Virtual Library

Background:
Surgical resection is the most important curative modality for NSCLC. However, gaps in the quality of surgery adversely affect patients’ survival. In the Mid-South region, at the center of the US lung cancer mortality belt, we began a project in 2009 to improve the quality of surgery and pathology examination across all hospitals. We report the evolution of surgical quality in this region from 2004-2013.

Methods:
The MS-QSR database includes patient-level details from all NSCLC resections in 11 institutions in 5 Dartmouth Hospital Referral Regions in Eastern Arkansas, North Mississippi, and Western Tennessee. Data span the care delivery process from initial radiographic detection, through diagnostic and staging tests, to surgical treatment and post-operative outcomes. We performed trend analysis and comparisons among institutions.

Results:
There were 2,410 curative-intent NSCLC resections. Patient demographics, rates of non-invasive staging tests and pre-operative adjuvant therapy did not change. 92% of patients had a pre-operative CT, 80% had a PET-CT scan. The use of invasive staging tests (endobronchial ultrasound, mediastinoscopy, etc.) increased from 11.3% in 2009 to 22.3% in 2013 (p<0.001). The pneumonectomy rate decreased from 12% in 2004 to 6.2% in 2013 (p=0.05). The margin positivity rate remained stable at 5.8%. Stage distributions remained unchanged, with 63% stage I, 18% stage II, and 19% stage III or above. The total number of lymph nodes retrieved during resection remained unchanged until 2010 (median 4-5 from 2004 to 2010), after which, it increased significantly (median 7 in 2011, 9.5 in 2012, and 10 in 2013) (p<0.001) (figure 1). The mediastinal lymph node (MLN) examination rate increased from 53% in 2004 to 82% in 2013 (p<0.001). However, the rate of non-examination of lymph nodes (pNX) remained stable at 10%. Although the proportion of patients with N1 disease remained stable (17.6%), the proportion with N2 disease increased during a pilot testing phase with a MLN specimen collection kit implementation (10.8% in 2010 and 2011, and 7-8% in all other years). Finally, the re-hospitalization rate was 13.3%; the 60-day mortality rate was 6.4%. Figure 1



Conclusion:
In this population-based cohort, pre-operative and intraoperative nodal staging practice improved significantly. However, other quality measures (margin positivity and pNX rates) need further improvement. This early analysis suggests that a regional quality improvement project can improve overall patient survival in this high lung cancer mortality zone of the US.

Background:
Lung cancer has the highest cancer mortality. The life expectancy of untreated NSCLC is dismal, while treatment for NSCLC improves survival. However, the perceived outcome of NSCLC therapy in general is less favorable compared to other types of solid tumors. The presence of comorbidities is thought to play a significant role on the decision to treat or not-to-treat a given patient. We aimed to evaluate the impact of comorbidities on the survival of patients treated for NSCLC.

Methods:
As part of Kentucky's LEADS Collaborative, we identified NSCLC patients older than 65 years between 2007 and 2011 on the SEER Kentucky Cancer Registry (KCR). We linked the SEER KCR data with Medicare claims data for therapies provided (surgery, radiation, chemotherapy) for patients who had Medicare PART A and B coverage, had no HMO coverage 12 months prior to their cancer diagnosis, and had the lung cancer as the first primary cancer. Charlson comorbidity index (CCI) was assigned to each patient based on the linked Medicare data. Kaplan-Meier estimates were plotted. Log-Rank test was used to compare survival estimates. Data on age, sex, CCI, stage, and type of therapy received were included in univariate and multivariate Cox proportional hazard analyses.

Results:
Between 2007 and 2011, we identified 3905 patients for analysis. The population was Caucasian in 95% and African American in 4.6%. 54.4% were male. There were 2336 patients (59.8%) between ages 66 and 75. 770 patients (19.7%) did not receive any surgery, radiation, chemotherapy or any combination of these modalities. The proportion of untreated patient per stage was 9.45% for Stage I, 4.35% for Stage II, 20.76% for Stage III and 26.7% for Stage IV. The median overall survival was 41 months for stage I, 22 months for stage II, 10.5 months for stage III and 4.1 months for stage IV (Log-rank test, P < 0.001) In the survival analysis, treatment for NSCLC resulted in significantly better survival (LR, P < 0.05), for patients that have no comorbidity burden (CCI score of 0), for those who have a low burden of comorbidities (CCI score of 1-2) as well as for those patients that had a significant comorbidity burden (CCI score of 3 or more). The better survival of patients with high burden of comorbidities who received treatment for their disease was consistently observed on Stage I (HR 0.31, 95% CI 0.20-0.48); Stage III (HR 0.27, 95% CI 0.18-0.40) and Stage IV (HR 0.46, 95% CI 0.34-0.62). The multivariate analysis confirms the established factors that negatively impact survival (older age, being male, higher stage, higher grade, and no treatment).

