Virtual Library

Background:
The prevailing patient care model for lung cancer involves serial referrals among multiple clinical specialists. This practice may cause delays in diagnosis and treatment, patient/caregiver confusion and anxiety, poor communication among physicians, and diminished opportunities for patients to receive evidence-based care. The multidisciplinary care model may rectify these problems with the serial model, and thereby improve the quality and outcomes of care. However, the value of the multidisciplinary care model has not been objectively established. We collected the perspectives of key stakeholders on the 2 models of care. We sought to: examine the perceived strengths and weaknesses of each model; uncover potential barriers to establishing an effective multidisciplinary care program; and establish meaningful benchmarks with which to measure care delivery in both models. This work preceded a prospective comparative effectiveness study of the 2 models of care.

Methods:
We conducted 21 focus groups, involving 106 subjects (22 patients, 24 caregivers, 9 nurses, 8 hospital administrators, 4 executives of health insurance companies, and 39 physicians). The physicians included groups of medical and radiation oncologists, hospitalists, pulmonologists, thoracic surgeons, and primary care physicians. Patients had received care for a confirmed or suspected lung cancer in the Baptist Memorial Health Care System within the preceding 6 months. Disease stage ranged from early, with curative-intent treatment, to advanced-stage with palliative-intent care. Providers may or may not have had personal experience of the multidisciplinary model. We used verbatim transcripts of the audio recordings and field notes to analyze the content of each focus group session using Dedoose Software. We identified recurring themes and variants within and across the various stakeholder groups.

Results:
Several overlapping themes emerged. There was a perception that the multidisciplinary care improved physician collaboration, care coordination, accuracy of diagnosis, concordance with treatment recommendations, timeliness of care, efficiency of care-delivery, and patient satisfaction. Potential obstacles to successful implementation of the multidisciplinary care model included problems with physician reimbursement, the duration of the patient-physician interaction, and acceptability/integration of the model within the current health care infrastructure. These concerns were especially prevalent among physicians. Overcoming these barriers would require physician and patient education, efficient use of electronic medical records, and improving general awareness about the multidisciplinary care model. Identified evaluative benchmarks included measures of patient/caregiver experience and satisfaction, survival rates, timeliness of care, the quality of patient-physician communication, consistency of recommendations among physicians, and the adequacy of consultation times.

Conclusion:
The stakeholders in lung cancer care had broadly overlapping beliefs about optimal care delivery for lung cancer. However, they also had different expectations, and motivations. These competing factors have the potential to influence perceptions about the quality, efficiency, and effectiveness of lung cancer care delivery. Patients, caregivers, clinicians, administrators, and third-party payers were in favor of the multidisciplinary model for lung cancer care. However, key barriers must be addressed for optimal implementation. Meaningful stakeholder input is essential to improving the quality of lung cancer care.

Background:
Pemetrexed maintenance therapy (MT) after induction with platinum-based chemotherapy plus pemetrexed has recently become a concrete strategy of treatment for advanced non-squamous NSCLC patients, by extending survival, delaying disease progression, and maintaining quality of life. However, the benefit of the MT has to be weighed against the potential burden of a long-term treatment, and thus patients’ perception and preferences should be taken into account in the definition of the strategy of treatment.

Methods:
After conducting a focus group with 8 physicians dealing with NSCLC and concerning their opinions about the MT from a clinical and emotional point of view, a 12 questions-anonymous survey has been carried out in 13 Italian Oncologic Institutions and supported by WALCE (Women Against Lung Cancer in Europe), with the aim to evaluate patients' attitude toward the MT, the benefit they expected and to provide data about physicians awareness about patients’ inclinations. The Distress Thermometer Questionnaire has also been employed to perform a bio-psycho-social-spiritual assessment of the evaluated patients. Patients' evaluations have been performed at the beginning of chemotherapy (T0) and at the beginning of MT (T1), while physicians fill the survey only once during the study.

Results:
The survey has been prospectively (1st of December 2014-28th of February-2015) administered to 92 newly diagnosed advanced non-squamous NSCLC patients (58,7% male, median age 63,9 years), EGFR wilde-type, consecutively enrolled and suitable for first-line platinum/pemetrexed-based chemotherapy, and to 37 referring physicians (equally distributed per gender, with median age 41 years). To date, after platinum-based induction chemotherapy (median number of cycles 3,3, equally distributed between cisplatin and carboplatin), 24 of 92 patients enrolled (26,1%) have already started the pemetrexed MT. Main results are shown in Table 1. Most of the patients (73,9%) are in favor of MT. Until life expectation is over 3 months, data show agreement between patients' and physicians' perceptions of patients. When OS benefit drops at 1 month the two perceptions split: a lower percentage of patients (44,5%) would perform MT. By contrast, even without OS benefit, 71,3% of patients accept MT if it can increase symptom control. Figure 1



Conclusion:
Study is ongoing and data about T1 evaluations are still immature. Our preliminary data suggest the importance, when MT communication is done by the referral physician, to stress more symptoms control rather than survival rates.

