Randomized Trial of Afatinib Plus Cetuximab Versus Afatinib Alone for First-Line Treatment of EGFR-Mutant Non-Small-Cell Lung Cancer: Final Results From SWOG S1403.

PURPOSE: The irreversible ErbB family tyrosine kinase inhibitor (TKI) afatinib plus the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to EGFR TKIs. We studied whether the combination of afatinib plus cetuximab compared with afatinib alone would improve progression-free survival (PFS) in patients with treatment-naive EGFR-mutant non-small-cell lung cancer (NSCLC) by preventing or delaying resistance. METHODS: Patients with EGFR-mutant NSCLC without prior treatment of advanced disease were enrolled in this phase II, multicenter trial and randomly assigned to receive afatinib 40 mg orally daily plus cetuximab 500 mg/m2 intravenously every 2 weeks or afatinib alone. The primary end point was PFS. RESULTS: Between March 25, 2015 and April 23, 2018, 174 patients were randomly assigned, and 168 (83 on afatinib + cetuximab and 85 on afatinib) were eligible. There was no improvement in PFS in patients receiving afatinib plus cetuximab compared with afatinib alone (hazard ratio [HR], 1.01; 95% CI, 0.72 to 1.43; P = .94; median, 11.9 months v 13.4 months). Similarly, there was no difference in response rate (67% v 74%; P = .38) or overall survival (HR, 0.82; 95% CI, 0.50 to 1.36; P = .44). Toxicity was greater with the combination: grade ≥ 3 adverse events related to treatment occurred in 72% of patients receiving afatinib plus cetuximab compared with 40% of those receiving afatinib alone, most commonly rash and diarrhea. Dose reductions were more common in patients receiving the combination, and 30% of patients in this arm discontinued cetuximab due to toxicity. At interim analysis, there was insufficient evidence to support continued accrual, and the trial was closed. CONCLUSIONS: The addition of cetuximab to afatinib did not improve outcomes in previously untreated EGFR-mutant NSCLC, despite recognized activity in the acquired resistance setting.

Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial.

BACKGROUND: We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort. METHODS: This was an open-label, phase 2 study of patients from the Yale Cancer Center (CT, USA). Eligible patients were at least 18 years of age with stage IV NSCLC with at least one brain metastasis 5-20 mm in size, not previously treated or progressing after previous radiotherapy, no neurological symptoms or corticosteroid requirement, and Eastern Cooperative Oncology Group performance status less than two. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease; systemic disease was not required for participation. Patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks. Patients were in two cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was patients with PD-L1 less than 1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response (partial response or complete response, according to mRECIST). All treated patients were analysed for response and safety endpoints. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT02085070. FINDINGS: Between March 31, 2014, and May 21, 2018, 42 patients were treated. Median follow-up was 8·3 months (IQR 4·5-26·2). 11 (29·7% [95% CI 15·9-47·0]) of 37 patients in cohort 1 had a brain metastasis response. There were no responses in cohort 2. Grade 3-4 adverse events related to treatment included two patients with pneumonitis, and one each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycaemia, and hypokalaemia. Treatment-related serious adverse events occurred in six (14%) of 42 patients and were pneumonitis (n=2), acute kidney injury, colitis, hypokalaemia, and adrenal insufficiency (n=1 each). There were no treatment-related deaths. INTERPRETATION: Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression at least 1% and is safe in selected patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted. FUNDING: Merck and the Yale Cancer Center.

Measuring the Impact of Academic Cancer Network Development on Clinical Integration, Quality of Care, and Patient Satisfaction.

PURPOSE: Many US academic centers have acquired community practices to expand their clinical care and research footprint. The objective of this assessment was to determine whether the acquisition and integration of community oncology practices by Yale/Smilow Cancer Hospital improved outcomes in quality of care, disease team integration, clinical trial accrual, and patient satisfaction at network practice sites. METHODS: We evaluated quality of care by testing the hypothesis that core Quality Oncology Practice Initiative measures at network sites that were acquired in 2012 were significantly different after their 2016 integration into the network. Clinical and research integration were measured using the number of tumor board case presentations and total accruals in clinical trials. We used Press-Ganey scores to measure patient satisfaction pre- and postintegration. RESULTS: Mean Quality Oncology Practice Initiative scores at Smilow Care Centers were significantly higher in 2016 than in 2012 for core measures related to improvement in tumor staging ( z = 1.33; P < .05), signed consent and documentation plans for antineoplastic treatment ( z = 2.69; P < .01; and z = 2.36; P < .05, respectively), and appropriately quantifying and addressing pain during office visits ( z = 2.95; P < .05; and z = 3.1; P < .01, respectively). A total of 493 cases were presented by care center physicians at the tumor board in 2017 compared with 45 presented in 2013. Compared with 2012, Smilow Care Center clinical trial accrual increased from 25 to 170 patients in 2017. Last, patient satisfaction has remained at greater than the 90th percentile pre- and postintegration. CONCLUSION: The process of integration facilitates the ability to standardize cancer practice and provides a platform for quality improvement.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 5.2018.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