Conclusion:
Undertreatment of lung cancer has many causes, but misconceptions about patients being eligible for treatment play a significant role. The presented SEER-Medicare data demonstrates a significant survival benefit from NSCLC therapy even in those patients with a high burden of comorbidities. The data supports the consideration for therapy even when the comorbidity burden is perceived as high. Further studies are needed to determine the effect of optimal comorbidities management on lung cancer outcomes.

Background:
Access to cancer specialists and directed therapies is critical in the management of patients with metastatic lung cancer (mLC). This study aims to assess treatment patterns overall and stratified based on whether patients were seen or not by a cancer specialist in patients with de novo mLC.

Methods:
Adult patients diagnosed with de novo mLC between January 1, 2008 and March 31, 2014 were selected from a US commercial health claims database. All patients were followed for a minimum 3 months after the index date, defined as their first biopsy date. Patients who saw an oncologist/hematologist from 6 weeks before index date until the end of follow-up (end of data availability or health plan eligibility) were included in the cohort of patients who saw a cancer specialist. The remaining patients were included in the cohort of patients who did not see a cancer specialist. In both cohorts, the use of systemic antineoplastic therapy (Table 1) and radiation therapy was assessed following the index date.

Results:
The study sample consisted of 25,191 mLC patients, followed for a median of 9 months. Median age was 63 years (interquartile range: 57-73). 28.4% of the patients did not see a cancer specialist. Overall, 89.9% of the mLC patients received a cancer directed therapy during the follow-up (Table 1). The proportion of patients who received a cancer directed therapy during the follow-up was larger among patients seen by a cancer specialist (91.2% vs. 86.7%, p < .0001) (Table 1). Among patients who did not see a cancer specialist, 86.7% received antineoplastic therapy and/or radiotherapy during the follow-up, 2.6% were untreated and admitted to hospice, and 10.6% were untreated and were not admitted to hospice. The majority of patients who were not seen by a cancer specialist and received treatment were seen prior to the initiation of therapy by pulmonologists, internists, family physicians, and/or radiologists. Figure 1



Conclusion:
Approximately one in ten patients with de novo mLC did not receive any cancer directed therapy and a little more than one in four patients were not seen directly by a cancer specialist. Among patients not seen by a cancer specialist many received some form of cancer directed therapy. However, the access to cancer directed therapy of these patients remained significantly lower than that of mLC patients seen by a cancer specialist. Further research should be directed towards understanding and addressing disparities in access to appropriate cancer care.

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Background:
Molecular testing-directed targeted therapies are transforming treatment paradigms for non-small cell lung cancer (NSCLC). The clinical application of next-generation sequencing (NGS) technologies has offered a more comprehensive understanding of the mutational landscape. Efforts have been made in the past three years in the Department of pathology at the Peking Union Medical College Hospital, to adopt NGS in the clinical setting allowing rapid and reliable detection of actionable mutations that facilitate therapeutic decision making and disease prediction for at-risk patients

Methods:
The NextDaySeq Lung panel on Ion Torrent[TM] System and DanPA bioinformatics pipeline have been implemented in our clinical laboratory. The workflow employs novel chemistry in library preparation and innovation in informatics, which allows a 48-hour turnaround from FFPE samples to identification of variants with demonstrated clinical importance. The test sequences 16 exons in EGFR, KRAS, BRAF, PIK3CA, ALK, DDR2 and PDGFRA, covering 82 well recognized hotspots. The end-to-end test performance has been established with analytical sensitivity and specificity as well as the assay’s repeatability and reproducibility. Up to date, more than 200 samples have been examined including both lung adenocarcinoma and lung squamous carcinoma. To characterize the analytical performance, the NGS results have been compared with Sanger sequencing that covers the same exons, as well as QPCR assays (CFDA approved IVD kits) that cover a majority of hotspots within these exons.

Results:
Analysis of 200 cases indicated 100% concordance for reportable variants mutually covered in both NGS and QPCR assays. Eight cases reported at least one additional potentially clinically relevant variant, for example, in EGFR and PIK3CA, that would not have been identified in previously implemented QPCR assays. The mutation rates reported in 200 cases ranged from 2.4% to 84.3% according to DanPA analysis, while Sanger sequencing failed to detect variants in 32 cases with mutation rates lower than 20%. The Indel analysis had been a challenge for previous NGS tests in the lab, and the current test resolved the issue with the DanPA pipeline, demonstrating 100% PPV and NPV values compared with QPCR, and Sanger when mutation rates higher than 20%. Additionally, we documented multiple cases that carry double and triple mutations, which were rare in lung cancer, and also identified several novel mutations.

Conclusion:
Therefore, we reported the validation of NextDaySeq Lung panel for high throughput detection of mutations in NSCLC, and the development of a wet-bench and informatics workflow enabling timely and informative molecular diagnosis. The implementation of the test offers significantly improved information benefit over previous tests, and holds the promise to impact patient management.

