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Patients with previous cancer are often excluded from clinical trials despite limited evidence about their prognosis. We examined the effect of previous cancer on overall and colorectal cancer (CRC)‐specific survival of patients newly diagnosed with CRC. This population‐based cohort study from the U.S.A. included patients aged ≥66 years and diagnosed with CRC between 2005 and 2015 in linked Surveillance, Epidemiology, and End Results‐Medicare data. We estimated the stage‐specific effects of a previous cancer on overall survival using Cox regression and on CRC‐specific survival using competing risk regression. We also examined the effect of previous cancer type, timing, and stage on overall survival. Of 112,769 patients, 14.1% were previously diagnosed with another cancer––commonly prostate (32.9%) or breast (19.4%) cancer, with many (47.1%) diagnosed <5 years of CRC. For all CRC stages except IV, in which there was no difference, patients with previous cancer (vs. without) had worse overall survival. However, patients with previous cancer had improved CRC‐specific survival. Overall survival for those with stage 0–III CRC varied by previous cancer type, timing, and stage; for example, patients with previous melanoma had overall survival equivalent to those with no previous cancer. Our results indicate that, in general, CRC patients with previous cancer have worse overall survival but superior CRC‐specific survival. Given their equivalent survival to those without previous cancer, patients with previous melanoma and those with stage IV CRC with any type of previous cancer should be eligible to participate in clinical trials. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have emerged as a remarkable treatment option for diverse cancer types. However, a significant number of patients on checkpoint inhibitors develop immune-related adverse events (irAEs) affecting a wide variety of organs. These events, which may reflect enhanced T cell activation, are unpredictable, heterogeneous, and in some instances permanent or life-threatening. It is not clear whether these toxicities are distinct from conventional autoimmune diseases or whether the manifestation of irAEs is associated with therapeutic efficacy. Studies across the spectrum of basic, preclinical and clinical research deciphering the role of genetics, epigenetics, gut microbiota and underlying immune status of patients who develop irAEs are required to gain a deeper mechanistic understanding. Insights gained from such studies will facilitate identification of biomarkers for optimal treatment and clinical management of patients. In this Review, we provide basic and clinical understanding of immune checkpoint inhibitors and irAEs. We discuss the connection between immune system, autoimmunity and cancer; immune checkpoint inhibitors and associated autoimmune toxicities; insights into potential underlying mechanisms of irAEs; impact of autoimmune diagnosis on cancer outcome; and management of irAEs. [ABSTRACT FROM AUTHOR]

• KRAS mutant non-small cell lung cancer (NSCLC) is a major unmet clinical need. • RHOA-focal adhesion kinase (FAK) pathway is a signaling axis for KRAS mutant NSCLC. • KRAS mutant NSCLC models with TP53 or CDKN2A alterations respond to FAK inhibition. • Defactinib (VS-6063) is a selective oral inhibitor of FAK. • Defactinib had modest effects in KRAS mutant NSCLC, independent of TP53 or CDKN2A. KRAS mutations, which occur in approximately 25% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either TP53 or CDKN2A (INK4A/ARF) loci are sensitive to focal adhesion kinase (FAK) inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK. Patients with previously treated advanced KRAS mutant NSCLC were prospectively assigned to one of four molecularly defined cohorts based on the presence or absence of TP53 or CDKN2A alterations and received treatment with defactinib 400 mg orally BID until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 12 weeks. Fifty-five patients were enrolled. Mean age was 62 years; 51% were female. The median number of prior lines of therapy was 4 (range 1–8). Fifteen (28%) patients met the 12-week PFS endpoint, with one patient achieving a partial response. Median PFS was 45 days. Clinical efficacy did not correlate with TP53 or CDKN2A status. The most common adverse events were fatigue, gastrointestinal, and increased bilirubin, and were generally grade 1 or 2 in severity. In heavily pretreated patients with KRAS mutant NSCLC, defactinib monotherapy demonstrated modest clinical activity. Efficacy was not associated with TP53 and CDKN2A status. Defactinib was generally well tolerated. [ABSTRACT FROM AUTHOR]

Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a β-lapachone (β-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death.Methods: We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200).Results: A total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m2 as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease (n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours (P = 0.06).Conclusions: ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia. [ABSTRACT FROM AUTHOR]

The article discusses issues associated with the concept of oligometastatic disease in non-small-cell lung cancer (NSCLC). Topics discused include major improvements in systemic therapy to provide disease control to more patients, state-of-the-art overview on the management of patients with oligometastatic NSCLC and use of stereotactic radiation to increase the likelihood of killing more cancer cells before development of resistance develops.

The National Lung Screening Trial demonstrated improved lung cancer mortality with annual low-dose computed tomography (CT) screening, leading to lung cancer screening endorsement by the United States Preventive Services Task Force and coverage by the Centers for Medicare and Medicaid. Adherence to annual CT screens in that trial was 95%, which may not be representative of real-world, particularly medically underserved populations. This pragmatic trial will determine the effect of patient-focused, telephone-based patient navigation on adherence to CT-based lung cancer screening in an urban safety-net population. 340 adults who meet standard eligibility for lung cancer screening (age 55–77 years, smoking history ≥ 30 pack-years, quit within 15 years if former smoker) are referred through an electronic medical record-based order by physicians in community- and hospital-based primary care settings within the Parkland Health and Hospital System in Dallas County, Texas. Eligible patients are randomized to usual care or patient navigation, which addresses adherence, patient-reported barriers, smoking cessation, and psycho-social concerns related to screening completion. Patients complete surveys and semi-structured interviews at baseline, 6-month, and 18-month follow-ups to assess attitudes toward screening. The primary endpoint of this pragmatic trial is adherence to three sequential, prospectively defined steps in the screening protocol. Secondary endpoints include self-reported tobacco use and other patient-reported outcomes. Results will provide real-world insight into the impact of patient navigation on adherence to CT-based lung cancer screening in a medically underserved population. This study was registered with the NIH ClinicalTrials.gov database ( NCT02758054 ) on April 26, 2016. [ABSTRACT FROM AUTHOR]

Background In non-small cell lung cancer (NSCLC), platelet-derived growth factor receptor (PDGFR) mediates angiogenesis, tissue invasion, and tumor interstitial pressure. Olaratumab (IMC-3G3) is a fully human anti-PDGFRα monoclonal antibody. This Phase II study assessed safety and efficacy of olaratumab + paclitaxel/carboplatin (P/C) versus P/C alone for previously untreated advanced NSCLC. Materials and methods Patients received up to six 21-day cycles of P 200 mg/m 2 and C AUC 6 (day 1) ± olaratumab 15 mg/kg (days 1 and 8). Primary endpoint was PFS. Olaratumab was continued in the olaratumab + P/C arm until disease progression. Results 131 patients were: 67 with olaratumab + P/C and 64 with P/C; 74% had nonsquamous NSCLC. Median PFS was similar between olaratumab + P/C and P/C (4.4 months each) (HR 1.29; 95% CI [0.86–1.93]; p = 0.21). Median OS was similar between olaratumab + P/C (11.8 months) and P/C (11.5 months) (HR 1.04; 95% CI [0.68–1.57]; p = 0.87). Both arms had similar toxicity profiles. All evaluable cases were PDGFR-negative by immunohistochemistry. Tumor stroma PDGFR expression was evaluable in 23/131 patients, of which 78% were positive. Conclusions The addition of olaratumab to P/C did not result in significant prolongation of PFS or OS in advanced NSCLC. Olaratumab studies in other patient populations, including soft tissue sarcoma (NCT02783599), pancreatic cancer (NCT03086369), and pediatric malignancies (NCT02677116) are underway. [ABSTRACT FROM AUTHOR]

