) can transform clinical care and contribute to new research discoveries. Despite advances in HIT and increased electronic health record adoption, many challenges to optimal use, interoperability, and data sharing exist. Data standardization across systems is limited, and scanned medical note documents result in unstructured data that make reporting on quality measures for reimbursement burdensome. Different policies and initiatives, including the Health Information Technology for Economic and Clinical Health Act, the Medicare Access and CHIP Reauthorization Act, and the National Cancer Moonshot initiative, among others, all recognize the impact that HIT can have on cancer care. Given the growing role HIT plays in health care, it is vital to have effective and efficient HIT systems that can exchange information, collect credible data that is analyzable at the point of care, and improves the patient-provider relationship. In June 2016, NCCN hosted the Emerging Issues and Opportunities in Health Information Technology Policy Summit. The summit addressed challenges, issues, and opportunities in HIT as they relate to cancer care. Keynote presentations and panelists discussed moving beyond Meaningful Use, HIT readiness to support and report on quality care, the role of HIT in precision medicine, the role of HIT in the National Cancer Moonshot initiative, and leveraging HIT to improve quality of clinical care.