Background:
The frequency of epidermal growth factor receptor mutations (EGFR-mut) in tumors from Hispanic (HIS) patients (pts) in Latin-America (LA) might be higher than the rate registered in the world literature from data coming mainly from Non-Hispanic White (NHW) pts with NSCLC (CLICaP: J Clin Oncol. 2012;30:(suppl; abstr e18114)). We wanted to verify this and investigate the gene expression profile (GEP) in tumors from HIS pts with NSCLC living in the US.

Methods:
To identify EGFR-mut and other molecular markers (MM) (ALK and ROS-1 translocations (trans), KRAS, c-Met and BRAF) genomic analysis by next generation sequencing (NGS) and FISH was done in tumors of pts with NSCLC at Memorial Cancer Institute in Florida. All MM were not available for all pts. Pts were divided into groups based on ethnic background. Chi-square and Fisher’s Exact tests were used to assess associations between genetic profile and ethnicity. All summary statistics on time-to-event variables were calculated according to the Kaplan-Meier method and were compared by means of the log-rank test. Adjusted hazard ratios (AHR) and 95% confidence intervals (95% CI) were reported based on the results of a multivariate Cox regression model for overall survival (OS) with adjustment for gender, age, and race. A p value 0.05 was significant. SPSS® software 21 was used for analyses.

Results:
MM were ordered in 282 pts and tumor samples were sufficient in 254 (90%). Of these pts: 35% were HIS, 59% were women, 92% had adenocarcinoma and 38% were non-smokers. EGFR-mut were seen in 21% of the tumors [93 % in exons 19 and 21]. EGFR resistant mutations [exon 20] in 1%. ALK and ROS-1 trans were 3% and 10%. c-MET in 25%, KRAS 24%, and BRAF 4%.

MM	% in HIS	% in NHW	# samples
EGFR mut	23%	20%	231
ALK trans	4%	3%	209
ROS-1 trans	8%	11%	63
KRAS mut	26%	22%	149
c-MET mut	25%	25%	51
BRAF mut	10%	0%	49

There was no significant association between HIS vs. NHW with any MM: EGFR-mut [χ[2 ]=0.22, p=0.64] or ALK and ROS-1 trans [Fisher’s Exact Tests, p=0.49 and 0.55] or other MM: KRAS, χ[2 ]=0.25, p=0.62, c-MET, χ[2 ]=0.00, p=1.00, or BRAF, Fisher’s Exact Tests, p=0.17. No differences in survival between HIS and NHW regardless of MM. Log Rank (Mantel-Cox) 0.73, p=0.39.

Conclusion:
GEP of NSCLC tumors in HIS pts in the US are similar to NHW contrary to what is found in LA. There might be selection bias in the data from LA due to the fact that very few of the eligible pts in LA are being tested yet, all of our NSCLC pts get GEP in our practice.

Background:
Sixteen percent of the U.S. population is Hispanic, predominantly of Mexican ancestry. Recently, two independent American reports demonstrated a higher overall survival (OS) in Hispanic populations compared with non-Hispanic-white populations (NHW) in patients with non-small-cell lung cancer (NSCLC) diagnosis. The latter even when most of the Hispanics are diagnosed at advanced stages of disease and are low-income patients. The aim of our study was to analyze the clinical, pathological, and molecular characteristics as well as the outcomes in a cohort of NSCLC Hispanic patients from the National Cancer Institute of Mexico that could explain this "Hispanic Paradox".

Methods:
A cohort of 1260 consecutive NSCLC patients treated at the National Cancer Institute of Mexico from 2007-2014 was analyzed. Their clinical- pathological characteristics, the mutation-status of EGFR and KRAS and the prognosis were evaluated.

Results:
Patients presented with stages of disease: II (0.6%), IIIa (4.8%), IIIb (18.4%) and IV (76.3%). NSCLC was associated with smoking in 56.5% of the patients (76.7% of male vs. 33.0% of female patients). Wood smoke exposure (WSE) was associated with 37.2% of the cases (27.3% in men vs. 48.8% in women). The frequency of EGFR mutations was 28.1% (18.5% in males vs. 36.9% in females, p<0.001) and the frequency for KRAS mutations was 10.2% (10.3% men vs. 10.1% in women p= 0.939). The median OS for all patients was 23.0 months [CI95% 19.4-26.2], whereas for patients at stage IV, it was 20.1 months [CI 95% 16.5-23.7]. The independent factors associated with the OS were as follows, the ECOG Performance Status, stage of disease, EGFR and KRAS mutation status.

Conclusion:
The high frequency of EGFR mutations and low frequency of KRAS mutations in Hispanic populations and different prevalence in lung cancer-related-developing risk factors compared with Caucasian populations, such as the lower frequency of smoking exposure and higher WSE, particularly in women, might explain the prognosis differences between foreign-born-Hispanics, US-born-Hispanics and NHWs.

