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PURPOSE: Early palliative care (PC) with standard oncology care has demonstrated improved patient outcomes, but multiple care delivery models are utilized. This study prospectively evaluated the feasibility of an embedded PC clinic model and collected patient-reported outcomes (PROs) and caregiver needs. METHODS: In this observational study of embedded outpatient PC for patients with advanced thoracic malignancies treated at The Ohio State University Thoracic Oncology clinic, patients received same-day coordinated oncology and palliative care visits at one clinic location. PC encounters included comprehensive symptom assessment and management, advanced care planning, and goals of care discussion. Multiple study assessments were utilized. We describe the feasibility of evaluating PROs and caregiver needs in an embedded PC model. RESULTS: Forty patients and 28 caregivers were enrolled. PROs were collected at baseline and follow-up visits. Over a 12-month follow-up, 36 patients discontinued study participation due to hospice enrollment, death, study withdrawal, or COVID restrictions. At baseline, 32 patients (80%) rated distress as moderate-severe with clinically significant depression (44%) and anxiety (36%). Survey completion rates significantly decreased over time: 3 months (24 eligible, 66% completed), 6 months (17 eligible; 41% completed), 9 months (9 eligible; 44% completed), and 12 months (4 eligible; 50% completed). CONCLUSION: We found that an embedded PC clinic was feasible, although there were challenges encountered in longitudinal collection of PROs due to high study attrition. Ongoing assessment and expansion of this embedded PC model will continue to identify strengths and challenges to improve patient and caregiver outcomes.
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COVID-19 , Neoplasias Torácicas , Humanos , Cuidados Paliativos , Estudios de Factibilidad , Pacientes Ambulatorios , Neoplasias Torácicas/terapiaRESUMEN
INTRODUCTION: Immune checkpoint inhibitors (ICI) are associated with unique immune-related adverse events (irAEs). Immune-related thrombocytopenia (irTCP) is an understudied and poorly understood toxicity; little data are available regarding either risk of irTCP or the effect of irTCP on clinical outcomes of patients treated with ICI. METHODS: We conducted a retrospective review of sequential cancer patients treated with ICI between 2011 and 2017 at our institution. All patients who received ICI alone or in combination with other systemic therapy in any line of treatment were included; those with thrombocytopenia ≥ grade 3 at baseline were excluded. We calculated the incidence of ≥ grade 3 irTCP and overall survival (OS). Patient factors associated with irTCP were assessed. RESULTS: We identified 1,038 patients that met eligibility criteria. Overall, 89 (8.6%) patients developed grade ≥ 3 thrombocytopenia; eighteen were attributed to ICI (1.73% overall). Patients who developed grade ≥ 3 irTCP had worse overall survival compared to those whose thrombocytopenia was unrelated to ICI (4.17 vs. 10.8 month; HR. 1.94, 95% CI 1.13, 3.33; log-rank p = 0.0164). Patients with grade ≥ 3 irTCP also had worse survival compared to those without thrombocytopenia (4.17 vs. 13.31 months; HR 2.22, 95% CI 1.36, 3.62; log-rank p = 0.001). The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy (p = 0.059) and was not associated with cancer type, smoking status, age, gender, race, or line of therapy. CONCLUSIONS: Unlike other irAEs, we found that irTCP was associated with worse overall survival. The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy.
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Neoplasias , Trombocitopenia , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Incidencia , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/epidemiologíaRESUMEN
BACKGROUND: Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort. PATIENTS AND METHODS: We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors. RESULTS: We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs. CONCLUSIONS: Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Nivolumab/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that may complicate treatment with immune checkpoint inhibitors (ICI) and can cause significant morbidity. We sought to identify predictors for the development of CIP, and whether the use of inhaled corticosteroids (ICS) at time of ICI may be protective. METHODS: Patients with advanced cancer treated with ICI from 2011 and 2018 were included in this study. CIP attribution to ICI was determined by treating physician at time of diagnosis. Predictors were assessed by univariate and multivariable Cox proportional hazard models. RESULTS: We identified 837 pts treated with ICI, of whom 30 (3.6%) developed grade 2 or higher CIP. 82 patients (9.8%) were receiving ICS at time of ICI and had increased risk of developing CIP with hazard ration (HR) of 4.22 (95% CI 1.93-9.21, p < 0.001) compared to those patients not receiving ICS. Patients with age ≥ 65 years had increased risk of developing CIP (HR 2.12, 95% CI 1.02-4.40, p = 0.044), as did 209 patients with lung cancer (198 NSCLC and 11 SCLC) compared to other types of cancers (HR 3.15, 95% CI 1.54-6.46, p = 0.002). In multivariable analysis, age ≥ 65 years, lung cancer diagnosis, and ICS use remained statistically associated with the development of CIP, with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009). CONCLUSIONS: Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age ≥ 65 years and lung cancers as independent risk factors for CIP.