Background:
Despite lung cancer being the leading cause of cancer death in developed countries, there is surprisingly little qualitative research that documents lung cancer patients’ diagnostic pathway and beyond. Recent evidence from the UK highlighted that people diagnosed with the disease will have had three or more consultations with their family physician (general practitioner, GP) before referral to a lung cancer specialist. This study aimed to document the diagnostic pathway from the patient perspective through qualitative interviews and process mapping. The study is one component of a lung cancer implementation research program in the Australian setting.

Methods:
We developed a qualitative interview schedule to conduct with patients and their caregivers. We recruited participants via treating clinician (respiratory physician/pulmonologist or medical oncologist) by sending a personal invitation letter. All patients were at least six months post-diagnosis at the time of first invitation and we obtained human ethics committee approvals. Interviews were conducted by telephone or face-to-face, according to the participant’s preference. All interviews were recorded, transcribed and coded using a coding framework developed by four members of the investigator team (SY, NR, ML, PB). The transcripts were coded in NVIVO 10 software. We interpreted the transcripts with two specific purposes in mind: first, to draw detailed maps of their journey, documenting the key points about which participants spoke about. Secondly, we conducted a content analysis and developed qualitative themes to understand and interpret patient journeys.

Results:
Twenty lung cancer patients participated in the qualitative interviews. Interviews took about one hour to complete. The patient journey maps provided rich data to understand the complexity of pathways that patients experience in the lead up to their lung cancer diagnosis, their subsequent treatment through to survivorship or palliation phase. A number of patients recalled very precise information about their journey and had recorded diary entries of key dates or times in their diagnostic pathway. We examined all the maps to identify common elements in the pathways. We used the qualitative material to understand how patient care was coordinated across the journey and will report on specific themes. In particular, we will highlight the theme of advocacy. It was evident that hospital-based clinicians were frequently perceived as the coordinator of their patient’s care. We will discuss their role in advocating for urgent patient diagnostic investigations when these were necessary. These clinicians were frequently perceived by patients as their advocates beyond diagnosis, as were GPs where the patient had an established relationship with this physician. We will also address the themes of patient anxiety and self-advocacy, and provide specific examples of how patients self-managed their care.

Conclusion:
The patient journey through lung cancer diagnosis is complex and qualitative interviews provide a rich source of information to better understand how clinicians and family physicians advocate for patients, and how some patients self-advocate in their care. The resulting patient maps and qualitative material will inform lung cancer implementation research projects to address the diagnostic pathway and improving patient care.

Abstract not provided

Background:
In health care several indicators are developed for measuring the quality of care. Many of these indicators address the process and structure of health care, rather than the outcome of treatment and aspects which are valuable for patients. Porter (N Engl J Med 2010 363;26) described a method concentrating on achieving high value for patients by identifying and prioritizing outcome measurements. In the project “Care for Outcome” of Santeon (a cooperation of six leading, top clinical hospitals in the Netherlands) we identified outcome indicators in lung cancer which are relevant for the patient and focus on treatment outcome, like survival and quality of life.

Methods:
The project was performed in two large, non-university teaching hospitals in the Netherlands. Our objective was to develop outcome indicators which are relevant for both patients and physicians. We evaluated patients with all stages and types of lung cancer. Using a “Care delivery value chain” (CDVC) scheme as developed by Porter, we identified determinants which are important for patients. Quality of life was evaluated by Patient Reported Outcome Measures (PROMs) at different times. Around 80 outcome indicators were found by literature research. These were classified by using the Outcome Measure Hierarchy and prioritized based on: impact on patient, influence of CDVC and statistical power. A first selection of 25 outcome indicators were then evaluated by an International Academic Council on lung cancer, a Methodological Advisory Council and representatives of the government, health insurance companies and patient federations. A final set of six indicators was selected based on quality of definition and feasibility of collection. A set of appropriate patient initial conditions was identified to be used for casemix correction.

Results:
The indicators which were formed in the “Care for Outcome” project were divided in three categories. The first category was survival: 1 and 2 year mortality after diagnosis, mortality 90 days after resection and 5-year survival using Kaplan-Meier curves and Cox-survival curves. The second category was recovery: the percentage of patients with positive resection margins and quality of life after 0, 3, 6, 12 months were evaluated. The third category concerned complications and adverse events: the percentage of patients with rethoracotomy, complications after resection and toxicity after (chemo)radiation were retrospectively measured over the years 2008-2011. Multivariate regression analysis showed that, in order of impact, tumor stage, performance status and age were the strongest predictors of outcome. Next to those, comorbidity (Charlson score) and pulmonary functioning (%FEV1 and %DLCO as a proxy of smoking history) were also relevant.