Purpose/Objectives: To identify nursing staff reactions to and perceptions of electronic portal use in a cancer setting. Research Approach: Qualitative. Setting: Outpatient clinic at the Harold C. Simmons Comprehensive Cancer Center of the University of Texas Southwestern Medical Center in Dallas. Participants: 13 nurses with a range of credentials and experience, representing infusion, medical oncology, and bone marrow transplantation clinics. Methodologic Approach: Two focus groups were conducted. Theoretical thematic content analysis of data was performed. Findings: Key themes that emerged for consideration of electronic portals included work volume and flow, patient expectations and safety, variation in use of communication technologies, and education and management. Interpretation: The current study provides insight into the implications of electronic portals by identifying nursing staff reactions to this technology. These reactions are predominantly related to the impact on clinical workload and patient safety and expectations. Implications for Nursing: As clinical cancer facilities incorporate electronic portal technology into their operations, attention to the impact on staff workload, division of labor, patient safety, and patient expectations should be considered. [ABSTRACT FROM AUTHOR]

The advent of precision medicine in non-small cell lung cancer has remarkably altered the direction of research and improved clinical outcomes. The identification of molecular subsets with differential response to targeted therapies began with the identification of epidermal growth factor receptor mutated tumors in subsets of non-small cell lung cancer (NSCLC). Emboldened by unprecedented response rates to kinase inhibitors seen in that subset, the oncologic community searched for other molecular subsets featuring oncogene addiction. An early result of this search was the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene. In an astoundingly brief period following the recognition of ALK-positive NSCLC, details of the biology, clinicopathologic features, development of targeted inhibitors, mechanisms of therapeutic resistance, and new generations of treatment were elucidated. This review summarizes the current understanding of the pathologic features, diagnostic approach, treatment options, resistance mechanisms, and future research areas for ALK-positive NSCLC. [ABSTRACT FROM AUTHOR]

This article describes the care processes for a 64-year-old man with newly diagnosed advanced non-small-cell lung cancer who was enrolled in a first-line clinical trial of a new immunotherapy regimen. The case highlights the concept of multiteam systems in cancer clinical research and clinical care. Because clinical research represents a highly dynamic entity--with studies frequently opening, closing, and undergoing modifications--concerted efforts of multiple teams are needed to respond to these changes while continuing to provide consistent, high-level care and timely, accurate clinical data. The case illustrates typical challenges of multiteam care processes. Compared with clinical tasks that are routinely performed by single teams, multiple-team care greatly increases the demands for communication, collaboration, cohesion, and coordination among team members. As the case illustrates, the described research team and clinical team are separated, resulting in suboptimal function. Individual team members interact predominantly with members of their own team. A considerable number of team members lack regular interaction with anyone outside their team. Accompanying this separation, the teams enact rivalries that impede collaboration. The teams have misaligned goals and competing priorities that create competition. Collective identity and cohesion across the two teams are low. Research team and clinical team members have limited knowledge of the roles and work of individuals outside their team. Recommendations to increase trust and collaboration are provided. Clinical providers and researchers may incorporate these themes into development and evaluation of multiteam systems, multidisciplinary teams, and cross-functional teams within their own institutions. [ABSTRACT FROM AUTHOR]

Purpose Preclinical studies demonstrated anti-tumor efficacy of the combination of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in non-small cell lung cancer (NSCLC) models that were insensitive to erlotinib monotherapy. We therefore studied this combination in a phase 1 clinical trial in previously treated advanced NSCLC. Methods Romidepsin (8 or 10 mg/m 2 ) was administered intravenously on days 1, 8, and 15 every 28 days in combination with erlotinib (150 mg orally daily), with romidepsin monotherapy lead-in during Cycle 1. Correlative studies included peripheral blood mononuclear cell HDAC activity and histone acetylation status, and EGFR pathway activation status in skin biopsies. Results A total of 17 patients were enrolled. Median number of prior lines of therapy was 3 (range 1–5). No cases had a sensitizing EGFR mutation. The most common related adverse events were nausea, vomiting, and fatigue (each 82%), diarrhea (65%), anorexia (53%), and rash (41%). Dose-limiting nausea and vomiting occurred at the romidepsin 10 mg/m 2 level despite aggressive antiemetic prophylaxis and treatment. Among 10 evaluable patients, the best response was stable disease ( n = 7) and progressive disease ( n = 3). Median progression-free survival (PFS) was 3.3 months (range 1.4–16.5 months). Prolonged PFS (>6 months) was noted in a KRAS mutant adenocarcinoma and a squamous cell cancer previously progressed on erlotinib monotherapy. Romidepsin monotherapy inhibited HDAC activity, increased histone acetylation status, and inhibited EGFR phosphorylation. Conclusions Romidepsin 8 mg/m 2 plus erlotinib appears well tolerated, has evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population. [ABSTRACT FROM AUTHOR]

As clinical trials have become more complex, with increasing numbers of required procedures and clinic visits, gaining access to promising new treatments has become even more challenging for many individuals. To address these barriers, we implemented a financial reimbursement and outreach program designed to increase the number and diversity of participants in cancer clinical trials at centers in Dallas, Houston, and Philadelphia. As endorsed by U.S. Food and Drug Administration (FDA) and the Texas and Pennsylvania State Legislatures, the program provides financial reimbursement for non-clinical costs (e.g., travel, lodging) to patients on cancer clinical trials with household income up to 700% the Federal poverty rate. The research study described here, centered at the Dallas site, evaluates program impact by assessing (1) numbers and diversity of patients enrolled to cancer clinical trials before and after program implementation; (2) characteristics of patients offered participation in the program who do versus do not enroll; (3) characteristics of patients enrolled in the program who do versus do not complete the reimbursement process. To evaluate perceived barriers and facilitators of program participation, we will conduct semi-structured interviews and administer the Comprehensive Score for Financial Toxicity Patient Reported Outcome Measure (COST PROM) and the Short Assessment of Health Literacy (SAHL). This program will examine how reimbursement of non-clinical costs can improve access to cancer clinical trials, with the eventual goal of increasing trial enrollment, diversity, representativeness, and generalizability. [ABSTRACT FROM AUTHOR]

Current standard for locally advanced non-small cell lung cancer (NSCLC) is combined concurrent therapy with a platinum-based regimen. Preclinical synergistic activity of pemetrexed with radiation therapy (RT) and favorable toxicity profile has led to clinical trials evaluating pemetrexed in chemoradiation regimens. This literature search of concurrent pemetrexed and RT treatment of patients with stage III NSCLC included MEDLINE database, meeting abstracts, and the clinical trial registry database. Nineteen unique studies were represented across all databases including 11 phase I studies and eight phase II studies. Of the six phase II trials with mature data available, median overall survival ranged from 18.7 to 34 months. Esophagitis and pneumonitis occurred in 0–16% and 0–23% of patients, respectively. Of the ongoing trials, there is one phase III and four phase II trials with pemetrexed in locally advanced NSCLC. Pemetrexed can be administered safely at full systemic doses with either cisplatin or carboplatin concomitantly with radical doses of thoracic radiation therapy. While results from the ongoing phase III PROCLAIM trial are needed to address definitively the efficacy of pemetrexed–cisplatin plus RT in stage III NSCLC, available results from phase II trials suggest that this regimen has promising activity with an acceptable toxicity profile. [ABSTRACT FROM AUTHOR]