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Abstract:
The clinical benefits of biomarker-driven targeted cancer therapy are clear in many tumor types, particularly in lung adenocarcinoma. At this time, use of targeted agents is predicated on access to tumor tissue; in lung cancer patients this tissue is often limited in quantity, a product of minimally invasive procedures using narrow-gauge biopsy needles intended to reduce complications. Current clinical practice has forced pathology labs to revisit approaches to tissue handling, diagnosis, and molecular platform selection. Coordinated efforts are critical to optimizing the handling of small biopsies, from the time of request, to the actual procedure, to receipt in the pathology lab. Ideally, the requesting physician clearly communicates the need for genomic studies to both the operator, who may consider the need/feasibility of multiple biopsies, and pathologist, who may perform rapid on site evaluation. Interventional techniques designed to improve the chances of obtaining material amenable to molecular diagnostics should be implemented whenever possible, including combined core biopsy and fine needle aspiration,[1]and preferential sampling of soft tissue components of bony metastases when possible, in order to avoid the need for specimen decalcification. In the future, in vivo microscopy may be used to guide the biopsy location.[2] Routine histology practices, such as cutting slides from a paraffin block in an iterative fashion only after a pathologist’s review, often requires “refacing” to optimize the plane of section and can waste valuable tumor tissue. The need for genomics studies should be clearly indicated to the receiving pathology laboratory, thereby facilitating histology protocols designed to conserve tissue. Such protocols may include embedding each tissue core in an individual block, delivering “up-front” unstained sections for use in immunohistochemistry and molecular studies, and/or triaging slides to a dedicated molecular diagnostics workflow. As an example, from a single 18-gauge core needle biopsy containing 30% tumor, 15-20 unstained slides can typically generate enough material to perform a diagnostic workup, immunohistochemistry and/or FISH for ALK and ROS1 rearrangements, and adequate DNA for hybrid capture next generation sequencing.[3]With careful histology embedding and sectioning, material will still remain in the block for future studies. International guidelines have recognized the centrality of molecular testing to the clinical management of lung cancer patients and have responded with recommendations for judicious use of immunohistochemical studies in pathology workups and introduced new diagnostic categories intended to eliminate ambiguous classifications, particularly for small biopsy specimens.[4]These guidelines advise against use of the term “non small cell lung carcinoma” whenever possible and recommend use of TTF-1 and p63 or p40 immunohistochemical stains as first line markers for distinguishing between adenocarcinoma and squamous cell carcinoma.[5] Simultaneous evaluation of fine needle aspirates and core biopsies with an optimized IHC protocol may significantly reduce rates of the NSCLC diagnosis and generate additional “testable” material.[6] In institutions that use touch imprints for rapid evaluation of core needle biopsies, careful specimen handling is required to maintain tumor cell adequacy in the needle biopsy specimen.[7] When cytology material is available for testing, cell blocks are preferred because a physical record of the sample can be retained in the form of a stained glass slide.[4] However, in many circumstances the most cellular material is in the form of a smear; these preps can generate abundant and high quality DNA and so should be considered for use in molecular testing, particularly if the slide can be scanned and a digital image archived. Validation of alternative specimens such as cytology smears for FISH can provide additional tissue for in situ assays when core needle or cell block specimens are inadequate.[8] In the molecular diagnostics lab, a plethora of testing platforms are available, many of which are evolving to accept low DNA inputs. Many targeted amplicon-sequencing based assays can accept as little as 10ng of input DNA, whereas hybrid capture approaches typically require around 50ng or more for targeted sequencing panels and whole exome sequencing. However, in today’s practice, it is rare that a single test can provide comprehensive analysis of all the desired targets; indeed, confirmation of individual events detected by sequencing by FISH or immunohistochemistry may be needed. Therefore, an interdisciplinary effort to optimize tumor sampling and conserve tissue is required to ensure successful and comprehensive molecular profiling of lung tumors. References 1. Poulou LS, Tsagouli P, Ziakas PD, Politi D, Trigidou R, Thanos L. Computed tomography-guided needle aspiration and biopsy of pulmonary lesions: A single-center experience in 1000 patients. Acta Radiol. 2013;54(6):640-645. 2. Hariri LP, Mino-Kenudson M, Applegate MB, et al. Toward the guidance of transbronchial biopsy: Identifying pulmonary nodules with optical coherence tomography. Chest. 2013;144(4):1261-1268. 3. Austin MC, Smith C, Pritchard CC, Tait JF. DNA yield from tissue samples in surgical pathology and minimum tissue requirements for molecular testing. Arch Pathol Lab Med. 2015. 4. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: Guideline from the college of american pathologists, international association for the study of lung cancer, and association for molecular pathology. Arch Pathol Lab Med. 2013;137(6):828-860. 5. Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of lung cancer in small biopsies and cytology: Implications of the 2011 international association for the study of lung cancer/american thoracic society/european respiratory society classification. Arch Pathol Lab Med. 2013;137(5):668-684. 6. Sigel CS, Moreira AL, Travis WD, et al. Subtyping of non-small cell lung carcinoma: A comparison of small biopsy and cytology specimens. J Thorac Oncol. 2011;6(11):1849-1856. 7. Rekhtman N, Kazi S, Yao J, et al. Depletion of core needle biopsy cellularity and DNA content as a result of vigorous touch preparations. Arch Pathol Lab Med. 2015;139(7):907-912. 8. Betz BL, Dixon CA, Weigelin HC, Knoepp SM, Roh MH. The use of stained cytologic direct smears for ALK gene rearrangement analysis of lung adenocarcinoma. Cancer Cytopathol. 2013;121(9):489-499.