Conclusion:
In the “Care for Outcome” project we systematically developed a compact set of outcome indicators for patients with lung cancer focusing on the value of treatment for these patients. We started a retrospective data analysis, looking back four years, using these outcome indicators. These reports help us to better understand our quality of care and to improve our processes. In the near future these indicators will be collected prospectively and are feasible to be used to compare different treatment modalities and hospitals across the country.

Background:
Reducing health inequalities in oncology is a major public health priority in France, particularly in terms of social and geographic exclusion and equity of access to health care services. However, no specific registry currently exists for patients with lung cancer allowing description and comparison of local situations. Our aim was to use available National medico-administrative databases to constitute a nationwide population-based cohort study to analyze disparities among French areas (the TERRITOIRE study).

Methods:
We included all patients who had a first diagnosis of lung cancer between January 1rst and December 31th 2011 in the National hospitals databases (PMSI, Programme de Médicalisation des Systèmes d'Information). Patients’ data were linked to create a retrospective cohort study with a two-year follow-up period. The 22 administrative regions were considered in this analysis. In addition of demographic characteristics, metastatic status, comorbidities and treatment procedures, we assigned each patient to socioeconomic deprivation and urbanization scores based on their postcode of residence.

Results:
We identified 41,715 patients newly diagnosed for lung cancer. Mean age at diagnosis was 66.4(±11.9) years and most of patients were men (71.8%). Patients from socioeconomic deprived areas represented 27.5% of the whole lung cancer population, ranging from 9.6% to 55.2% according to the region. Incidences of lung cancer were 35.1 per 100,000 in women and 95.3 per 100,000 in men. Age-standardized incidences showed important disparities between French regions ranging from 27.5 to 55.0 and from 82.4 to 118.2 per 100,000 in women and men, respectively. Higher incidences were found in the northern and eastern regions for men and in the southern and eastern regions for women. Although patients living in rural areas were the larger group (34.5%), Age-standardized incidence significantly increased with urbanization: from 61.8 per 100.000 in rural areas to 73.9 per 100.000 in urban areas. A majority of patients was diagnosed at a metastatic stage (52.7%) and regional disparities were important ranging from 45.0% to 58.1%. This rate also appeared higher in patients diagnosed in public hospitals compared to private ones (56.1% vs 42.9%, p<0.0001) and in local hospitals compared to university ones (60.2% vs 49.6%, p<0.0001). Adjusted comparisons showed significantly higher incidences of stage IV patients at the time of diagnosis in five regions for men and two regions for women. A majority of patients (N=23,842; 57.2%) died in the hospital during the 2-year follow-up, including 15,642 patients (71.2%) having metastasis at the time diagnosis.

Conclusion:
We have demonstrated that a comprehensive population-based cohort using medico-administrative data is a suitable approach to illustrate disparities in lung cancer incidence, management care and outcomes in France. Data from this study should help local clinical teams and health stakeholders to better understand inequality issues in their areas.

Background:
Strict legislation and regulatory standards for the approval of drugs represent a safety guarantee for the population of any country. However, inappropriate delays in the process of evaluation of new medications have potentially serious consequences that can be measured. The objective of this analysis is to estimate the impact of the delay in the registration of medicines by the Brazilian regulatory agency, ANVISA, on the life span and life with symptoms related to the disease of patients who might potentially benefit from treatment. We use the example of crizotinib (Xalcori® Pfizer, NY, USA), which had its registration refused by the agency in 2014.

Methods:
We arbitrarily selected the 3-year period from August 2011 (FDA approval) to June 2014 (refusal by ANVISA) for this analysis. The number and prevalence of NSCLC cases eligible for treatment were estimated according to data from the Brazilian National Cancer Institue (INCA). The percentage of patients with ALK-positive tumors was inferred from the literature. We assumed that every ALK-positive NSCLC patient in Brazil would have access to the drug regardless if seeking treatment through the private or public health systems. The benefits from treatment with crizotinib were considered according to the published literature available at the time of regulatory assessment.

Results:
We estimated 24.460 new cases of NSCLC/year in Brazil (INCA), 70,6% (17.269) of which are diagnosed as advanced disease. Approximately 4,3% (743) would qualify as ALK positive. In a phase III crossover trial, crizotinib treatment ensued an improved PFS (3.0 vs. 7.7 mo; HR 0.49, p<0.001) and a significant extension in the median time to deterioration of symptoms (1.4 vs. 5.6 mo; p<0.001) when compared to standard second line chemotherapy. Survival estimates were obtained from a retrospective analysis (Shaw et al. Lancet 2011) as follows: chemotherapy 6.0 vs. crizotinib 20.3 months. We estimated 707 prevalent cases of ALK+ NSCLC in Brazil at the start of our analysis and 62 new cases per month during the 3-year analysis period were projected. Applying the premises above we calculated 1.367 years of life lost, and 772 additional patients who would remain alive after the selected period between August 2011 and July 2014. Furthermore, a total of 846 years of life free of symptoms’ deterioration are lost with the associated human suffering during the same period of time.