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Corticoesteroides/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Neumonía/inducido químicamente , Administración por Inhalación , Adulto , Anciano , Antiinflamatorios/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
PURPOSE: Early integration of palliative care (PC) with standard oncology care is driving the development of innovative PC delivery models. METHODS: This was a single-institution retrospective study of outpatient PC before and after the opening of an embedded thoracic oncology-palliative clinic at The Ohio State University. Patients included in the preintervention (October 2017-July 2018) and postintervention (October 2018-July 2019) cohorts had a diagnosis of any non-small-cell lung cancer (stages I-IV) or small-cell lung cancer (limited or extensive stage) and were newly established in the thoracic medical oncology clinic during the study time periods. All patients in the preintervention cohort had access to outpatient PC through a freestanding clinic, while the postintervention cohort had access to both freestanding and embedded clinics. Using time-to-event analyses, we evaluated differences in time intervals from first medical oncology visit to PC referral and first PC visit between cohorts. RESULTS: The majority of patients in both cohorts had metastatic disease at diagnosis. In the postintervention cohort, 20.9% of patients were referred to outpatient PC compared with 9.2% in the preintervention cohort (P < .01). PC referrals for patients outside of Franklin and adjacent counties increased from 4.0% to 14.2% after opening the embedded clinic (P < .01). Completion percentages of PC referrals increased from 57.6% to 76.0% in the preintervention versus postintervention cohorts (P = .048). Median time from palliative referral order to first PC visit decreased from 29 to 20 days (P = .047). Similarly, median time from the first oncology visit to PC referral completion decreased from 103 to 41 days (P = .08). CONCLUSION: Implementation of an embedded PC model was associated with increased access to early PC among patients with thoracic malignancies.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Torácicas , Humanos , Cuidados Paliativos , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/terapia , Estudios Retrospectivos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/terapia , Neoplasias Torácicas/terapiaRESUMEN
PURPOSE: Immune checkpoint inhibitors (ICIs) are associated with a unique set of immune-related adverse events (irAEs). Few studies have evaluated the risk factors and outcomes of patients who develop ICI-induced hepatitis (ICIH). METHODS: We utilized an institutional database of patients with advanced cancers treated with ICI to identify patients with ICIH. irAEs were graded using the Common Terminology Criteria for Adverse Events v4. Overall survival (OS) was calculated from the date of ICI to death from any cause or the date of the last follow-up. OS with 95% confidence intervals were estimated using the Kaplan-Meier method and stratified by the occurrence of ICIH. RESULTS: We identified 1096 patients treated with ICI. The most common ICIs were PD1/L1 (n = 774) and CTLA-4 inhibitors (n = 195). ICIH occurred among 64 (6%) patients: severity was < grade 3 in 30 and ≥ grade 3 in 24 patients (3.1% overall). Median time to ICIH was 63 days. ICIH was more frequent in women (p = 0.038), in patients treated with combination ICIs (p < 0.001), and when given as first-line therapy (p = 0.018). Occurrence of ICIH was associated with significantly longer OS, median 37.0 months (95% CI 21.4, NR) compared to 11.3 months (95% CI 10, 13, p < 0.001); there was no difference in OS between patients with ≥ grade 3 ICIH vs grade 1-2. CONCLUSIONS: Female sex, combination immunotherapy, and the first line of immunotherapy were associated with ICIH. Patients with ICIH had improved clinical survival compared to those that did not develop ICIH. There is a need for prospective further studies to confirm our findings.