Background In oncology clinical trials, the assumption that a prior cancer diagnosis could interfere with study conduct or outcomes results in frequent exclusion of such patients. We determined the prevalence and characteristics of this practice in lung cancer clinical trials and estimated impact on trial accrual. Methods We reviewed lung cancer clinical trials sponsored or endorsed by the Eastern Oncology Cooperative Group for exclusion criteria related to a prior cancer diagnosis. We estimated prevalence of prior primary cancer diagnoses among lung cancer patients using Surveillance Epidemiology and End Results (SEER)-Medicare linked data. We assessed the association between trial characteristics and prior cancer exclusion using chi-square analysis. All statistical tests were two-sided. Results Fifty-one clinical trials (target enrollment 13072 patients) were included. Forty-one (80%) excluded patients with a prior cancer diagnosis as follows: any prior (14%), within five years (43%), within two or three years (7%), or active cancer (16%). In SEER-Medicare data (n = 210 509), 56% of prior cancers were diagnosed within five years before the lung cancer diagnosis. Across trials, the estimated number and proportion of patients excluded because of prior cancer ranged from 0-207 and 0%-18%. Prior cancer was excluded in 94% of trials with survival primary endpoints and 73% of trials with nonsurvival primary endpoints (P = .06). Conclusions A substantial proportion of patients are reflexively excluded from lung cancer clinical trials because of prior cancer. This inclusion criterion is applied widely across studies, including more than two-thirds of trials with nonsurvival endpoints. More research is needed to understand the basis and ramifications of this exclusion policy. [ABSTRACT FROM AUTHOR]

Introduction: Electronic portals are secure Web-based servers that provide patients with real-time access to their personal health record (PHR). These applications are now widely used at cancer centers nationwide, but their impact has not been well studied. This study set out to determine predictors and patterns of use of a Web-based portal for accessing PHRs and communicating with health providers among patients with cancer. Methods: Retrospective analysis of enrollment in and use of MyChart, a PHR portal for the Epic electronic medical record system, among patients seen at a National Cancer Institute– designated cancer center. Predictors of MyChart use were analyzed through univariable and multivariable regression models. Results: A total of 6,495 patients enrolled in MyChart from 2007 to 2012. The median number of log-ins over this period was 57 (interquartile range 17-137). The most common portal actions were viewing test results (37%), viewing and responding to clinic messages (29%), and sending medical advice requests (6.4%). Increased portal use was significantly associated with younger age, white race, and an upper aerodigestive malignancy diagnosis. Thirty- seven percent of all log-ins and 31% of all medical advice requests occurred outside clinic hours. Over the study period, the average number of patient log-ins per year more than doubled. Conclusions: Among patients with cancer, PHR portal use is frequent and increasing. Younger patients, white patients, and patients with upper aerodigestive malignancies exhibit the heaviest portal use. Understanding the implications of this new technology will be central to the delivery of safe and effective care. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Maintenance chemotherapy is a recently approved approach to the treatment of advanced non-small cell lung cancer (NSCLC). We sought to gain insight into patients’ perceptions of maintenance chemotherapy using qualitative methods. Methods: We conducted thematic content analysis of focus groups at a freestanding cancer center and at an associated safety-net county hospital. Patients with advanced NSCLC who had started but not yet completed first-line platinum doublet chemotherapy were provided visual and written explanations of maintenance chemotherapy before being guided in group discussion. Results: Key themes to emerge for consideration of maintenance chemotherapy included: (1) survival benefits, disease control, and “buying time”; (2) the importance of “doing something”; (3) quality of life concerns; (4) the role of provider opinion/preference; and (5) the importance of logistics. Conclusions: Patients undergoing first-line chemotherapy for advanced NSCLC were able to understand the concept of maintenance chemotherapy, distinguish it from traditional treatment paradigms, identify pros and cons of this approach, and convey reasons for considering it. Practice implications: Advances in oncology care that alter therapy modalities and delivery may significantly impact patient perceptions and treatment experiences. Clinical team members may wish to elicit treatment preferences of first-line patients through clinical discussion that anticipate these considerations. [Copyright &y& Elsevier]

Purpose: Low rates of participation in cancer clinical trials have been attributed to patient, institutional, and study characteristics. However, few studies have examined factors related to the consent process. We therefore evaluated the impact of consent timing and experience on markers of patient interest in research. Methods: We performed a retrospective analysis of patients enrolled in a cancer center tissue repository. During enrollment,patients were asked if they were willing to be contacted in the future to provide medical follow-up information and/or to participate in other clinical research. We analyzed the association between patient responses to these questions and consent process factors using univariate analysis and multivariate logistic regression. Results: Of 922 patients evaluated, 85% agreed to be contacted to provide follow-up information, and 83% agreed to be contacted to participate in future research studies. In univariate analysis, willingness to be contacted for future research was associated with consenter experience (P =.01) and had a trend toward association with the timing of enrollment in relation to diagnosis (P = .08), but it was not associated with patient sex, race, or diagnosis. In multivariate analysis, responses remained associated with consenter experience (P = .02). Conclusion: Factors related to the consent process, including consenter experience and timing of study enrollment, are significantly associated with or have a trend toward association with markers of patient interest in clinical research. These understudied and potentially modifiable variables warrant further evaluation. [ABSTRACT FROM AUTHOR]

The article offers information regarding a study which aims to analyze the effects of the distribution of counterfeit erythropoietin and recommendation for anticounterfeiting of pharmaceuticals in the U.S. The study has gathered data from a patient who has received counterfeit erythropoietin, a physician, and employees of the U.S. Food and Drug Administration (FDA). Results showed that 17 persons were found guilty of selling counterfeit pharmaceuticals. Moreover, two patients have reported loss of efficacy of the said counterfeit erythropoietin.

It was only 3 years ago that an acquired translocation of EML4 with ALK leading to the expression of an EML4-ALK oncoprotein in non-small cell lung cancer (NSCLC) was reported. Tumor cells expressing EML4-ALK are “addicted” to its continued function. Now, crizotinib, an oral ALK inhibitor, is demonstrated to provide dramatic clinical benefit with little toxicity in patients having such advanced NSCLC, and a mechanism of clinical resistance to crizotinib is identified. Such therapy “targeted” at oncogenic proteins provides “personalized” medicine and prompts genome-wide mutation analysis of human tumors to find other therapeutic targets. [ABSTRACT FROM AUTHOR]

Recent medical advances have improved the understanding, diagnosis, and treatment of paraneoplastic syndromes. These disorders arise from tumor secretion of hormones, peptides, or cytokines or from immune cross-reactivity between malignant and normal tissues. Paraneoplastic syndromes may affect diverse organ systems, most notably the endocrine, neurologic, dermatologic, rheumatologic, and hematologic systems. The most commonly associated malignancies include small cell lung cancer, breast cancer, gynecologic tumors, and hematologic malignancies. In some instances, the timely diagnosis of these conditions may lead to detection of an otherwise clinically occult tumor at an early and highly treatable stage. Because paraneoplastic syndromes often cause considerable morbidity, effective treatment can improve patient quality of life, enhance the delivery of cancer therapy, and prolong survival. Treatments include addressing the underlying malignancy, immunosuppression (for neurologic, dermatologic, and rheumatologic paraneoplastic syndromes), and correction of electrolyte and hormonal derangements (for endocrine paraneoplastic syndromes). This review focuses on the diagnosis and treatment of paraneoplastic syndromes, with emphasis on those most frequently encountered clinically. Initial literature searches for this review were conducted using PubMed and the keyword paraneoplastic in conjunction with keywords such as malignancy, SIADH, and limbic encephalitis, depending on the particular topic. Date limitations typically were not used, but preference was given to recent articles when possible. [ABSTRACT FROM AUTHOR]

The author presents insights on a study of variations in oncologist recommendations for chemotherapy for stage IV lung cancer. Topics covered include the hypothetical patient scenarios given to the oncologists, the potential explanations for oncologists in solo practice who were more likely to recommend chemotherapy and the difficulty of rendering treatment recommendations on the basis of functional status.