Conclusion:
The delay in the analysis, approval and registration process of new medications in Brazil and other developing or developed countries has an important impact in terms of human lives that can be potentially measured or estimated. While this kind of scrutiny has clear methodological limitations to consider, our main objective in this analysis is to raise the issue of the urgent need for a detailed and transparent evaluation of all the steps involved in the evaluation and registration process to stall this unnecessary suffering and loss of human life.

Abstract not provided

Abstract:
In the United States, almost 50% of lung cancer patients are 70 years of age or older. Moreover, shifting demographics in the United States -- indeed, across the world -- suggest that oncologists will be seeing many more older patients with lung cancer in years to come. With cancer therapy, older patients often suffer higher and more severe rates of adverse events than their younger counterparts, yet many derive benefit from therapy. The challenges of treating older patients remain notable largely because enrollment in cancer clinical trials tends to show an underrepresentation of older patients. In this context, this talk with discuss 1) the ongoing challenges faced in treating older patients with lung cancer; 2) the relevant and instructive data derived to date from clinical trials; 3) the role of the comprehensive geriatric assessment; and 4) general recommendations on approaches to treating elderly lung cancer patients.

Abstract:
Non-small cell lung cancer is a disease of the elderly. In Australia in 2010, 84% of new lung cancers in men and 81% in women were diagnosed in people aged 60 years and older. The definition of “elderly” in the lung cancer radiotherapy literature varies with the lower limit ranging from 65 years (1) up to 85 (2). Older patients are not only more likely to develop toxicities of intensive treatment, but also to have less physiologic reserve to tolerate these toxicities. They include fatigue, pneumonitis, esophagitis and myelosuppression. Although older patients may have good performance status (ECOG 0-1), and be judged suitable for radical treatment, they may become deconditioned and harmed by treatment. Identification of these patients pre-treatment is challenging. An instrument to measure “frailty”, such as that devised by Fried et al (3) to predict post surgery complications would be useful in the radiotherapy setting. Frailty should be distinguished from performance status, which is only one measure of physiologic reserve; Fried’s frailty score includes measures of weight loss, grip strength and walking speed as well. Given the above, it is not surprising that older patients have worse survival than younger patients (4). Partly this may be due to a higher likelihood of suboptimal treatment (radiotherapy alone rather than concomitant chemoradiotherapy), and partly to the competing risks of non-neoplastic comorbidities. Once survival is adjusted for these effects, age is no longer associated with increased risk of death (4). It is generally agreed that functional rather than chronological age is a more important consideration in patient selection for radical treatment (2, 5). Age is certainly not a contraindication to treatment with SABR for stage I disease (6). The choice of chemotherapy to accompany radiotherapy in pateints with locally advanced disease is unclear because of a lack of trials performed specifically in a geriatric population. Carboplatin is usually preferred to cisplatin in patients over 70 because of its more favorable toxicity profile. The evidence for two drugs rather than one is limited. In a study of the Japan Clinical Oncology Group limited to patients 70 years and older, daily carboplatin added to 60 Gy of radiotherapy improved median survival from 16.9 to 22.4 months (p=0.02) compared with radiotherapy alone (7). Performance status, in the absence of a validated frailty score, remains a critical determinant of suitability for (chemo)radiotherapy. Patients with performance status ECOG 2 or worse seem not to benefit from treatment intensification, including when the intent of treatment is palliation (8). Comorbidity scores (Charlson, Colinet) appear to be closely linked to performance status, but there is insufficient evidence to support their use in clinical decision making. Diminished pulmonary function is sometimes thought to be a contraindication to radical radiotherapy - yet patients who are unfit for surgery, usually because of diminished cardiopulmonary reserve, are the very patients most likely to be referred for stereotactic ablative body radiotherapy (SABR). In fact, some studies suggest that patients developing symptomatic radiation induced lung injury were more likely to have a higher FEV1(9). However caution should be exercised in treating patients with pre-existing interstitial lung disease, including with SABR (10). Our approach is to judge a patient’s suitability for treatment based on their biological age. In older patients with locoregional disease and performance status ECOG 0-1 who are suitable for radical treatment, we would recommend full dose SABR for patients with peripheral stage I disease, and chemoradiation for locally advanced disease, 60 Gy with concomitant carboplatin and paclitaxel. Patients who are not fit for chemotherapy are treated with radiotherapy alone. If there is concern regarding the patient’s capacity to undergo a six week course, we either review the patient at 40 Gy , and if there is evidence of diminished tolerance, cease at that point. If there is concern that a patient will not tolerate a risk of grade 3 esophagitis, but the aim is improved local control rather than paliiation, we would offer a split course to allow for mucosal recovery (20 Gy in 5 fractions, followed by a 4 week break, then another 20 Gy). Although thought to be suboptimal because of the risk of repopulation, a split course schedule is less likely to produce high grade esophagitis than 36 Gy in 12 continuous fractions. For older patients with diminished performance status (ECOG 2 or greater) and for whom palliation is the objective, 20 Gy in five fractions is a reasonable option, and little more demanding on resources and patient inconvenience than a large single dose. References 1. Sigel K, Lurslurchachai L, Bonomi M, Mhango G, Bergamo C, Kale M, et al. Effectiveness of radiation therapy alone for elderly patients with unresected stage III non-small cell lung cancer. Lung Cancer. 2013;82(2):266-70. 2. Khor RC, Bressel M, Tedesco J, Tai KH, Ball DL, Duchesne GM, et al. Tolerability and outcomes of curative radiotherapy in patients aged 85 or more years. Med J Aust. 2015;202(3):153-5. 3. Makary MA, Segev DL, Pronovost PJ, Syin D, Bandeen-Roche K, Patel P, et al. Frailty as a predictor of surgical outcomes in older patients. J Am Coll Surg. 2010;210(6):901-8. 4. Aridgides PD, Janik A, Bogart JA, Duffy S, Rosenbaum P, Gajra A. Radiotherapy for stage III non-small-cell lung carcinoma in the elderly (age >/= 70 years). Clin Lung Cancer. 2013;14(6):674-9. 5. Wanders R, Steevens J, Botterweck A, Dingemans A-MC, Reymen B, Baardwijk Av, et al. Treatment with curative intent of stage III non-small cell lung cancer patients of 75 years: A prospective population-based study. European Journal of Cancer. 2011;47(18):2691-7. 6. Palma D, Visser O, Lagerwaard FJ, Belderbos J, Slotman B, Senan S. Treatment of stage I NSCLC in elderly patients: a population-based matched-pair comparison of stereotactic radiotherapy versus surgery. Radiother Oncol. 2011;101(2):240-4. 7. Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, et al. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol. 2012;13(7):671-8. 8. Strom HH, Bremnes RM, Sundstrom SH, Helbekkmo N, Aasebo U. How Do Elderly Poor Prognosis Patients Tolerate Palliative Concurrent Chemoradiotherapy for Locally Advanced Non-Small-Cell Lung Cancer Stage III? A Subset Analysis From a Clinical Phase III Trial. Clin Lung Cancer. 2015;16(3):183-92. 9. Kong FM, Wang S. Nondosimetric risk factors for radiation-induced lung toxicity. Semin Radiat Oncol. 2015;25(2):100-9. 10. Ueki N, Matsuo Y, Togashi Y, Kubo T, Shibuya K, Iizuka Y, et al. Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer. J Thorac Oncol. 2015;10(1):116-25.