Abstract:
Management of patients with advanced Non-Small Cell Lung Cancer (NSCLC) in recent years has been approached based on defining the histologic subtype and identifying actionable genetic alterations in the tumor. Many of the recent developments in the management of advanced NSCLC are applicable only to non-squamous NSCLC patients. Cytotoxic chemotherapy has remained the primary systemic therapy for squamous cell lung cancer patients. Despite a decline in the incidence in some parts of the world, squamous cell lung cancer as a single entity remains one of the major causes of cancer related mortality worldwide. Therefore there is a need to advance therapy of squamous cell lung cancer patients beyond chemotherapy. Recently several new agents have been studied in squamous cell lung cancer patients and promising results have been observed, with some of the trial results leading to drug approval for NSCLC patients in general and squamous cell lung cancer patients in particular. The recent advances in drug therapy can be categorized according to drug type into cytotoxic chemotherapy agents, immune checkpoint inhibitors and molecularly targeted agents. Nab paclitaxel, an albumin bound formulation of paclitaxel combined with carboplatin was compared with the standard combination of the carboplatin and paclitaxel in advanced NSCLC patients (1). The nab paclitaxel combination showed a significant improvement in response rate in squamous cell patients (41% vs. 24%), p < 0.001). This improvement in response rate was associated with a modest but statistically non-significant improvement in progression free survival (PFS) and overall survival. These results, have led to the approval of this combination for the management of advanced NSCLC patients and this combination is preferentially considered in squamous cell patients. The immune check point inhibitors have generated most excitement in recent years. In a randomized trial, Checkmate 017, the anti-PD-1 drug nivolumab was compared with docetaxel in patients with progressive squamous cell lung cancer and demonstrated both PFS (HR-0.62) and survival (HR-0.59) improvement (2). Toxicities in general were less in patients who received nivolumab and immune related toxicities were not common. In this trial PD-L1 expression did not correlate with benefit from nivolumab. Ipilimumab, an anti-CTLA4 antibody, has also been evaluated in squamous cell lung cancer patients. In a randomized phase II trial phased in ipilimumab with chemotherapy demonstrated superior outcomes compared to advanced NSCLC patients receiving chemotherapy alone (3). Retrospective analysis suggested greater benefit in squamous cell patients. Based on these results, a randomized study evaluating ipilimumab with chemotherapy in advanced squamous cell patients as front line therapy was initiated and has completed accrual (NCT01285609). Drugs targeting EGFR (Epidermal Growth Factor Receptor) have been studied in squamous cell lung cancer patients. Though EGFR-tyrosine kinase mutations are extremely uncommon in squamous cell lung cancer patients EGFR amplification has been observed in 7-10% of the patients and EGFR is expressed in a high proportion of squamous cell lung cancers. Necitumumab, a recombinant human EGFR antibody combined with chemotherapy cisplatin and gemcitabine demonstrated a modest survival advantage (HR- 0.84, p = 0.01) compared to chemotherapy alone (4). Afatinib, an irreversible EGFR tyrosine kinase inhibitor demonstrated superior survival compared to erlotinib in patients with recurrent squamous cell lung cancer following front line therapy (HR-0.81, p = 0.007) (5). The modest benefit observed suggests that EGFR targeting drugs are useful only in a proportion of squamous cell lung cancer patients and a biomarker to identify patients that benefit from these drugs could be valuable in the future use of these drugs. Another drug that showed clinical benefit in squamous cell lung cancer patients, along with other NSCLC patients is ramucirumab, a VEGFR2 receptor directed monoclonal antibody. In the REVEL study NSCLC patients with progressive disease following front therapy were randomized to docetaxel with or without ramucirumab (6). The combination demonstrated a superior survival compared to single agent docetaxel (HR-0.86, p = 0.023). Benefits were seen across all histologies, including squamous cell lung cancer. Several drugs targeting other signaling pathways, specifically PI3K and FGFR, are currently undergoing evaluation. Results to date in patients with tumors that have these specific molecular alterations have shown only modest benefit or no benefit at all. The reasons for these results are unclear. Ongoing clinical trials will determine the potential benefit for targeting these pathways. A major effort in analyzing targeted drugs based on molecular alteration in the patient’s tumor is ongoing with the LUNG MAP study, led by Southwest Oncology Group (SWOG) with participation from all the US Oncology Cooperative Groups. In conclusion, after a period of no advances for the treatment of squamous cell lung cancer patients, several drugs recently have shown clinical benefit and several others are currently being evaluated. It is clear that therapy of advanced squamous cell lung cancer patients has evolved beyond cytotoxic chemotherapy and will provide greater clinical benefit. References 1. Socinski MA, Bondarenko I, Kasareva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first line therapy in patients with advanced non-small cell lung cancer: final results of a phase III trial. J Clin Oncol 2012;30:2055-62. 2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35. 3. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first line treatment in stage IIIB/IV non-small-cell lung cancer: results of a randomized, double-blind, multicenter phase II study. 4. Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015;16:763-74. 5. Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; epub ahead of print. 6. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicenter, double-blind, randomised phase 3 trial. Lancet 2014;384:665-73.