High-dose methotrexate (HDMTX) (≥3 g/m2), the cornerstone of therapy for primary CNS lymphoma (PCNSL), is commonly dosed using a measured 24 h creatinine clearance (CrCl) every 2–4 weeks. Because these collections are cumbersome and at times unreliable, the use of a calculated CrCl was evaluated as a potential alternative. A retrospective analysis was performed on data from all 287 treatment cycles from the 25 patients with PCNSL who participated in a multi-center phase II clinical trial of HDMTX conducted by the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. The 25 patients had a median age of 61 years (range 32–75). Seventeen (68%) were men. The patients received a median of 14 (range 2–21) HDMTX treatments. For 256 of 287 treatments (89%), data were available to compare the measured and calculated (using the Cockcroft–Gault equation) CrCl. The average measured CrCl was 93 ml/min (95% CI, 89–96 ml/min), and the average calculated CrCl was 107 ml/min (95% CI, 102–112 ml/min). The Pearson correlation coefficient ( r) was 0.49 ( P < 0.0001) between the measured and calculated CrCl. The average MTX dose determined using measured CrCl was 14.1 g (95% CI, 13.6–14.5 g), and the average MTX dose determined using calculated CrCl was 14.7 g (95% CI, 14.2–15.1 g). MTX doses based on measured and calculated CrCl were significantly correlated ( r = 0.72, P < 0.0001). Of the 256 HDMTX treatments evaluated, 158 (62%) had reliable 48 h serum MTX levels documented. Forty-seven levels (30%) were within target range (0.3–1 μmol/l), 99 levels (62%) were below target range (<0.3 μmol/l), 12 levels (8%) were in the range associated with mild toxicity range (>1–3 μmol/l), and no levels were in the range associated with severe toxicity (>3 μmol/l). Of these 158 treatments, the use of a calculated rather than measured CrCl would have yielded an identical MTX dose for 48 treatments (30%), a higher MTX dose for 62 treatments (40%), and a lower MTX dose for 48 treatments (30%). This distribution was not significantly different among the subsets of below target, within target range, and above target MTX levels ( P = 0.87). In this cohort of patients with PCNSL, there is significant correlation between the calculated and measured CrCl. MTX doses determined using calculated and measured CrCl are not significantly different. For these patients, there is no clear association between the method of determining CrCl and serum MTX levels. As a result, calculated CrCl is a reasonable alternative to measured CrCl in this patient population and would avoid the inconvenience and potential inaccuracies associated with measured CrCl. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion The shared risk profiles for cancer and heart disease suggest many individuals with cancer may have an implantable cardioverter defibrillator (ICD). ICDs can have dramatic cancer end‐of‐life care implications including painful and distressing shocks. ICD prevalence and association with aggressive end‐of‐life care among individuals with breast, colorectal, and pancreatic cancer was evaluated using the Surveillance, Epidemiology, and End Results‐Medicare dataset.A total of 37,306 Medicare beneficiaries aged ≥66 years with stage 3 or 4 cancer who died between 2005 and 2016 were identified. ICD prevalence, ICD‐related care utilization that might present opportunities to discuss end‐of‐life implications and association with aggressive end‐of‐life care (>1 emergency department visit, intensive care unit admission, >1 hospitalization, terminal hospitalization, chemotherapy, and invasive or life‐extending procedures) in the last month of life was assessed using multivariable logistic regression.Among cancer decedents, 6% had an ICD. More individuals with an ICD (31%) died in the hospital than individuals without an ICD (25%; p < .001). Half (46%) of individuals with an ICD had device programming or interrogation visits that could be an opportunity for device discussion. In adjusted models, ICD presence was associated with higher odds of every indicator of aggressive end‐of‐life care other than chemotherapy.Many older cancer decedents in the United States had an ICD, and those with ICDs received more aggressive care at the end of life. Results suggest there are opportunities to discuss ICD and goals of care, raise awareness and encourage shared decision‐making for this population to ensure goal‐concordant care, and improve end‐of‐life care quality. [ABSTRACT FROM AUTHOR]

Background: Pseudoprogression, the initial apparent worsening of cancer prior to eventual improvement, is a documented feature of immune checkpoint inhibitor administration and presents a challenge to clinicians distinguishing true progression from pseudoprogression. This phenomenon does not typically occur with traditional cytotoxic chemotherapy. We present a case in which a patient treated with combination carboplatin-pemetrexed plus pembrolizumab experienced transient radiographic worsening of disease with subsequent regression.Case Presentation: A 65-year-old never-smoking white male with advanced sarcomatoid non-small cell lung cancer (NSCLC) harboring a MET exon 14 skipping mutation and with PD-L1 tumor proportion score of 80% was initiated on combination chemotherapy plus immune checkpoint inhibitor (ICI) therapy after progression on a MET inhibitor. After two cycles of carboplatin-pemetrexed plus pembrolizumab, repeat imaging suggested disease progression. Following discontinuation of the carboplatin-pemetrexed plus pembrolizumab regimen, the patient reported improved symptoms and energy levels, which were attributed to the waning of treatment-associated toxicities. On the day prior to initiation of the next planned line of therapy, repeat imaging was preformed to provide a baseline for treatment efficacy. Imaging revealed improvement compared to the prior imaging. Chemotherapy with carboplatin-pemetrexed plus pembrolizumab was resumed, with response ongoing 8 months later.Conclusions: Pseudoprogression is a documented feature of ICI administration. Pseudoprogression is not typically observed in patients treated with traditional cytotoxic chemotherapy and has not yet been documented in patients treated with combination cytotoxic chemotherapy plus immunotherapy. At this time, there are no reliable means to predict or diagnose these rare events; therefore, more studies should be conducted to understand which patients are predisposed to developing this phenomenon and to increase clinical recognition. [ABSTRACT FROM AUTHOR]

Background: As use of oral cancer therapies increases, patient adherence has become critical when evaluating the effectiveness of therapy. In a phase III trial for renal cell carcinoma, we: (a) characterized adherence to sorafenib, sunitinib, and/or placebo and (b) identified factors associated with non‐adherence. Methods: ECOG‐ACRIN E2805 was a double‐blind, placebo‐controlled, randomized trial comparing adjuvant sorafenib or sunitinib in patients with resected primary renal cell carcinoma at high risk for recurrence. We used patient‐completed pill diaries to measure adherence as the number of pills taken divided by the number of pills prescribed. Log‐binomial regression was used to identify correlates of non‐adherence (<80% of prescribed pills reported as taken). Results: Mean adherence was 90.7% among those assigned to sunitinib (n = 613) and 84.8% among those assigned to sorafenib (n = 616). Among those assigned to placebo, mean adherence was 94.9% and 92.4% to sunitinib and sorafenib placebo, respectively. Non‐adherence was associated with race/ethnicity (non‐Hispanic Black: prevalence ratio [PR] 2.22, 95% CI 1.63, 3.01; Hispanic: PR 1.54, 95% CI 1.05, 2.26), high volume enrollment (≥10 patients: PR 1.30, 95% CI 1.03, 1.64), treatment group (sunitinib: PR 2.24, 95% CI 1.66, 3.02; sorafenib: PR 2.37, 95% CI 1.74, 3.22), and skin rash (PR 1.36, 95% CI 1.03, 1.80). Conclusion: Among patients participating in a randomized clinical trial, adherence to oral cancer therapies was lower compared to placebo. Adherence was also worse in racial/ethnic minorities, those experiencing toxicities, and high volume enrolling sites. Our findings highlight several challenges to address in clinical practice as use of oral therapies continues to increase. Clinical trial registration number: This trial is registered with ClinicalTrials.gov, number NCT00326898. [ABSTRACT FROM AUTHOR]