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Hepatitis , Neoplasias , Humanos , Femenino , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estudios Retrospectivos , Neoplasias/tratamiento farmacológico , Factores de RiesgoRESUMEN
Video: Lorlatinib podcast video.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Aminopiridinas/efectos adversos , Humanos , Lactamas , Lactamas Macrocíclicas/efectos adversos , PirazolesRESUMEN
Introduction: Palliative care is beneficial for patients with advanced lung cancer, but the optimal model of palliative care delivery is unknown. We investigated healthcare utilization before and after embedding a palliative care physician within a thoracic medical oncology "onco-pall" clinic. Methods: This is a retrospective cross-sectional cohort study comparing healthcare outcomes in two cohorts: "pre-cohort" 12 months prior to and "post-cohort" 12-months after the onco-pall clinic start date. Patients were included if they had a new diagnosis of lung cancer and received care at The Ohio State University Thoracic Oncology Center, and resided in Franklin County or 6 adjacent counties. During the pre-cohort time period, access to palliative care was available at a stand-alone palliative care clinic. Palliative care intervention in both cohorts included symptom assessment and management, advance care planning, and goals of care discussion as appropriate. Outcomes evaluated included rates of emergency department (ED) visits, hospital admissions, 30-day readmissions, and intensive care unit (ICU) admissions. Estimates were calculated in rates per-person-years and with Poisson regression models. Results: In total, 474 patients met criteria for analysis (214 patients included in the pre-cohort and 260 patients in the post-cohort). Among all patients, 52% were male and 48% were female with a median age of 65 years (range 31-92). Most patients had non-small cell lung cancer (NSCLC - 17% stage 1-2, 20% stage 3, 47% stage 4) and 16% had small cell lung cancer. The post-cohort was older [median age 66 years vs 63 years in the pre-cohort (p-value: < 0.01)]. The post-cohort had a 26% reduction in ED visits compared to the pre-cohort, controlling for age, race, marital status, sex, county, Charlson score at baseline, cancer type and stage (adjusted relative risk: aRR: 0.74, 95% CI: 0.58-0.94, p-value = 0.01). Although not statistically significant, there was a 29% decrease in ICU admissions (aRR: 0.71, 95% CI: 0.41-1.21, p-value = 0.21) and a 15% decrease in hospital admissions (aRR: 0.85, 95% CI: 0.70-1.03, p-value = 0.10). There was no difference in 30-day readmissions (aRR: 1.03, 95% CI: 0.73-1.45, p-value = 0.85). Conclusions: Embedding palliative care clinics within medical oncology clinics may decrease healthcare utilization for patients with thoracic malignancies. Further evaluation of this model is warranted.
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BACKGROUND: Brigatinib, a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is central nervous system (CNS) penetrant and active against anaplastic lymphoma kinase (ALK) resistance mutations. We prospectively studied the activity of brigatinib in patients with disease progression after second generation ALK TKIs. METHODS: Patients with stage IIIB/IV ALKâ¯+â¯non-small cell lung cancer (NSCLC), and progressive disease after second ALK TKIs were eligible. Cohort A enrolled patients with disease progression on any second ALK TKI, cohort B enrolled patients with disease progression after first-line therapy with alectinib, and cohort C enrolled patients who experienced disease progression on standard dose brigatinib. Brigatinib treatment was 90â¯mg daily for seven days and then escalated to 180â¯mg daily in cohorts A and B, and 240â¯mg daily in cohort C. The primary endpoint was objective response rate (ORR), and a 2-stage design was used. The intended enrollment was 20 patients in stage 1, and 20 patients in stage 2. RESULTS: The study was closed due to slow accrual. Between March 2017 and June 2020, 32 patients received study therapy; three patients in cohort A moved to cohort C after initial progression for a total of 35 study subjects. Of the 32 patients, 16 (50%) were male, the median age was 55â¯years (range 32-76), and patients received a median number of 2 prior ALK TKI's (range 1-3). Cohort A enrolled 27 patients, cohort B enrolled four patients, and cohort C enrolled four patients. The ORR in cohorts A, B, and C was 33% (95% confidence interval (CI: 16% to 54%), 25% (95% CI: 0.63% to 81%), and 0%, respectively. CONCLUSION: Brigatinib has activity in ALK positive NSCLC patients with disease progression after second generation ALK TKIs.