Do older patients with non-small cell lung cancer also benefit from first-line platinum-based doublet chemotherapy? Observations from a pooled analysis of 730 prospectively-treated patients (Alliance Study A151622).

OBJECTIVE: This study sought to define the role of first-line platinum-based doublet chemotherapy in older patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We analyzed three first-line NSCLC trials: CALGB 9730, CALGB 30203, and CALGB 30801, which tested carboplatin and paclitaxel; carboplatin and gemcitabine; and carboplatin with either pemetrexed or gemcitabine, respectively. Overall survival was the primary endpoint. Age-based comparisons with a cutpoint of 65 years were performed with Cox proportional hazards models with adjustments for sex, tumor histology, cancer stage, chemotherapy, and smoking history and after stratifying by performance score. Secondary endpoints were grade 3-5 adverse events, chemotherapy cycles completed, and whether toxicity prompted chemotherapy discontinuation. RESULTS: 730 patients were included; 337 (46%) were 65+ years of age. No statistically significant difference in survival was observed for older (≥65) versus younger patients (HR = 1.096; 95% CI = (0.94, 1.28); p = 0.25). A trend emerged with increased odds of a grade 3-5 adverse event for patients ≥65 years versus <65 years (OR = 1.52; 95% CI = (0.99, 2.31); p = 0.05). The proportion of completed chemotherapy cycles was marginally lower in older patients (difference = -5%; 95% CI = (-9, 0.2); p = 0.06) for those ≥65 years versus <65 years, but no statistically significant difference occurred in the rate of chemotherapy discontinuation for toxicity (OR = 1.4; 95% CI = (0.85, 2.19); p = 0.21) for patients ≥65 years versus <65 years. A cutpoint of 70 years yielded similar results. CONCLUSION: These findings support carboplatin doublet-based chemotherapy in select older patients with advanced NSCLC.

Time-to-Treatment-Failure and Related Outcomes Among 1000+ Advanced Non-Small Cell Lung Cancer Patients: Comparisons Between Older Versus Younger Patients (Alliance A151711).

INTRODUCTION: Time-to-treatment-failure (TTF) is the interval from chemotherapy initiation to premature discontinuation. We evaluated TTF based on age. METHODS: Pooled analyses were conducted with first-line chemotherapy trials for advanced NSCLC (CALGB 9730, 30203, and 30801). Comparisons among patients who were 65 years and older and 70 years and older were performed for TTF (primary endpoint), reasons for early chemotherapy cessation, grade 3+ adverse events, and overall survival. RESULTS: Among 1006 patients, 460 (46%) were older than 65 years of age. One hundred forty-five older patients (32% of this age cohort) completed all six planned chemotherapy cycles as did 170 (32%) younger patients. Median TTF was 2.9 months (95% confidence interval: 2.7- 3.2) in older patients and 3 months (95% confidence interval: 2.9-3.5) in younger patients; adjustment for performance status and stratification by chemotherapy by trial yielded no statistically significant age-based difference in TTF. However, reasons for early chemotherapy cessation differed between age groups (multivariate p = 0.004). Older patients were less likely to discontinue from cancer progression (41% versus 55%) and more likely from toxicity or patient choice (16% and 15%, respectively) compared to younger patients (13% and 6%, respectively). Older patients were more likely to experience grade 3+ adverse events (86% versus 79%) with no statistically significant difference in survival. An age cutpoint of 70+ years showed no difference in TTF, a lower trend of early cessation due to cancer progression, and somewhat shorter older patient survival. CONCLUSIONS: TTF was comparable between older and younger patients; but different, age-based, and potentially modifiable reasons account for it.

Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: With expanding indications for programmed death 1 (PD-1) axis inhibitors in non-small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients. METHODS: Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either Response Evaluation Criteria in Solid Tumors v1.1 or immune-related response criteria. RESULTS: Twenty-six patients with AR to PD-1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; the 2-year survival rate from AR was 70% (95% confidence interval: 0.53-0.92). Twenty patients (77%) experienced AR in lymph nodes (LNs), including 11 patients with LN-only progression. Twenty-three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD-1 axis inhibitor therapy beyond progression. Three patients were re-challenged with the same PD-1 axis inhibitor after holiday from and progression off therapy, 2 again responded. Fifteen patients (58%) received local therapy to site(s) of AR, 11 continued respective PD-1 axis inhibitor after local therapy. The 2-year survival rate from AR among these 15 patients was 92% (95% confidence interval: 0.77-1). CONCLUSIONS: Acquired resistance to PD-1 axis inhibitors is often limited to one or two sites when local therapy and continuation of PD-1 axis inhibitor therapy can result in prolonged benefit. LN metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD-1 axis inhibitor, re-challenge can again lead to tumor regression.

Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer.

BACKGROUND: KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. RESULTS: Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. CONCLUSION: In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.

Development of Imminent Mortality Predictor for Advanced Cancer (IMPAC), a Tool to Predict Short-Term Mortality in Hospitalized Patients With Advanced Cancer.

PURPOSE: End-of-life care for patients with advanced cancer is aggressive and costly. Oncologists inconsistently estimate life expectancy and address goals of care. Currently available prognostication tools are based on subjective clinical assessment. An objective prognostic tool could help oncologists and patients decide on a realistic plan for end-of-life care. We developed a predictive model (Imminent Mortality Predictor in Advanced Cancer [IMPAC]) for short-term mortality in hospitalized patients with advanced cancer. METHODS: Electronic health record data from 669 patients with advanced cancer who were discharged from Yale Cancer Center/Smilow Cancer Hospital were extracted. Statistical learning techniques were used to develop a tool to estimate survival probabilities. Patients were randomly split into training (70%) and validation (30%) sets 20 times. We tested the predictive properties of IMPAC for mortality at 30, 60, 90, and 180 days past the day of admission. RESULTS: For mortality within 90 days at a 40% sensitivity level, IMPAC has close to 60% positive predictive value. Patients estimated to have a greater than 50% chance of death within 90 days had a median survival time of 47 days. Patients estimated to have a less than 50% chance of death had a median survival of 290 days. Area under the receiver operating characteristic curve for IMPAC averaged greater than .70 for all time horizons tested. Estimated potential cost savings per patient was $15,413 (95% CI, $9,162 to $21,665) in 2014 constant dollars. CONCLUSION: IMPAC, a novel prognostic tool, can generate life expectancy probabilities in real time and support oncologists in counseling patients about end-of-life care. Potentially avoidable costs are significant.

Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.

Preparing for Value-Based Payment: A Stepwise Approach for Cancer Centers.

Most cancer centers are ill-equipped to pursue value-based payment (VBP) because of limited information on their population's cost of care. Herein, we outline the stepwise approach used by Smilow Cancer Hospital at Yale-New Haven in our pursuit of better value care. First, we addressed institutional barriers. A move toward value required demonstration to Yale-New Haven Health System leadership that OCM would improve patient care, fund new infrastructure, and provide the opportunity to gain experience with VBP without a major threat to the financial stability of the health system. We evaluated patterns of care and found that of patients presenting to the emergency department (ED), 88% were admitted, 62% arrived during the workday, and 50% could have been stabilized with urgent care services. Within 30 days of death, 27% were admitted to the intensive care unit, 38% presented to the ED, and 52% were admitted. To quantify total cost of care, we accessed the 5% Medicare Limited Data Set to map out total cost of care for patients receiving chemotherapy at Smilow Cancer Hospital. Costs increased as patients moved through 6-month episodes, used the ED (patients with two or more visits were twice as expensive as those with one or fewer), or died during an episode (costs were twice as high as episodes in which the patient lived). To determine strategic interventions to improve value, we targeted investments in urgent care to reduce ED utilization, care management to prevent hospital admissions, and referral to palliative care for clarification of goals of care and avoidance of costly futile treatment. Developing internal metrics to evaluate success will require monitoring our interventions by having utilization measures for each site of care and individual provider.

NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016.