The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, double-blind trial of treatment-naïve patients with EGFR mutant NSCLC, osimertinib was compared to standard-of-care EGFR TKIs (i.e., erlotinib or gefinitib) in the first-line setting. Osimertinib demonstrated improvement in median progression-free survival (18.9 months vs. 10.2 months; hazard ratio 0.46; 95% CI, 0.37 to 0.57; p < 0.001) and a more favorable toxicity profile due to its lower affinity for wild-type EGFR. Furthermore, similar to later-generation anaplastic lymphoma kinase (ALK) inhibitors, osimertinib has improved efficacy against brain metastases. Despite this impressive effect, the optimal sequencing of osimertinib, whether in the first line or as subsequent therapy after the failure of earlier-generation EGFR TKIs, is not clear. Because up-front use of later-generation TKIs may result in the inability to use earlier-generation TKIs, this treatment paradigm must be evaluated carefully. For EGFR mutant NSCLC, considerations include the incidence of T790M resistance mutations, quality of life, whether there is a potential role for earlier-generation TKIs after osimertinib failure, and overall survival. This review explores these issues for EGFR inhibitors and other molecularly targeted therapies. [ABSTRACT FROM AUTHOR]

Circulating tumor DNA (ctDNA) is utilized for molecular profiling of cancers, and is under investigation for a growing number of applications based on the assumption that ctDNA levels faithfully reflect disease burden. Our objective was to investigate whether patient and tumor characteristics may impact ctDNA detection or levels and the prognostic significance of ctDNA levels or mutations. We performed a retrospective cohort analysis of a comprehensively annotated cohort of 561 patients at a National Cancer Institute–designated comprehensive cancer center with advanced solid cancers who underwent ctDNA testing using a commercial targeted next-generation sequencing assay. ctDNA detection in advanced cancers was associated with older age, non-obese body mass index, and diabetes, but not with tumor diameter, volume, lesion number, or other pathological features. Regression models indicate that no more than 14.3% of the variance in ctDNA levels between patients was explained by known clinical factors and disease burden. Even after adjusting for established prognostic factors and tumor burden, ctDNA levels were associated with worse survival among patients without prior systemic therapy, while ctDNA mutations were associated with survival among patients who previously received systemic treatment. These findings uncover clinical factors that affect ctDNA detection in patients with advanced cancers and challenge the convention that ctDNA is a surrogate for tumor burden. Our study also indicates that the prognostic value of ctDNA levels and mutations are independent of tumor burden and dependent on treatment context. [ABSTRACT FROM AUTHOR]

Objective: The introduction of oral cancer therapies presents new challenges to delivery of quality cancer care. Little is known about how patients and providers address and overcome these challenges. We conducted a qualitative study exploring the range of patient and provider perspectives on oral cancer therapies.Methods: We conducted semi-structured interviews with patients and providers at a tertiary referral center and county safety-net hospital in Dallas, TX. Interviews probed perspectives on differences between parenteral chemotherapy and oral therapies, adherence, communication, and cost/insurance. Interview transcripts were analyzed thematically using a deductively-driven coding scheme corresponding to the interview guide.Results: We conducted 22 patient (13 at tertiary referral center, 9 at safety-net hospital) and 10 provider (7 oncologists, 2 nurses, 1 pharmacist) interviews. Key themes from interviews included: (1) differences in parenteral chemotherapy vs. oral therapy; (2) adherence and dosing; and (3) experiences related to cost and communication.Conclusions: Nearly all providers described challenges engaging with and educating patients about oral cancer therapies. Despite our initial hypothesis, safety-net patients encountered few barriers accessing oral therapies compared to patients receiving care in the tertiary referral center.Practice Implications: Our findings will guide future interventions to monitor and support cancer patients receiving oral therapies. [ABSTRACT FROM AUTHOR]

Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell survival, leading to immunogenic cell death and enhanced antitumour immune response. In preclinical models of non-small-cell lung cancer, TTFields amplified the effects of chemotherapy and immune checkpoint inhibitors. We report primary results from a pivotal study of TTFields therapy in metastatic non-small-cell lung cancer. This randomised, open-label, pivotal phase 3 study recruited patients at 130 sites in 19 countries. Participants were aged 22 years or older with metastatic non-small-cell lung cancer progressing on or after platinum-based therapy, with squamous or non-squamous histology and ECOG performance status of 2 or less. Previous platinum-based therapy was required, but no restriction was placed on the number or type of previous lines of systemic therapy. Participants were randomly assigned (1:1) to TTFields therapy and standard systemic therapy (investigator's choice of immune checkpoint inhibitor [nivolumab, pembrolizumab, or atezolizumab] or docetaxel) or standard therapy alone. Randomisation was performed centrally using variable blocked randomisation and an interactive voice–web response system, and was stratified by tumour histology, treatment, and region. Systemic therapies were dosed according to local practice guidelines. TTFields therapy (150 kHz) was delivered continuously to the thoracic region with the recommendation to achieve an average of at least 18 h/day device usage. The primary endpoint was overall survival in the intention-to-treat population. The safety population included all patients who received any study therapy and were analysed according to the actual treatment received. The study is registered with ClinicalTrials.gov , NCT02973789. Between Feb 13, 2017, and Nov 19, 2021, 276 patients were enrolled and randomly assigned to receive TTFields therapy with standard therapy (n=137) or standard therapy alone (n=139). The median age was 64 years (IQR 59–70), 178 (64%) were male and 98 (36%) were female, 156 (57%) had non-squamous non-small-cell lung cancer, and 87 (32%) had received a previous immune checkpoint inhibitor. Median follow-up was 10·6 months (IQR 6·1–33·7) for patients receiving TTFields therapy with standard therapy, and 9·5 months (0·1–32·1) for patients receiving standard therapy. Overall survival was significantly longer with TTFields therapy and standard therapy than with standard therapy alone (median 13·2 months [95% CI 10·3–15·5] vs 9·9 months [8·1–11·5]; hazard ratio [HR] 0·74 [95% CI 0·56–0·98]; p=0·035). In the safety population (n=267), serious adverse events of any cause were reported in 70 (53%) of 133 patients receiving TTFields therapy plus standard therapy and 51 (38%) of 134 patients receiving standard therapy alone. The most frequent grade 3–4 adverse events were leukopenia (37 [14%] of 267), pneumonia (28 [10%]), and anaemia (21 [8%]). TTFields therapy-related adverse events were reported in 95 (71%) of 133 patients; these were mostly (81 [85%]) grade 1–2 skin and subcutaneous tissue disorders. There were three deaths related to standard therapy (two due to infections and one due to pulmonary haemorrhage) and no deaths related to TTFields therapy. TTFields therapy added to standard therapy significantly improved overall survival compared with standard therapy alone in metastatic non-small-cell lung cancer after progression on platinum-based therapy without exacerbating systemic toxicities. These data suggest that TTFields therapy is efficacious in metastatic non-small-cell lung cancer and should be considered as a treatment option to manage the disease in this setting. Novocure. [ABSTRACT FROM AUTHOR]

Surprisingly, survival from a diagnosis of lung cancer has been found to be longer for those who experienced a previous cancer than for those with no previous cancer. A possible explanation is lead-time bias, which, by advancing the time of diagnosis, apparently extends survival among those with a previous cancer even when they enjoy no real clinical advantage. We propose a discrete parametric model to jointly describe survival in a no-previous-cancer group (where, by definition, lead-time bias cannot exist) and in a previous-cancer group (where lead-time bias is possible). We model the lead time with a negative binomial distribution and the post-lead-time survival with a linear spline on the logit hazard scale, which allows for survival to differ between groups even in the absence of bias; we denote our model Logit-Spline/Negative Binomial. We fit Logit-Spline/Negative Binomial to a propensity-score matched subset of the Surveillance, Epidemiology, and End Results-Medicare linked data set, conducting sensitivity analyses to assess the effects of key assumptions. With lung cancer-specific death as the end point, the estimated mean lead time is roughly 11 months for stage I&II patients; with overall survival, it is roughly 3.4 months in stage I&II. For patients with higher-stage lung cancers, the mean lead time is 1 month or less for both outcomes. Accounting for lead-time bias reduces the survival advantage of the previous-cancer group when one exists, but it does not nullify it in all cases. [ABSTRACT FROM AUTHOR]