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PURPOSE: Central nervous system metastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges. PATIENTS AND METHODS: Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses. RESULTS: Per investigator assessment, in arms 1 (n = 42), 2 (n = 40), 3 (n = 12), and 4 (n = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6-52.0), 30.0% (16.6-46.5), 50.0% (21.1-78.9), and 59.1% (43.2-73.7); whole-body DCR (95% CI): 66.7% (50.5-80.4), 82.5% (67.2-92.7), 66.7% (34.9-90.1), and 70.5% (54.8-83.2); intracranial ORRs (95% CI): 39.3% (21.5-59.4), 27.6% (12.7-47.2), 28.6% (3.7-71.0), and 51.5% (33.5-69.2). In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI, 3.6-41.4) and DCR was 66.7% (95% CI, 41.0-86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood-brain barrier. CONCLUSIONS: Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease. See related commentary by Murciano-Goroff et al., p. 2477.
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Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Primarias Secundarias , Quinasa de Linfoma Anaplásico/genética , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Sistema Nervioso Central , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas , SulfonasRESUMEN
BACKGROUND: Cancer cachexia exhibits decreased albumin and associates with short overall survival (OS) in patients with non-small cell lung cancer (NSCLC), but whether on-treatment albumin changes associate with OS in NSCLC patients treated with immune checkpoint inhibitors (ICIs) and combination chemoimmunotherapy has not been thoroughly evaluated. PATIENTS AND METHODS: We conducted a single-center retrospective study of patients with advanced NSCLC who received first-line ICI with or without chemotherapy between 2013 and 2020. The association of pretreatment albumin and early albumin changes with OS was evaluated using Kaplan-Meier method and Cox regression models. RESULTS: A total of 210 patients were included: 109 in ICI cohort and 101 in ICI + Chemo cohort. Within a median of 21 days from treatment initiation, patients with ≥ 10% of albumin decrease had significantly shorter OS compared to patients without albumin decrease in ICI cohort. Pretreatment albumin and albumin decrease within the first or second cycle of treatment were significantly and independently associated with OS in ICI cohort, but not in ICI + Chemo cohort. The lack of association between albumin and OS with the addition of chemotherapy was more pronounced among patients with ≥ 1% PD-L1 expression in subgroup analysis. CONCLUSION: Pretreatment serum albumin and early albumin decrease in ICI monotherapy was significantly associated with OS in advanced NSCLC. Early albumin change, as a routine lab value tested in clinic, may be combined with established biomarkers to improve outcome predictions of ICI monotherapy. The underlying mechanism of the observed association between decreased albumin and ICI resistance warrants further investigation.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Pronóstico , Estudios Retrospectivos , Albúmina Sérica/uso terapéuticoRESUMEN
Oncology and Palliative Medicine lack guidance on routine opioid risk screening and compliance monitoring. This study explored relationships among risk screening and aberrant medication related behaviors in patients with advanced lung cancer receiving embedded palliative care. This was a single center, prospective study and data was collected from December 2018 to March 2020. At the initial palliative visit, patients provided a baseline urine drug screen (UDS) test and completed the Screener and Opioid Assessment for Patients with Pain - Revised (SOAPP-R) self-assessment. Clinical pharmacists provided comprehensive review and interpretation of UDS results. Among 39 patients, 12 (30.8%) scored positive for risk of aberrant medication behaviors on the SOAPP-R. Only 34 of 39 patients provided a baseline UDS test and were included in further analysis. Prior to pharmacist review, 11/11 (100%) baseline UDS results in the positive-risk group and 13/23 (56.5%) in the negative-risk group appeared unexpected (p = 0.01). After pharmacist review, aberrant baseline UDS results were confirmed for 5/11 (45.5%) positive-risk and 4/23 (17.4%) negative-risk patients (p = 0.11). Overall, the SOAPP-R alone may be inadequate in this population and clinical pharmacists play an important role in comprehensive UDS result interpretation. Future studies are needed to validate this risk-screening tool in palliative cancer populations.
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Neoplasias Pulmonares , Trastornos Relacionados con Opioides , Analgésicos Opioides/efectos adversos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Cuidados Paliativos , Estudios Prospectivos , Medición de Riesgo , Detección de Abuso de SustanciasRESUMEN
Epigenetic ("above genetics") modifications can alter the gene expression without altering the DNA sequence. Aberrant epigenetic regulations in cancer include DNA methylation, histone methylation, histone acetylation, non-coding RNA, and mRNA methylation. Epigenetic-targeted agents have demonstrated clinical activities in hematological malignancies and therapeutic potential in solid tumors. In this review, we describe mechanisms of various epigenetic modifications, discuss the Food and Drug Administration-approved epigenetic agents, and focus on the current clinical investigations of novel epigenetic monotherapies and combination therapies in solid tumors.