These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Malignant Pleural Mesothelioma (MPM). These NCCN Guidelines Insights discuss systemic therapy regimens and surgical controversies for MPM. The NCCN panel recommends cisplatin/pemetrexed (category 1) for patients with MPM. The NCCN panel also now recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. The complete version of the NCCN Guidelines for MPM, available at NCCN.org, addresses all aspects of management for MPM including diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis; NCCN Guidelines are intended to assist with clinical decision-making.

Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer.

For appropriate treatment selection, the updated NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) recommend broad molecular profiling for all patients with nonsquamous disease. Three different tyrosine kinase inhibitors (TKIs) are recommended as first-line treatment of EGFR mutation-positive NSCLC: gefitinib, erlotinib, and afatinib. Most patients whose disease responds will still experience progression, and the type of disease progression drives management. Systemic progression requires switching TKI treatment, whereas patients with oligoprogression and central nervous system progression may have their new lesions treated but continue on their TKI. A new third-generation TKI has been approved and others are currently under development, and new combinations of these drugs with a VEGFR inhibitor offer promise to improve outcomes.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016.

These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.

Assessing Clinical Trial-Associated Workload in Community-Based Research Programs Using the ASCO Clinical Trial Workload Assessment Tool.

PURPOSE: Clinical research program managers are regularly faced with the quandary of determining how much of a workload research staff members can manage while they balance clinical practice and still achieve clinical trial accrual goals, maintain data quality and protocol compliance, and stay within budget. A tool was developed to measure clinical trial-associated workload, to apply objective metrics toward documentation of work, and to provide clearer insight to better meet clinical research program challenges and aid in balancing staff workloads. A project was conducted to assess the feasibility and utility of using this tool in diverse research settings. METHODS: Community-based research programs were recruited to collect and enter clinical trial-associated monthly workload data into a web-based tool for 6 consecutive months. Descriptive statistics were computed for self-reported program characteristics and workload data, including staff acuity scores and number of patient encounters. RESULTS: Fifty-one research programs that represented 30 states participated. Median staff acuity scores were highest for staff with patients enrolled in studies and receiving treatment, relative to staff with patients in follow-up status. Treatment trials typically resulted in higher median staff acuity, relative to cancer control, observational/registry, and prevention trials. Industry trials exhibited higher median staff acuity scores than trials sponsored by the National Institutes of Health/National Cancer Institute, academic institutions, or others. CONCLUSION: The results from this project demonstrate that trial-specific acuity measurement is a better measure of workload than simply counting the number of patients. The tool was shown to be feasible and useable in diverse community-based research settings.

Optimizing Treatment Risk and Benefit for Elderly Patients With Advanced Non-Small-Cell Lung Cancer: The Right Treatment for the Right Patient.

The Oncology Grand Rounds series is designed to place original reports published in theJournal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published inJournal of Clinical Oncology, to patients seen in their own clinical practice.A 78-year-old woman with a 40-pack-year smoking history has been referred for treatment of advanced non-small-cell lung cancer. She presented with a persistent cough and worsening dyspnea on exertion. A chest x-ray followed by a chest computed tomography scan revealed a 3-cm right upper lobe mass along with a moderate-size pleural effusion. Pleural fluid cytology was positive for adenocarcinoma. A brain magnetic resonance imaging scan was negative. A reflex molecular profile, includingKRAS,EGFR,ALK,BRAF,HER2,RET,MET, andROS, did not reveal an actionable abnormality. Her past medical history includes diabetes, hypertension, and osteopenia. Her medications include a ß-blocker, angiotensin-converting enzyme inhibitor, oral antidiabetic agent, calcium, and vitamin D. The laboratory evaluation is notable for a hemoglobin of 10.8 g/dL and a creatinine clearance of 36 mL/min. The other laboratories are within normal limits. She is somewhat limited by the shortness of breath but maintains an Eastern Cooperative Oncology Group performance status of 1. She is independent in all of her instrumental and basic activities of daily living and denies falls. She has been referred to discuss treatment options.

Role of Chemoradiotherapy in Elderly Patients With Limited-Stage Small-Cell Lung Cancer.