Objectives In the literature, inconsistent associations between the primary locations of lung adenocarcinomas (ADCs) with patient prognosis have been reported, due to varying definitions for central and peripheral locations. In this study, we investigated the clinical characteristics and prognoses of ADCs located in the main bronchus. Methods A total of 397,189 lung ADCs registered from 2004 to 2013 in the National Cancer Database (NCDB) were extracted and divided into main bronchus-located ADCs (2.5%, N = 10,111) and non-main bronchus ADCs (97.5%, N = 387,078). The ADCs located in the main bronchus and those not in the main bronchus were compared in terms of patient prognosis, lymph node involvement, distant metastases and other clinical features, including rate of curative-intent resection, histologic grade, and stage. Results ADCs located in the main bronchus had significantly worse patient survival than those in the non-main bronchus, both for all patients (HR = 1.82, 95% CI 1.78–1.86) and for those undergoing curative-intent resection (HR = 2.49, 95% CI 2.23–2.78). Furthermore, ADCs located in the main bronchus had a significantly higher rate of lymph node involvement and distant metastasis than those not in the main bronchus, when stratified by tumor size (trend test, p < e −16 ). Multivariate analysis of overall survival showed that main bronchus location is a prognostic factor (HR = 1.15, 95% CI 1.08–1.23) independent of other clinical factors. Conclusions Main bronchus location is an independent predictor for metastasis and worse outcomes irrespective of stage and treatment. Tumor primary location might be considered in prognostication and treatment planning. [ABSTRACT FROM AUTHOR]

Although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is effective only in a subset of non-small cell lung cancer (NSCLC) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. TNF is a major mediator of inflammation-induced cancer. We find that a rapid increase in TNF level is a universal adaptive response to EGFR inhibition in NSCLC, regardless of EGFR status. EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21, resulting in decreased TNF mRNA stability. Conversely, EGFR inhibition results in loss of miR-21 and increased TNF mRNA stability. In addition, TNF-induced NF-κB activation leads to increased TNF transcription in a feed-forward loop. Inhibition of TNF signaling renders EGFRwt-expressing NSCLC cell lines and an EGFRwt patient-derived xenograft (PDX) model highly sensitive to EGFR inhibition. In EGFR-mutant oncogene-addicted cells, blocking TNF enhances the effectiveness of EGFR inhibition. EGFR plus TNF inhibition is also effective in NSCLC with acquired resistance to EGFR inhibition. We suggest concomitant EGFR and TNF inhibition as a potentially new treatment approach that could be beneficial for a majority of lung cancer patients. [ABSTRACT FROM AUTHOR]

Background: In oncology clinical trials, the assumption that a prior cancer diagnosis could interfere with study conduct or outcomes results in frequent exclusion of such patients. We determined the prevalence and characteristics of this practice in lung cancer clinical trials and estimated impact on trial accrual.Methods: We reviewed lung cancer clinical trials sponsored or endorsed by the Eastern Oncology Cooperative Group for exclusion criteria related to a prior cancer diagnosis. We estimated prevalence of prior primary cancer diagnoses among lung cancer patients using Surveillance Epidemiology and End Results (SEER)-Medicare linked data. We assessed the association between trial characteristics and prior cancer exclusion using chi-square analysis. All statistical tests were two-sided.Results: Fifty-one clinical trials (target enrollment 13072 patients) were included. Forty-one (80%) excluded patients with a prior cancer diagnosis as follows: any prior (14%), within five years (43%), within two or three years (7%), or active cancer (16%). In SEER-Medicare data (n = 210509), 56% of prior cancers were diagnosed within five years before the lung cancer diagnosis. Across trials, the estimated number and proportion of patients excluded because of prior cancer ranged from 0-207 and 0%-18%. Prior cancer was excluded in 94% of trials with survival primary endpoints and 73% of trials with nonsurvival primary endpoints (P = .06).Conclusions: A substantial proportion of patients are reflexively excluded from lung cancer clinical trials because of prior cancer. This inclusion criterion is applied widely across studies, including more than two-thirds of trials with nonsurvival endpoints. More research is needed to understand the basis and ramifications of this exclusion policy. [ABSTRACT FROM AUTHOR]

Purpose: Fenretinide (4-HPR) is a synthetic retinoid that induces cytotoxicity through dihydroceramide production. Safingol, a stereochemical-variant dihydroceramide precursor, exhibits synergistic effects when administered with fenretinide in preclinical studies. We conducted a phase 1 dose-escalation clinical trial of this combination. Methods: Fenretinide was administered as a 600 mg/m2 24-h infusion on Day 1 of a 21-day cycle followed by 900 mg/m2/day on Days 2 and 3. Safingol was concurrently administered as a 48-h infusion on Day 1 and 2 using 3 + 3 dose escalation. Primary endpoints were safety and maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetics and efficacy. Results: A total of 16 patients were enrolled (mean age 63 years, 50% female, median three prior lines of therapy), including 15 patients with refractory solid tumors and one with non-Hodgkin lymphoma. The median number of treatment cycles received was 2 (range 2–6). The most common adverse event (AE) was hypertriglyceridemia (88%; 38% ≥ Grade 3), attributed to the fenretinide intralipid infusion vehicle. Other treatment-related AEs occurring in ≥ 20% of patients included anemia, hypocalcemia, hypoalbuminemia, and hyponatremia. At safingol dose 420 mg/m2, one patient had a dose-limiting toxicity of grade 3 troponinemia and grade 4 myocarditis. Due to limited safingol supply, enrollment was halted at this dose level. Fenretinide and safingol pharmacokinetic profiles resembled those observed in monotherapy trials. Best radiographic response was stable disease (n = 2). Conclusion: Combination fenretinide plus safingol commonly causes hypertriglyceridemia and may be associated with cardiac events at higher safingol levels. Minimal activity in refractory solid tumors was observed. Trial registration number: NCT01553071 (3.13.2012). [ABSTRACT FROM AUTHOR]

Low-dose computed tomography-based lung cancer screening represents a complex clinical undertaking that could require multiple referrals, appointments, and time-intensive procedures. These steps may pose difficulties and raise concerns among patients, particularly minority, under-, and uninsured populations. The authors implemented patient navigation to identify and address these challenges. They conducted a pragmatic randomized controlled trial of telephone-based navigation for lung cancer screening in an integrated, urban safety-net health care system. Following standardized protocols, bilingual (Spanish and English) navigators educated, motivated, and empowered patients to traverse the health system. Navigators made systematic contact with patients, recording standardized call characteristics in a study-specific database. Call type, duration, and content were recorded. Univariable and multivariable multinomial logistic regression was performed to investigate associations between call characteristics and reported barriers. Among 225 patients (mean age 63 years, 46% female, 70% racial/ethnic minority) assigned navigation, a total of 559 barriers to screening were identified during 806 telephone calls. The most common barrier categories were personal (46%), provider (30%), and practical (17%). System (6%) and psychosocial (1%) barriers were described by English-speaking patients, but not by Spanish-speaking patients. Over the course of the lung cancer screening process, provider-related barriers decreased 80% (P = 0.008). The authors conclude that patients undergoing lung cancer screening frequently report personal and health care provider-related barriers to successful participation. Barrier types may differ among patient populations and over the course of the screening process. Further understanding of these concerns may increase screening uptake and adherence. Clinical Trial Registration number: (NCT02758054). [ABSTRACT FROM AUTHOR]