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Antineoplásicos/uso terapéutico , Metilación de ADN/genética , Epigénesis Genética/genética , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Humanos , Neoplasias/inmunologíaRESUMEN
Background: Integration of early outpatient palliative care for patients with advanced cancer requires overcoming logistical constraints as well as attitudinal barriers of referring providers. This pilot study assessed provider perception of logistical and attitudinal barriers to outpatient palliative care referral as well as provider acceptability of an embedded onco-palliative clinic model. Methods: This was a cross-sectional survey-based study of medical oncologists, palliative care physicians, advanced practice providers (APP), and oncology nurses at a large U.S. academic center. Participants were invited to participate through anonymous online survey. Participants rank ordered logistical barriers influencing referral to an outpatient palliative clinic. Respondents indicated level of agreement with attitudinal perception of palliative care and acceptability of an embedded palliative clinic model through five-item Likert-like scales. Results: There were a total of 54 study participants (28 oncology physicians/APPs, 15 palliative physicians/APPs, and 11 oncology nurses). Across the three cohorts, most survey respondents ranked "time burden to patients" as the primary logistical barrier to outpatient palliative care referral. Both oncology and palliative providers indicated comfort with primary palliative care skills although palliative providers were more comfortable with symptom management compared with oncology providers (93.3% vs. 32.2%). A majority of participants (94.9%) were willing to refer to a palliative care provider embedded within an oncology clinic. Conclusion: Additional health care time cost to patients is a major barrier to outpatient palliative care referral. Embedding a palliative care provider in an oncology clinic may be an acceptable model to increase patient access to outpatient palliative care while supporting the oncology team.
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BACKGROUND: Next-generation sequencing of circulating cell-free DNA (cfDNA) can identify sensitizing and resistance mutations in non-small-cell lung cancer (NSCLC). cfDNA is helpful when tissue is insufficient for genomic testing or repeat biopsy is not feasible or poses unacceptable risk. Here we report the experience of cfDNA testing at the time of diagnosis and how this intervention can help avoid further invasive interventions, how it can be used to determine initiation of therapy, and how variation allele frequency of the somatic alteration affects response to subsequent treatment. PATIENTS AND METHODS: This is a single-institution retrospective study of patients with advanced NSCLC who had cfDNA from plasma tested using the Guardant360 panel, which identifies somatic genomic alterations by massive parallel sequencing of target genes. An institutional Clinical Laboratory Improvement Amendments tissue panel using fluorescence in situ hybridization (for MET, RET, ROS1, and ALK) and next-generation sequencing for selected genes was used for tissue analysis. Actionable mutations are those with US Food and Drug Administration-approved targeted therapies (EGFR, ALK, ROS, BRAF, NTRK fusions) or therapies soon to be approved (RET fusions and MET amplifications, or MET exon 14 skipping mutation). RESULTS: A total of 163 blood samples from 143 patients were evaluated, 82 at diagnosis and 81 at disease progression. A total of 94 cases had tissue and cfDNA testing performed within 12 weeks of each other. Seventy-six (81%) of 94 cases were concordant, of which 22 cases were concordantly positive and 54 concordantly negative. Eighteen (19%) of 94 cases were discordant, of which 11 had negative blood and positive tissue results, and 7 had positive blood and negative tissue results. cfDNA testing had a sensitivity of 67% (95% confidence interval [CI], 51%, 83%), specificity of 89% (95% CI, 81%, 97%), negative predictive value of 83% (95% CI, 74%, 92%), and positive predictive value of 76% (95% CI, 60%, 91%). Nineteen (21%) of 82 cfDNA samples analyzed at diagnosis had actionable mutations identified (4 EGFR exon 19 deletion, 2 EGFR exon 21 L858R, 2 EGFR L861Q, 1 L861R, 4 EML4-ALK fusion, 2 CD74-ROS1 fusion, 