Abstract:
It is difficult to define what an elderly or truly “high risk” patient is in regards to offering surgical treatment of lung cancer. The World Health organization defines an elderly patient as being over age 65 although most practitioners of thoracic surgery would likely define an elderly patient as someone over age 70 (1) . Likewise the definition of a truly high-risk patient is difficult to determine. These patients are often described as having significant cardiopulmonary or other organ dysfunction that could be potentially worsened by the surgical event. In developed countries the average population age is increasing and the incidence of lung cancer is also increasing in elderly patients. Combined with the natural decline in lung and cardiac function these data suggests that there will likely be a steady and significant increase in elderly and high-risk patients who present for consideration of resection for localized lung cancer. Clinical data in the elderly and high-risk patients is hard to come by, as many of these patients are not represented in clinical trials despite the high proportion of these patients in the lung cancer population. The data that is available is often retrospective in nature but it suggests that treatment decisions in these patient groups should not solely be based on chronological age but should take into account the patient’s life expectancy, quality of life desires, presence of comorbidities, and estimated risks and benefits of the procedure (2). Several studies have demonstrated the feasibility of surgically treating lung cancer in elderly patients including octogenarians. Likewise several studies evaluating patients with compromised lung function and other comorbidities have suggested that surgery is feasible in these patients (3,4). What is not clear is what the true limits of age and underlying organ dysfunction is that represent absolute contraindications to surgery. It is likely that improvements in anesthesia and surgical care have allowed older and more high-risk patients to be operated on safely. The use of video assisted thoracoscopy has greatly enhanced our ability to perform surgical resections on these elderly and high-risk patients. The gold standard operation of lobectomy for these patients can potentially be modified in high risk and elderly patients. Several retrospective studies suggest that in the elderly a lesser resection can be equivalent or superior to lobectomy in survival and perioperative morbidity (5). In addition the use of pneumonectomy in these patients should be avoided as the morbidity and mortality is increased significantly (6). It is clear that treatment with stereotactic radiotherapy will play an emerging role in the therapy if these patients. Long-term follow up is needed to truly understand the utility of radiotherapy in high risk and elderly patients. References 1) World Health Organization. Health statistics and health information systems. Available from URL http://www.who.int/healthinfo/survey/ageingdefnolder/en/index.html. 2) Pallis AG, Gridelli C, Wedding U, Faivre-Finn C, Veronesi G, Jaklitsch M, Luciani A, O'Brien M. Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology. Ann Oncol. 2014 Jul;25(7):1270-83. 3) Rivera C, Dahan M, Bernard A et al. Surgical treatment of lung cancer in the octogenarians: results of a nationwide audit. Eur J Cardiothorac Surg 2011; 39: 981–986. 4) Zhang R, Ferguson MK. Video-Assisted versus Open Lobectomy in Patients with Compromised Lung Function: A Literature Review and Meta-Analysis. PLoS One. 2015 Jul 6;10(7) 5) Cheng YD, Duan CJ, Dong S et al. Clinical controlled comparison between lobectomy and segmental resection for patients over 70 years of age with clinical stage I non-small cell lung cancer. Eur J Surg Oncol 2012; 38: 1149–1155. 6) Zuin A, Marulli G, Breda C et al. Pneumonectomy for lung cancer over the age of 75 years: is it worthwhile? Interact Cardiovasc Thorac Surg 2010; 10: 931–935.