Abstract:
The National Lung Screening Trial results provided convincing evidence to the US Preventive services Task Force (USPSTF) to give a B recommendation (same as mammography) to screening high-risk individuals with low-dose CT (LDCT) in 2013.[1,2] In response in 2015 the Center for Medicare and Medicaid services (CMS) determined payment for screening those age 55 to 77 with the same smoking requirements.[3] So how is the medical community supposed to implement screening? At this point it appears easier to come up with the questions than the answers and it is unclear if there will be additional large randomized studies to guide the process. Programs will have similar elements with yet with features reflective of local needs and resources. In the US much of this process is being dictated by CMS and the American College of Radiology (ACR) which will maintain the registry through which reimbursement by CMS has been approved. As of July, this registry has not been set up and reimbursement by CMS is promised but not being done. As the NLST is the only randomized control trial to show benefit, whether international adoption occurs remains to be seen. Policy statements are available to help identify the key components and implementation strategies for a CT screening program.[4,5] A multidisciplinary committee that meets regularly consisting of pulmonology, radiology, primary care, thoracic surgery, interventional radiology, and medical and radiation oncology is important to facilitate LDCT screening, and evaluation and treatment of screening results. The inclusion of each of these disciplines helps to assure the patient has a complete complement of options regarding diagnosis and treatment and also limits the implementation of screening to systems with the needed expertise available. Having dedicated secretarial and administrative support is as important to a program’s success. Who to screen? The simplest answer is to screen those for whom benefit has been shown, namely those fitting the NLST criteria: age 55-74 with a 30 pk-year history of smoking and either current smokers or those who have quit within 15 years.[1] But it should be more complicated that as there are many patients at equivalent or higher risk who don’t fit the NLST criteria. There are several guidelines published and they all differ. USPSTF recommends ages 55 to 80 (and is so mandated within the Affordable Care Act), CMS is reimbursing for those age 55 to 77 (in medicare or medicaid), the National Comprehensive Care Network (NCCN) additionally recommends screening for those age > 50 with a 20 pack-year history and one additional risk factor such as COPD, family history of lung cancer, occupational exposure to carcinogens, and significant radon exposure.[6] Similarly the American Association of Thoracic Surgery recommends screening for those ages 55-79 within the NSLT smoking criteria as well as those > age 50 with a > 20 pk-year history and a cumulative risk of > 5% over 5 years.[7] At present the American Academy of Family Physicians recommends against LDCT screening.[8] Our program is recommending screening based on risk rather than reimbursement and, as a consequence, in additional to those who meet USPSTF criteria, recommends screening to those who have equivalent or higher risk using the PLCO~2012~ model.[9] Exclusion criteria should be similar between programs and based on the NLST.[1] Shared Decision Making. The USPSTF recommendation includes a shared decision making process (not recommended for breast cancer screening); this is also mandated by CMS as an identifiable visit with specific components: eligibility, absence of signs or symptoms of lung cancer, benefits and harms of screening, follow-up diagnostic testing, over-diagnosis, false positive rate, radiation exposure; importance of adherence to annual screening, impact of comorbidities, willingness to undergo treatment; and the importance cigarette smoking abstinence or cessation.