PURPOSE: To investigate outcomes for elderly patients treated with chemotherapy (CT) alone versus chemoradiotherapy (CRT) in the modern era by using a large national database. PATIENTS AND METHODS: Elderly patients (age ≥ 70 years) with limited-stage small-cell lung cancer clinical stage I to III who received CT or CRT were identified in the National Cancer Data Base between 2003 and 2011. Hierarchical mixed-effects logistic regression with clustering by reporting facility was performed to identify factors associated with treatment selection. Overall survival (OS) of patients receiving CT versus CRT was compared by using the log-rank test, Cox proportional hazards regression, and propensity score matching. RESULTS: A total of 8,637 patients were identified, among whom 3,775 (43.7%) received CT and 4,862 (56.3%) received CRT. The odds of receiving CRT decreased with increasing age, clinical stage III disease, female sex, and the presence of medical comorbidities (all P < .01). Use of CRT was associated with increased OS compared with CT on univariable and multivariable analysis (median OS, 15.6 v 9.3 months; 3-year OS, 22.0% v 6.3%; log-rank P < .001; Cox P < .001). Propensity score matching identified a matched cohort of 6,856 patients and confirmed a survival benefit associated with CRT (hazard ratio, 0.52; 95% CI, 0.50 to 0.55; P < .001). Subset analysis of CRT treatment sequence showed that patients alive 4 months after diagnosis derived a survival benefit with concurrent CRT over sequential CRT (median OS, 17.0 v 15.4 months; log-rank P = .01). CONCLUSION: In elderly patients with limited-stage small-cell lung cancer, modern CRT appears to confer an additional OS advantage beyond that achieved with CT alone in a large population-based cohort. Our findings suggest that CRT should be the preferred strategy in elderly patients who are expected to tolerate the toxicities of the combined approach.

The Treatment of Advanced Lung Cancer in the Elderly: The Role of a Comprehensive Geriatric Assessment and Doublet Chemotherapy.

The US lung cancer population is aging, the majority of which receive a diagnosis of incurable advanced non-small cell lung cancer (NSCLC). In US clinical oncology practice, elderly is defined as patients older than 70 years. Treatment of elderly patients with advanced NSCLC is complex. Choosing appropriate chemotherapy in this setting is complicated by multiple chronic conditions in addition to geriatric syndromes, challenging the traditional oncology practice. Although promising new options are on the horizon, the standard of care remains either platinum-based doublet or single-agent chemotherapy. Clinical trials have determined doublet therapy is appropriate for elderly patients; however, out of concern for excessive toxicity, many elderly patients do not receive appropriate treatment. Determining which patients are most likely to benefit from doublet chemotherapy versus monotherapy is a difficult challenge. Researchers have started to implement geriatric assessment and predictive chemotherapy toxicity tools in prospective clinical trials; however, knowledge gaps remain on how to appropriately select and treat elderly patients with advanced NSCLC in efforts to improve disease management and symptoms, maintain functional status, and minimize toxicity.

Non-Small Cell Lung Cancer, Version 6.2015.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

The spectrum of neuroendocrine tumors: histologic classification, unique features and areas of overlap.

Neuroendocrine neoplasms are diverse in terms of sites of origin, functional status, and degrees of aggressiveness. This review will introduce some of the common features of neuroendocrine neoplasms and will explore the differences in pathology, classification, biology, and clinical management between tumors of different anatomic sites, specifically, the lung, pancreas, and prostate. Despite sharing neuroendocrine differentiation and histologic evidence of the neuroendocrine phenotype in most organs, well-differentiated neuroendocrine tumors (WD-NETs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) are two very different families of neoplasms. WD-NETs (grade 1 and 2) are relatively indolent (with a natural history that can evolve over many years or decades), closely resemble non-neoplastic neuroendocrine cells, and demonstrate production of neurosecretory proteins, such as chromogranin A. They arise in the lungs and throughout the gastrointestinal tract and pancreas, but WD-NETs of the prostate gland are uncommon. Surgical resection is the mainstay of therapy, but treatment of unresectable disease depends on the site of origin. In contrast, PD-NECs (grade 3, small cell or large cell) of all sites often demonstrate alterations in P53 and Rb, exhibit an aggressive clinical course, and are treated with platinum-based chemotherapy. Only WD-NETs arise in patients with inherited neuroendocrine neoplasia syndromes (e.g., multiple endocrine neoplasia type 1), and some common genetic alterations are site-specific (e.g., TMPRSS2-ERG gene rearrangement in PD-NECs arising in the prostate gland). Advances in our understanding of the molecular basis of NETs should lead to new diagnostic and therapeutic strategies and is an area of active investigation.