Abstract not provided

Abstract:
While genomic studies of lung adenocarcinomas over the past decade have enabled substantial improvements in treatment and patient outcomes, advances in squamous cell carcinomas of the lung have been far more modest. At present there are no targeted agents approved for the treatment of squamous cell lung cancers and there has been limited success in the use of targeted kinase inhibition in this disease. Here, I will review the results of genomic studies of squamous cell carcinomas and highlight the molecular features which drive these cancers and make them distinct from lung adenocarcinomas. I will discuss specific subtypes of squamous cancers, animal models of the disease and associations among genomic features and patient outcomes. I will discuss therapeutically relevant genetic alterations and efforts aimed at exploring these targets both pre-clinically and clinically with an emphasis on FGFR pathway genes. I will discuss heterogeneity and adaptive responses to therapy in squamous cell carcinomas as potential challenges to the treatment paradigms which have been successful in adenocarcinomas and these concepts in the context of the recent introduction of immunotherapeutic approaches.

Abstract:
Squamous cell carcinoma of the lung accounts for 20-30% of all non-small cell lung cancer (NSCLC). Until recently, treatment options for advanced squamous NSCLC (sqNSCLC) were limited. Compared to non-squamous NSCLC, standard care of sqNSCLC was restricted to first-line platinum-based doublet chemotherapy and second-line docetaxel or the epidermal-growth factor receptor (EGFR) inhibitor, erlotinib, and did not include pemetrexed because of inferior efficacy[1], bevacizumab because of increased risk of pulmonary hemorrhage[2] or agents active against known oncogenic driver mutations. Prompted by the high levels of EGFR overexpression in sqNSCLC and encouraging activity of EGFR-targeted therapies in patients with squamous histology [3,4] EGFR-inhibition trials limited to patients with sqNSCLC were initiated, the results of which are redefining the treatment of sqNSCLC. In the first-line setting, the addition of the second-generation recombinant human IgG1 EGFR monoclonal antibody (Mab), necitumumab, to gemcitabine and cisplatin has been shown to improve overall survival (OS) 11.5m vs 9.9 m (HR: 0.84, 95%CI: 0.74-0.96) in the phase III open-label SQUIRE trial, with comparable adverse events (AE) leading to treatment discontinuation in both treatment arms.[5] The better tolerability of necitumumab over the first-generation chimeric EGFR Mab, cetuximab, is supported by the similar OS efficacy in patients with good (PS: 0-1) (HR: 0.85, 95%CI: 0.74-0.98) and poor performance status (PS=2) (HR: 0.78, 95%CI: 0.51-1.21), in the absence of additional safety risk.[6] In fact, in SQUIRE, necitumumab was notably more effective at higher levels of baseline symptom severity[7] , which is contrary to the belief that patients with sqNSCLC deteriorate too quickly to benefit from combination approaches. In the second-line setting, the newer second-generation EGFR small molecule inhibitor, afatinib, has also been shown to improve OS. Most recently, the results of the phase III LUX-Lung 8 trial of afatinib vs erlotinib in patients with sqNSCLC progressing after four cycles of platinum-based chemotherapy have been published, demonstrating improved OS with afatinib 7.9m vs 6.8m (HR: 0.81, 95%CI: 0.69-0.95), with similar adverse events profiles noted between groups.[8 ]Based on these results, afatinib is clearly a treatment option for patients in the second-line management of sqNSCLC. Together, the recent results of these small molecule and MAb anti-EGFR studies support the continued relevance of EGFR as a target in the treatment of sqNSCLC and are shaping management strategies. Despite being a hallmark of cancer, the inhibition of angiogenesis has historically proven challenging in the treatment of patients with sqNSCLC due to the central location of these tumors and their close proximity to large blood vessels in the chest wall, and has been associated with an increased risk of bleeding. Findings from newer second-generation angiogenesis inhibitors, however, show comparable levels of gastrointestinal and respiratory tract bleeding events across all NSCLC histologies. [9 ] Compared to placebo, the anti-VEGFR-2 IgG MAb, ramucirumab, has recently been shown to improve progression-free survival (PFS) 4.5m vs 3.0 m (HR: 0.76, 95%CI: 