[3] We mandate tobacco cessation counseling for current smokers prior to screening in an attempt to make clear that cessation is more lifesaving than screening. In the NLST there were 16 deaths within 60 days of an invasive procedure and only 10 of those had cancer; patients need to know process of screening can be fatal.[1] Radiology, results and Data collection. The ACR and Society of Thoracic Radiology have identified specifications for a LDCT and the registry requires that those technical parameters be met.[10] A structured reporting system is desired yet unfortunately the ACR registry requires that LungRADS be used which is not consistent with evidence based guidelines, is ambiguous, and is not aimed at patient communication. Nodule Evaluation. An optimal nodule evaluation algorhythm is yet to be determined, and since patient preference is to be weighed, no one fit will size all. Doing the CT scan is the easy part; follow-up is imperative - a dedicated registry is mandatory in this regard. Many raise concerns about the false positives of CT screening; within the NLST (positive defined as > 4mm) false positives were 96%. The 4 mm nodule has a likelihood of lung cancer of less than 1%. Should we call it a positive with that probability? The reality is that the vast majority of nodules found by CT screening need no additional evaluation other than CT follow-up – most with the next annual scan. We are recommending PET or biopsy (depending on the circumstances) only for nodules 1cm or greater and that eliminates immediate evaluation for 95% of the participants. But we don’t call a 6 mm nodule negative; it exists and needs follow-up – a key is to provide accurate information to the patient and their provider as to the likelihood of malignancy. Our program is responsible for the evaluation and followup of findings in a desire to favorably the tip the balance of benefit versus harms. People don’t die from false positives, but they can die from their evaluation. Nodule evaluation should be done by those who do it every day; we don’t feel this is appropriate for the primary provider and perhaps why the AAFP rejects LDCT screening. A multidisciplinary tumor/nodule board can help share the decision making, cross fertilize, and facilitate care for those who need treatment. 1. Aberle DR, Adams AM, Berg CD, et al. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365: 395–409. 2. Moyer VA. Screening for lung cancer: U.S. Preventive services task force recommendation statement. Ann Intern Med 2014;160:330-338. 3. Centers for Medicare & Medicaid Services. Decision memo for screening for lung cancer with low dose computed tomography (ldct) (cag-00439n) 2015. Available from: http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=274&NcaName=Screening+for+Lung+Cancer+with+Low+Dose+Computed+Tomography+(LDCT)&MEDCACId=68&IsPopup=y&bc=AAAAAAAAAgAAAA%3d%3d&. 4. Mazzone P, Powell CA, Arenberg D et al. Components necessary for high-quality lung cancer screening: American College of Chest Physicians and American Thoracic Society Policy Statement. Chest. 2015;147:295-303. 5. Wiener RS, Gould MK, Arenberg D, et al. Official American Thoracic Society / American College of Chest Physicians Policy Statement: Implementation of Lung Cancer Screening Programs with Low-Dose Computed Tomography in Clinical Practice. Am J Respir Crit Care Med. 2015; in press. 6. National Comprehensive Cancer Network. Nccn clinical practice guidelines in oncology (nccn guidelines) - lung cancer screening, version 1.2015. 2014. Available from: http://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf. 7. Jaklitsch MT, Jacobson FL, Austin JH, et al. The american association for thoracic surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. J Thorac Cardiovasc Surg 2012;144:33-38. 8. American Academy of Family Physicians Policy Statement available from: http://www.aafp.org/patient-care/clinical-recommendations/all/lung-cancer.html 9. Kazerooni EA, Austin JH, Black WC, et al. Acr-str practice parameter for the performance and reporting of lung cancer screening thoracic computed tomography (CT): 2014 (resolution 4). J Thorac Imaging 2014;29:310-316. 10. Tammemagi MC, Katki HA, Hocking WG, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013;368:728-736.