This article provides a summary of discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group in coordination with the US FDA Oncology Center of Excellence and LUNGevity Foundation on January 14, 2021, and February 8, 2021. Diverse stakeholders including oncologists, patient advocates, experts from international regulatory agencies, academicians, and representatives of the pharmaceutical industry engaged in a discussion on how best to incorporate lessons learned during the COVID-19 pandemic into the design of future oncology trials. While recognizing that decentralized or hybrid cancer trials may increase variability associated with measurement error and potentially increase bias in treatment effect estimation, panel discussions highlighted the importance of flexibility for decreasing patient burden, which has the potential to increase access to and retention in cancer clinical trials and may broaden the representation of real-world patients in the trial setting. [ABSTRACT FROM AUTHOR]

Patients diagnosed with lung cancer (LC) exhibit increased susceptibility to SARS-CoV-2 infection. Rodilla et al. monitor the levels of plasma anti-nucleocapsid antibodies within a cohort of fully vaccinated LC patients and reveal that the actual infection rate is nearly twice the documented rate, indicating a significant prevalence of unreported cases. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) cause a variety of toxicities, including immune-related adverse events (irAEs), but there are no biomarkers to predict their development. Guidelines recommend measuring circulating cardiac troponin I (cTnI) during ICI therapy to detect related cardiotoxicities. Moreover, elevated cTnI has also been associated with worse outcomes in non-cardiac patients, including cancer. Thus here, we investigated whether cTnI levels were higher in patients with irAEs. The study consisted of three groups; 21 cancer patients undergoing ICI immunotherapies who presented with irAEs, four patients without irAEs, and 20 healthy controls. Patient samples were assessed at baseline (n=25), during ICI treatment (n=25, median=6 weeks of treatment) and at toxicity (n=6, median=13 weeks of treatment). In addition to blood high sensitivity cardiac troponin I (hs-cTnI), anti-thyroglobulin (TG) and anti-thyroid peroxidase (TPO) antibodies were also quantitated to detect thyroid dysfunction, constituting the second leading toxicity (23.8%) after pneumonitis (28.6%). Four patients with irAEs (n=4/21; 19%) and one without irAEs (n=1/4; 25%) showed higher hs-cTnI levels at any time-point; the remaining had physiological levels. None of these patients developed cardiotoxicity. Concurrent elevated levels of anti-thyroid antibodies and hs-cTnI were detected in one patient with thyroid dysfunction (n=1/5, 20%). However, these antibodies were also elevated in three patients (n=3/16, 19%) with non-thyroid irAEs and in up to 40% of healthy controls. hs-cTnI was not elevated in patients with irAEs, but larger studies are needed to confirm these observations. [ABSTRACT FROM AUTHOR]

Background: Persons newly diagnosed with pancreas cancer and who have survived a previous cancer are often excluded from clinical trials, despite limited evidence about their prognosis. We examined the association between previous cancer and overall survival. Methods: This US population‐based cohort study included older adults (aged ≥66 years) diagnosed with pancreas cancer between 2005 and 2015 in the linked Surveillance, Epidemiology, and End Results‐Medicare data. We used Cox proportional hazards models to estimate stage‐specific effects of previous cancer on overall survival, adjusting for sociodemographic, treatment, and tumor characteristics. Results: Of 32,783 patients, 18.7% were previously diagnosed with another cancer. The most common previous cancers included prostate (29.0%), breast (18.9%), or colorectal (9.7%) cancer. More than half of previous cancers (53.9%) were diagnosed 5 or more years prior to pancreas cancer diagnosis or at an in situ or localized stage (47.8%). The proportions of patients surviving 1, 3, and 5 years after pancreas cancer were nearly identical for those with and without previous cancer. Median survival in months was as follows for those with and without previous cancer respectively: 7 versus 8 (Stage 0/I), 10 versus 10 (Stage II), 7 versus 7 (Stage III), and 3 versus 2 (Stage IV). Cox models indicated that patients with previous cancer had very similar or statistically equivalent survival to those with no previous cancer. Conclusions: Given nearly equivalent survival compared to those without previous cancer, cancer survivors newly diagnosed with pancreas cancer should be considered for inclusion in pancreas cancer clinical trials. [ABSTRACT FROM AUTHOR]

Background: Thyroid dysfunction is among the most common autoimmune diseases and immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAE). We determined the association between longitudinal thyroid function and clinical outcomes in patients treated with ICI. Methods: We identified all patients treated with ICI at UT Southwestern Medical Center from January 1, 2011, through December 31, 2020. We defined normal thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels according to institutional reference range. We defined clinical thyroid dysfunction using established criteria incorporating labs and treatment. We determined the association between thyroid function and overall survival (OS) using Kaplan–Meier curves, log-rank tests, and multivariate Cox proportional hazards model. Results: A total of 1781 patients were included in analyses, of whom 381 (21%) had abnormal baseline TSH. Patients with abnormal baseline TSH were more likely to be female, have kidney cancer, and initiate levothyroxine after ICI initiation (all P < 0.001). Patients with abnormal baseline TSH had inferior OS (median 16 vs 27 months; P < 0.001). Among patients with normal baseline TSH, those who had abnormal TSH after ICI initiation had improved OS (median 41 vs 22 months; P < 0.001). In a multivariate Cox model, abnormal baseline TSH was associated with worse OS (HR 1.62; 95% CI, 1.30–2.02; P < 0.001), while initiation of levothyroxine after ICI initiation was associated with improved OS (HR 0.62; 95% CI, 0.44–0.88; P = 0.008). Conclusions: ICI-induced thyroid dysfunction is associated with improved survival, although abnormal TSH prior to ICI initiation is associated with inferior survival. Precis: Thyroid abnormalities occur commonly in the general population and as immunotherapy toxicities. We found that immunotherapy-induced thyroid dysfunction is associated with better survival, but pre-existing thyroid abnormalities convey worse outcomes. [ABSTRACT FROM AUTHOR]

Purpose Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC. Methods and Materials Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiation therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy. Results Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity ( P =.24). The median overall survival was 6 months with no significant differences between dose levels ( P =.59). Conclusions Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long-term safety and efficacy of this therapy are warranted. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 67-year-old woman with one month of diffuse itching. She was exposed to the 1984 Bhopal gas leak that cause to the release of 30 tons of methyl isocyanate gas while she worked as a nurse and living in India. She underwent a bone marrow biopsy which reveals an acute myeloid leukemia (AML). It examines the long-term health effects of the gas disaster at Bhopal.

• Brigatinib demonstrated activity after second-generation ALK TKI's. • The ORR was similar after 1st or 2nd line therapy with second generation ALK TKI's. • ctDNA testing for ALK resistance mutations is feasible when ctDNA is detectable. 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. Patients with stage IIIB/IV ALK + 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 90 mg daily for seven days and then escalated to 180 mg daily in cohorts A and B, and 240 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. 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 55 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. Brigatinib has activity in ALK positive NSCLC patients with disease progression after second generation ALK TKIs. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Certain chemotherapeutic agents commonly used for advanced non-small cell lung cancer (NSCLC) require minimum threshold renal function for administration. To determine how such requirements affect treatment options, we evaluated renal function patterns in this population. Methods: We performed a single-center retrospective analysis of patients treated for stage IV NSCLC from 2000 to 2007. Associations between patient characteristics, calculated creatinine clearance (CrCl), and clinical outcomes were determined using univariate and multivariate analyses, Cox proportional hazard models, and mixed model analysis. Results: 298 patients (3930 creatinine measurements) were included in the analysis. Patients had a median of 5 (interquartile range [IQR] 4–18) Cr measurements. Median baseline CrCl was 96mL/min (IQR 74–123mL/min); median nadir CrCl was 78mL/min (IQR 56–100mL/min). Renal function was associated with age (P <0.001), race (P =0.009), and gender (P =0.001). 23% of patients had a recorded CrCl<60mL/min (threshold for cisplatin), with median onset 83 days after diagnosis and median time to recover to ≥60mL/min of 27 (IQR 3–85) days; 11% of patients had a recorded CrCl<45mL/min (threshold for pemetrexed), with median onset 122 days after diagnosis and median recovery time of 36 (IQR 3–73) days. For both thresholds, approximately 35% of patients had no documented recovery. Conclusions: In this cohort of patients treated for stage IV NSCLC, renal function falls below commonly used thresholds for cisplatin and for pemetrexed in fewer than a quarter of patients. However, these declines may preclude administration of these drugs for prolonged periods. [Copyright &y& Elsevier]