0.68-0.86) and OS 10.5m vs 9.1m (HR: 0.86, 95%CI:0.75-0.98) in patients with advanced NSCLC progressing after first-line platinum-based chemotherapy, with significant improvements in patients with squamous histology in terms of overall objective response (ORR) (26.8% vs 10.5%, p=0.001), disease control rate (59.9% vs 45%, p=0.015) and PFS 4.2m vs 2.7m (HR 0.78, 95%CI0.61-0.96) and a numerically superior OS benefit 9.5m vs 8.2m (HR: 0.88, 95%CI: 0.69-1.13). [9 ] In Dec 2014, ramucirumab received FDA approval for use with docetaxel in the second-line management of advanced NSCLC, including patients with squamous histology. Finally, the inhibition of T-cell activation through programmed death (PD-1) receptor interaction with the tumor expressing PD-L1 ligand (immune checkpoint) is a noted mechanism of tumor immune surveillance escape in NSCLC. From early clinical trials immune checkpoint blockade is an attractive therapeutic strategy in NSCLC, given its ability to activate the immune system and produce long-term response. In the management of sqNSCLC, the fully human IgG4 anti-PD-1 monoclonal antibody, nivolumab, has recently replaced docetaxel as the preferred second-line therapy based on the results of CHECKMATE 017 [10], a phase III study of nivolumab versus docetaxel. Findings in CHECKMATE 017 demonstrated improved median OS 9.2m vs 6.0m (HR: 0.59, 95%CI: 0.44-0.79) and improved 1-year survival over docetaxel (42% vs 24%), with a more favorable safety profile and fewer treatment related grade 3/4 AE (7% vs 55%).[10] With the recent FDA approval of nivolumab in the second-line setting in March 2015, docetaxel will likely be relegated to third-line therapy in the management of sqNSCLC. However, additional studies are required to confirm the results of CHECKMATE 017 given the lower than expected median survival observed in the docetaxel arm, to identify biomarkers of response, and to better define the unique toxicities associated with these immune-modulating agents. The last year has seen an unprecedented evolution in the management of sqNSCLC, with survival gains noted in both the first and second-line setting in randomized clinical trials. Unfortunately, to date the identification of oncogenic driver mutations in sqNSCLC have yet to yield the significant improvements seen in non-squamous histology, however it is likely that the relevant biomarkers of efficacy will soon be identified. Regardless, with the current regulatory approvals and the numerous novel agents in development, improved outcomes in patients with squamous cell carcinoma of the lung are anticipated. The immediate task, with the expanded treatment options now available for sqNSCLC, is the interrogation of new combinations and the sequencing of available therapies to maximize the benefit for this historically underserved subgroup of patients with NSCLC. References 1. Scagliotti G, Brodowicz T, Shepherd FA et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in non-squamous non-small cell lung cancer. J Thorac Oncol 2011; 6: 64-70. 2. Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 2004; 22: 2184-91. 3. Pujol JL, Pirker R, Lynch TJ et al. Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer 2014; 83: 211-218. 4. Kim JH, Grossi F, De Marinis F et al. Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy : interim subset analysis from a phase III trial. Proc Am Soc Clin Oncol 2012; 30 (suppl 15): abstr 7558. 5. Thatcher N, Hirsch F, Luft A 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, randomized, controlled phase 3 trial. Lancet Oncol 2015; 16(7): 763-774. 6. Socinski M, Luft A, Szczesna A et al. Subgroup analyses by performance status (PS) in the phase III SQUIRE study: First-line necitumumab (N) plus gemcitabine-cisplatin (GC) vs. GC in squamous non-small cell lung cancer (NSCLC). J Clin Oncol 2015; 33:suppl; abstr e19023. 7. Reck M, Gralla RJ, Bonomi P et al. Maximum severity score (MSS) of baseline patient-reported Lung Cancer Symptom Scale (LCSS) as a prognostic and predictive factor for overall survival (OS) in the Phase III SQUIRE study. ASCO Meeting 2015 abst; 33: 8099. 8. Soria J-C, 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; dx.doi.org/10.1016/s1470-2045(15)00006-6. 9. 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 multicentre, double-blind, randomized phase 3 trial. Lancet 2014; 384: 665-73. 10. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in advanced squamous-cell non small cell lung cancer. NEJM 2015; doi: 10.1056/NEJMoa1504627.