2 MET exon 14 skipping mutation, 2 KIF5B-RET fusion). Of the 82 patients with cfDNA testing performed at the time of diagnosis, 8 patients (10%) initiated targeted therapy on the basis of cfDNA results only, with 6 patients experiencing partial response, 1 patient complete response, and 1 patient stable disease. The response rate for patients who initiated targeted therapies on the basis of cfDNA only at diagnosis was 88%. Variant allele frequency had no impact on response. CONCLUSIONS: Initiation of targeted therapy for advanced NSCLC was feasible based only on identification of actionable mutations by cfDNA testing in 9% of the cases for which tissue diagnosis could not be obtained. Actionable targets were identified by cfDNA in 20% of the samples sent at diagnosis. A substantial number of patients benefited from cfDNA testing at initial diagnosis because it identified actionable mutations that led to appropriate targeted treatments.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Ácidos Nucleicos Libres de Células/genética , Neoplasias Pulmonares/terapia , Terapia Molecular Dirigida , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Osimertinib is an effective therapy in EGFR-mutant non-small cell lung cancer (NSCLC), but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of EGFR-mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance. PATIENTS AND METHODS: This single-arm phase Ib study evaluated safety, tolerability, and feasibility of osimertinib and navitoclax, including dose expansion in T790M-positive patients at the recommended phase II dose (RP2D). Eligible patients had advanced EGFR-mutant NSCLC with prior tyrosine kinase inhibitor exposure. Five dose levels were planned with osimertinib from 40 to 80 mg orally daily and navitoclax from 150 to 325 mg orally daily. RESULTS: A total of 27 patients were enrolled (18 in the dose-escalation cohort and nine in the dose-expansion cohort): median age 65, 67% female, 48% exon 19 del, and 37% L858R, median one prior line of therapy. The most common adverse events were lymphopenia (37%), fatigue (22%), nausea (22%), and thrombocytopenia (37%). No dose-limiting toxicities were seen in dose-escalation cohort; osimertinib 80 mg, navitoclax 150 mg was chosen as the RP2D. Most patients (78%) received >95% of planned doses through three cycles. In expansion cohort, objective response rate was 100% and median progression-free survival was 16.8 months. A proapoptotic effect from navitoclax was demonstrated by early-onset thrombocytopenia. CONCLUSIONS: Oral combination therapy with navitoclax and osimertinib was safe and feasible at RP2D with clinical efficacy. Early thrombocytopenia was common, supporting an target engagement by navitoclax. Further study of BCL-2/BCL-xL inhibition to enhance osimertinib activity is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Acrilamidas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Compuestos de Anilina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Sulfonamidas/administración & dosificación , Distribución TisularRESUMEN
Chronic lymphocytic leukemia (CLL) is associated with perturbed immune function and increased risk for second primary malignancies (SPM). Ibrutinib and acalabrutinib (BTKi) are effective therapies for CLL resulting in partial restoration of immune function. The incidence of and risk factors for SPM in CLL patients receiving BTKi are not yet characterized. We retrospectively determined the incidence of SPM in CLL patients treated with ibrutinib or acalabrutinib at our institution between 2009 and 2017, assessed for association between baseline characteristics and SPM incidence, and compared the observed to expected cancer incidence among age, sex, and year matched controls without CLL. After a median of 44 months follow-up, 64/691 patients (9%) were diagnosed with SPM (excluding non-melanoma skin cancer [NMSC]). The 3-year cumulative incidence rate was 16% for NMSC and 7% for other SPM. On multivariable analysis, smoking was associated with increased SPM risk (HR 2.8 [95% CI: 1.6-4.8]) and higher baseline CD8 count was associated with lower SPM risk (HR 0.9 for 2-fold increase [95% CI: 0.8-0.9]). The observed over expected rate of SPM was 2.2 [95% CI: 1.7-2.9]. CLL patients treated with BTKi remain at increased risk for SPM, and secondary cancer detection is an important consideration in this population.