The timing of immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI) is highly variable. Although the development of irAE has been associated with ICI clinical benefit, how irAE timing influences this association is unknown. We analyzed two independent cohorts including 154 patients with non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors at a single institution (UTSW cohort) and a multi-center cohort of 433 patients with NSCLC who received second-line anti-PD-1/PD-L1 therapy (Global cohort) to assess the association between ICI outcomes and irAE timing. In both cohorts, late-onset irAE occurring more than 3 months after ICI initiation compared to irAE occurring earlier were associated with greater rates of radiographic response (UTSW cohort, 41% versus 28%, P = .26; Global cohort, 60% versus 35%, P = .02), longer progression-free (UTSW cohort, 13.7 versus 5.6 months, P < .01; Global cohort, not reached versus 6.0 months, P < .01) and overall survival (UTSW cohort, 30.9 versus 14.6 months, P < .01; Global cohort, not reached versus 10.6 months, P < .01). Modified landmark analysis at 6 months confirmed an overall survival difference between early- and late-onset irAE. Lateonset irAE was similarly associated with greater response rates and prolonged survival in a cohort of 130 patients with non-NSCLC malignancies, suggesting a conserved association across tumor types. The favorable association between irAE and ICI clinical outcomes may be attributed to later-onset events, which is not wholly explained by survivor bias. These results allude to a distinct biology between earlyand late-onset irAE and may guide clinician expectations and thresholds for continuing or modifying immunotherapy. [ABSTRACT FROM AUTHOR]

Background: The overall prevalence of potential drug–drug interactions (DDIs) among patients with lung cancer is unknown. Objective: The objective of this study was to determine the prevalence of potential DDIs and major DDIs among individuals newly diagnosed with lung cancer in a national cohort. Patients and Methods: We performed a retrospective cross-sectional study of adult patients in the United States Veterans' Affairs (VA) medical system diagnosed with lung cancer between 2003 and 2016. The primary endpoint was the prevalence of prescriptions for medications associated with any potential DDIs during the 3 months leading up to and including the date of lung cancer diagnosis. The secondary endpoint was the prevalence of prescriptions associated with major DDIs during the same time period. Results: Overall, 280,068 patients were included in the study; 55.9% of patients were prescribed medications associated with potential DDIs, while 5.3% received prescriptions for medications associated with major DDIs. Among the 20 most commonly prescribed drugs associated with potential DDIs, only two were associated with major DDIs. Conclusion: Medications with potential DDIs are prescribed to the majority of patients with lung cancer; however, only about 5% of patients are prescribed medications with major DDIs that might be prohibited in certain clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Opioid-induced constipation (OIC) is the most common side effect in patient-prescribed opioids for cancer pain treatment. Current guidelines recommend routine prescription of a laxative for preventing OIC in all patients prescribed an opioid unless a contraindication exists. We determined patterns of prescription of laxative agents in patients with lung cancer initiating opioids.Methods: We performed a retrospective cohort study evaluating the prescription of laxatives for OIC to adult patients with incident lung cancer seen in the Veteran's Affairs (VA) system, between January 1, 2003, and December 31, 2016. Exposure to laxative agents was categorized as follows: none, docusate monotherapy, docusate plus another laxative, and other laxatives only. Prevalence of OIC prophylaxis was analyzed using descriptive statistics. Linear regression was performed to identify time trends in the prescription of OIC prophylaxis.Results: Overall, 130,990 individuals were included in the analysis. Of these, 87% of patients received inadequate prophylaxis (75% no prophylaxis and 12% docusate alone), while 5% received OIC prophylaxis with the unnecessary addition of docusate to another laxative. Through the study period, laxative prescription significantly decreased, while all other categories of OIC prophylaxis were unchanged. We noted an inverse relationship with OIC prophylaxis and likelihood of a diagnosis of constipation at 3 and 6 months.Conclusions: In this study of veterans with lung cancer, almost 90% received inadequate or inappropriate OIC prophylaxis. Efforts to educate physicians and patients to promote appropriate OIC prophylaxis in combination with systems-level changes are warranted. [ABSTRACT FROM AUTHOR]

Background: Clinical outcomes for resected early‐stage non‐small cell lung cancer (NSCLC) are superior at high‐volume facilities, but reasons for these differences remain unclear. Understanding these differences and optimizing outcomes across institutions are critical to the management of the increasing incidence of these cases. We evaluated the extent to which surgical best practices account for resected early‐stage NSCLC outcome differences between facilities according to case volume. Methods: We performed a retrospective cohort study for clinical stage 1 or 2 NSCLC undergoing surgical resection from 2004 to 2013 using the National Cancer Database (NCDB). Surgical best practices (negative surgical margins, lobar or greater resection, lymph node (LN) dissection, and examination of > 10 LNs) were compared between the highest and lowest quartile volumes. Results: A total of 150,179 patients were included in the cohort (89% white, 53% female, median age 68 years). In a multivariate model, superior overall survival (OS) was observed at highest volume centers compared to lowest volume centers (hazard ratio (HR) = 0.89; 95% CI, 0.82‐0.96; P =.002). After matching for surgical best practices, there was no significant OS difference (HR = 0.95; 95% CI, 0.87‐1.05; P =.32). Propensity score‐adjusted HR estimates indicated that surgical best practices accounted for 54% of the numerical OS difference between low‐volume and high‐volume centers. Each surgical best practice was independently associated with improved OS (all P ≤.001). Conclusion: Quantifiable and potentially modifiable surgical best practices largely account for resected early‐stage NSCLC outcome differences observed between low‐ and high‐volume centers. Adherence to these guidelines may reduce and potentially eliminate these differences. [ABSTRACT FROM AUTHOR]

Background: Patient participation in cancer clinical trials is suboptimal. A challenge to capturing physicians' insights about trials has been low response to surveys. We conducted a study using varying combinations of mail and email to recruit a nationally representative sample of medical, surgical, and radiation oncologists to complete a survey on trial accrual.Methods: We randomly assigned eligible physicians identified from the American Medical Association MasterFile (n = 13,251) to mail- or email-based recruitment strategies. Mail-based recruitment included a survey packet with: (1) cover letter describing the survey and inviting participation; (2) paper copy of the survey and postage-paid return envelope; and (3) a web link for completing the survey online. Email-based recruitment included an e-mail describing the survey and inviting participation, along with the web link to the survey, and a reminder postcard 2 weeks later.Results: Response was higher for mail-based (11.8, 95% CI 11.0-12.6%) vs. email-based (4.5, 95% CI 4.0-5.0%) recruitment. In email-based recruitment, only one-quarter of recipients opened the email, and even fewer clicked on the link to complete the survey. Most physicians in mail-based recruitment responded after the first invitation (362 of 770 responders, 47.0%). A higher proportion of responders vs. non-responders were young (ages 25-44 years), men, and radiation or surgical (vs. medical) oncologists.Conclusions: Most physicians assigned to mail-based recruitment actually completed the survey online via the link provided in the cover letter, and those in email-based recruitment did not respond until they received a reminder postcard by mail. Providing the option to return a paper survey or complete it online may have further increased participation in the mail-based group, and future studies should examine how combinations of delivery mode and return options affect physicians' response to surveys. [ABSTRACT FROM AUTHOR]