Abstract:
Thoracic radiation therapy (RT) has been historically the first definitive therapy for Stage III non-small cell lung cancer (NSCLC), achieving median survival time (MST) of 10 months (mo). Adding chemotherapy extended MST to 13.8 mo (induction chemotherapy) or 17-20 mo. (concurrent chemotherapy) in randomized trials which used two-dimensional (2D) RT. Most recently, large randomized clinical trials for PET-staged patients treated with modern thoracic RT reported MST of 28.7 mo. (1). The reasons for such impressive survival improvement over last two decades are not fully understood and are likely multifactorial, including universal FDG-PET staging on presentation (therefore removing unsuspected Stage IV patients); progress in thoracic RT (precise target definition with CT simulation; widespread 3D RT or Intensity Modulated RT[IMRT], allowing volumetric rather than point radiation dose prescribing; heterogeneity correction accounting for different density of air vs. soft tissue; increased understanding of normal tissue tolerance, such as spinal cord, allowing relative sparing of lung parenchyma; image-guided RT minimizing normal tissue margins and “missed targets” etc.); widespread use of low-dose well-tolerated outpatient chemotherapy regimens; improved supportive care; effectiveness of second- and third-line systemic therapy etc. In a population study of >5,000 SEER-Medicare patients with NSCLC, wider adoption of CT simulation for thoracic RT planning was associated with improved overall survival (2). Local control rate was 70% at 2 years in the large cooperative group Phase III randomized trial (RTOG 0617) in the 60 Gy standard arms, defined as lack of tumor progression within the irradiated field. Most patients succumb to distant metastases which continue to be the leading cause of death of patients with lung cancer. Since death from distant metastases and local failure constitute competing risks, the likely incidence of local failure may be higher if longer overall survivals are achieved. The optimal RT dose allowing improved local control has not been fully established and the current recommendation is to use 60 Gy in daily 2 Gy fractions, with concurrent chemotherapy in fit patients. RT dose escalation to 74 Gy was associated with worse MST when compared to 60 Gy in a randomized trial (20.3 vs. 28.7 mo., respectively) (RTOG 0617). While the reasons for such worse survival are not clear, the possibilities include higher RT heart doses in the 74 Gy arm, greater number of deaths in the high-dose group, extended duration of radiation therapy to 7.5 weeks, and uncertainty about true causes of death (1). Nevertheless, efforts toward RT dose intensification continue, with particular attention given to the shortening of the overall treatment time through hypofractionation (for example, in the RTOG 1106 a mid-treatment PET-adapted hypofractionated RT boost is applied to the residual tumor volumes during a total duration of 30 RT fractions )(NCT01507428). While the proportion of patients with Stage III NSCLC receiving IMRT has been increasing as compared to 3D RT (3% in 2002 vs. 26.8% in 2009)(3), the superiority of IMRT has not been convincingly demonstrated. Among patients receiving potentially curative treatment, there was no difference in overall survival (propensity adjusted HR .99, p = 0.83) or number of hospital days in the 90 days following radiation start, as demonstrated by the SEER-Medicare analysis of over 7,000 patients. The technology currently being investigated involves proton therapy, which has been shown in treatment-planning comparisons to deliver high-dose, highly conformal radiation to targets while minimizing damage to surrounding normal tissues. In particular, the subclinical cardiovascular toxicity suspected to be detrimental in the RTOG 0617 trial, which might have accounted for worse survival in the high-dose arms, may be mitigated with protons due to their physical property of a sharp distal dose edge. Long term results from a prospective single institution study of 134 patients receiving concurrent proton thoracic RT (median dose: 74 Gy) and chemotherapy (4) demonstrated the MST of 40 mo. for Stage II NSCLC patients and 30 mo. for Stage III patients, and a local + marginal failure-free rate of approximately 50% at 5 years. Grade 2 radiation pneumonitis was reported in 29 (22%) patients and Grade 3, in 2(1.5%). An ongoing study, the NRG Oncology/RTOG 1308, is a phase III trial exploiting the potential of protons compared with photons to escalate radiation dose to 70 Gy while applying strict dose volume constraints to adjacent normal tissues (NCT01993810). In summary, while numerous advances in thoracic RT for Stage III NSCLC were introduced over the last 20 years, local tumor control and overall survival need refinement and no single RT technology/RT dose and fractionation have been identified as the most optimal approach. (1) Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. LancetOncol. 2015 Feb;16(2):187-99. PMID: 25601342 (2) Chen AB, Neville BA, Sher DJ, Chen K, Schrag D. Survival outcomes after radiation therapy for stage III non-small-cell lung cancer after adoption of computed tomography-based simulation. J Clin Oncol. 2011 Jun 10;29(17):2305-11. PMID: 21537034 (3) Chen AB, MD, Ling L, Cronin A, Schrag D. Comparative Effectiveness of Intensity-Modulated Versus 3D Conformal Radiation Therapy Among Medicare Patients with Stage III Lung Cancer. J Thorac Oncol. 2014;9:1788–1795 (4) Nguyen QN, Ly NB, Komaki R, Levy LB, Gomez DR, Chang JY, Allen PK, Mehran RJ, Lu C, Gillin M, Liao Z, Cox JD. Long-term outcomes after proton therapy, with concurrent chemotherapy, for stage II–III inoperable non-small cell lung cancer. Radiother and Oncology, e-published May 2015

Abstract not provided

Abstract not provided

Abstract:
It has been 10 years since we first understood about the importance of targeted therapies in lung cancer. This group of medications are now part of our everyday clinical care for patients with lung cancer who harbour an EGFR or ALK mutation. Mechanisms of action and the associated toxicities of targeted therapies, such as tyrosine kinase inhibitors (TKI), differ from chemotherapy. Whilst these medications tend to be better tolerated in patients, they still carry a number of associated side effects which require intervention and management. Amongst these are acneform rash, paronychia, diarrhoea, nausea, raised liver functions, interstitial lung disease, loss of appetite, neuropathy,vision problems,and fatigue. With many lung patients on multiple medications due to comorbidities at presentation there should also be consideration of drug interactions with the CYP450 pathway utilised to metabolise many medications. This session will explore traditional and more novel approaches to supporting patients on TKI medications, patient resources, and the role nurses play in ensuring compliance and improved outcomes for lung cancer patients.