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Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/etiología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas/efectos adversos , Benzamidas/uso terapéutico , Femenino , Humanos , Incidencia , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Pirazinas/efectos adversos , Pirazinas/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVES: Chemotherapy remains a cornerstone treatment in non-small cell lung cancer either in combination with checkpoint inhibitors or as subsequent therapy. Identifying molecular predictors of response allows for optimal treatment selection. We performed genomic analysis on tumor samples of patients treated with carboplatin and nab-paclitaxel as part of a phase II trial to evaluate the prognostic and predictive value of mutations in DNA repair pathway in patients treated with this regimen. MATERIALS AND METHODS: Next-generation sequencing libraries were produced using a capture-based targeted panel covering the coding exons of 278 genes on patients treated on clinical trial NCT00729612. Overall survival (OS) and progression-free survival (PFS) were assessed as part of the clinical outcomes and correlated with mutation analysis. RESULTS: Of 63 patients enrolled, 25 patients had sufficient and acceptable DNA isolated from archival tumor samples for targeted sequencing. The most commonly altered pathways included DNA repair (DR) including Fanconi anemia and homologous recombination, JAK-STAT signaling, IGF-1, mTOR, and MAPK-ERK. Four patients with mutations in homologous recombination mutations had a shorter PFS (hazard ratio [HR]â¯=â¯4.54, 95% CI 1.2, 17.1, pâ¯=â¯0.026) and OS (HRâ¯=â¯6.3, 95% CI 1.8, 21.3, pâ¯=â¯0.003). CONCLUSION: In this analysis of patients with predominantly squamous cell non-small cell lung cancer treated with carboplatin and nab-paclitaxel in a phase II trial, patients with mutations in homologous recombination pathways had shorter overall and progression-free survival. Validation on additional datasets of patients treated with platinum-based chemotherapy and immunotherapy combinations is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Reparación del ADN , Recombinación Homóloga , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Masculino , Metástasis de la Neoplasia , Estadificación de Neoplasias , Paclitaxel/administración & dosificaciónRESUMEN
BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR. METHODS: A retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in R, and SPSS. RESULTS: 509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8-33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1-16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9-9.1). CONCLUSIONS: We confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.
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Recuento de Leucocitos , Recuento de Linfocitos , Linfocitos , Neoplasias/sangre , Neoplasias/mortalidad , Neutrófilos , Adulto , Anciano , Biomarcadores , Femenino , Humanos , Inmunoterapia , Estimación de Kaplan-Meier , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Neoplasias/terapia , Neutrófilos/inmunología , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
IMPORTANCE: Erlotinib is a standard first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) with erlotinib is approximately 10 months. OBJECTIVE: To determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 randomized clinical trial compared erlotinib plus bevacizumab with erlotinib alone in EGFR-mutant NSCLC. The trial was conducted in 17 US academic and community medical centers among 88 patients with EGFR exon 19 deletion or exon 21 L858R mutation based on local testing and stage 4 NSCLC who were eligible for bevacizumab. Patients were enrolled between November 2, 2012, and August 22, 2016, and followed up for a median (range) of 33 (0.7-62.5) months. Data were analyzed on August 28, 2018, and included data from November 2, 2012, to August 20, 2018. INTERVENTIONS: Patients were randomized with equal allocation to 150 mg of oral erlotinib daily alone or with 15 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent. MAIN OUTCOMES AND MEASURES: The primary outcome was PFS as assessed by the investigator; secondary outcomes were objective response rate (ORR), adverse events, and overall survival (OS). Analysis was designed to detect a hazard ratio (HR) of 0.667 for PFS (an improvement from a median PFS of 10 to 15 months). RESULTS: Among 88 patients enrolled, the median (range) age was 63 (31-84) years; 62 patients (70%) were female; 75 (85%) were white, 8 (9%) were African American, 3 (3%) were Asian, and for 2 (2%), data on race were not available. Forty-eight patients (55%) were never smokers, 45 patients (51%) were of Eastern Cooperative Oncology Group performance status 1, and 59 patients (67%) had EGFR exon 19 deletion. Compared with erlotinib, the combination did not result in a significant difference in PFS (HR, 0.81; 95% CI, 0.50-1.31; P = .39; median PFS 17.9 [combination] and 13.5 months [erlotinib]), ORR (81% vs 83%; P = .81), and OS (HR, 1.41; 95% CI, 0.71-2.81; P = .33; median OS, 32.4 months [combination] and 50.6 months [erlotinib]). Adverse events of grade 3 or higher observed in 5 or more patients in the combination and erlotinib arms were skin eruption in 11 (26%) vs 7 (16%) patients, diarrhea in 4 (9%) vs 6 (13%) patients, hypertension in 17 (40%) vs 9 (20%) patients, and proteinuria in 5 (12%) vs 0 (0%) patients. CONCLUSIONS AND RELEVANCE: Erlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01532089.