Abstract:
In recent years, our understanding of non-small cell lung cancer (NSCLC) has evolved from thinking of this malignancy as a single disease, or a small number of histologic subtypes, to now a multitude of genomically-defined subsets, both in adenocarcinoma and squamous lung cancer. In development of new targeted therapies against these abnormalities, so-called Master Protocols offer a number of advantages over traditional single study designs for drug-biomarker approval, including a common infrastructure, homogeneous patient populations with consistent eligibility across multiple independent sub-studies, and the ability to screen large numbers of patients in rapid fashion. Thus, the Lung-MAP project was designed to facilitate approval of targeted therapy-predictive biomarker combinations in squamous lung cancer, a recognized area of unmet need. Lung-MAP is constructed as a unique public-private partnership engaging the National Cancer Institute (NCI) and its Thoracic Malignancies Steering Committee (TMSC), the Foundation of the NIH (FNIH), the pharmaceutical industry and advocacy groups such as Friends of Cancer Research (FOCR), along with an advisory role by the Federal Drug Administration (FDA). The design is multiple simultaneously running Phase II/III trials, each capable of independently opening and/or closing without affecting the other sub-studies, in which patients eligible for 2[nd] line therapy for lung SCC have their cancers genomically screened through a next generation sequencing (NGS) platform (Foundation Medicine). Patients are then randomized into one of several sub-studies, each comparing an experimental targeted therapy with standard of care therapy, based on identification of candidate predictive biomarkers associated with each sub-study. At launch, drug targets under study consisted of “match sub-studies” for PI3K, FGFR, CDK 4/6 and HGF, and a non-match sub-study testing PD-L1-directed therapy, as described below. Rapid turn-around time of NGS screening results, within 2 weeks, allows real time assignment into the appropriate sub-study. For those patients with cancers that do not “match” into a biomarker-driven sub-study, there is a ‘non-match” sub-study, in which a predictive biomarker is not yet of sufficient validation to utilize it in a drug-biomarker registration strategy. Due to changes in the therapeutic landscape since the launch of Lung-MAP, a number of amendments and modifications have been implemented, which will be discussed during this presentation.

Abstract:
Copy number alterations are common events in squamous cell lung cancers. A number of these play defined roles in tumorigenesis. Some are known to be oncogenic drivers in a subset of cases. Broad high-level amplification of the 3q26-28 cytoband occurs in about 30% of squamous cell lung cancers and was one of the first recurrent alterations characterized in this disease.(1) More focal amplification of 8p11 occurs between 10-20% of tumors.(2, 3) Specific genes in 3q26 that are recurrently amplified include SOX2, PIK3CA, and PRKCI. Other genes commonly amplified in 3q27-28 include BCL6, TP63, and EPHB3. Genes that are amplified at lower frequencies include EGFR, MYC, MCL1, RICTOR, CCND1, and CDK6. The table below summarizes these alterations.

Gene	Chromosome	Frequency
SOX2	3q26	35%
PIK3CA	3q26	30%
BCL6	3q27	20%
PRKCI	3q26	25%
TP63	3q28	21%
FGFR1	8p11	12%
MYC	8q24	8%
MCL1	1q21	6%
RICTOR	5p13	6%
EGFR	7p12	5%
CCND1	11q13	10%
CDK6	7q21-22	3%

Pharmacologic targeting of gene amplification events in squamous cell lung cancers has centered largely on 4 genes- FGFR1, PIK3CA, CCND1, and CDK6. The pre-clinical data and clinical trial work defining FGFR1 amplification as an oncogenic driver and drug target, respectively, are the most mature. Three abstracts summarizing the preliminary efficacy of the pan-FGFR inhibitors AZD4547, BGJ398, and JNJ42756493 were presented in 2014.(4-6) The overall response rates were low, ranging from 8-15%. Some of these have continued on as phase 2 trials (NCT02154490, AD4547). Other studies using less-specific FGFR inhibitors are also ongoing (NCT01935336, ponatinib; NCT02109016, lucitanib). Upstream PI3K pathway alterations have been the therapeutic targets for a number of trials of PI3K inhibitors, though only a subset have included PIK3CA amplification as a biomarker of interest. These include two phase 1 trials of PI3K-α or PI3K/mTOR inhibitors that have added expansion arms for PIK3CA amplified squamous cell lung cancers (NCT01296555, GDC0032; NCT01655225, LY3023414). Data for these studies have not yet been presented. Finally, G1/S checkpoint inhibitors, whose efficacy has been best defined in breast cancer, are now being tested for CCDN1 and CDK4/6 amplified squamous cell lung cancers. Drugs include palbociclib (S1400, NCT02154490) and abemaciclib (NCT02450539). It is worth noting, however, that the pre-clinical rationale for targeting the G1/S checkpoint alone is substantially weaker than for other pathways. The clinical experience derived from targeting FGFR1 amplification in squamous cell lung cancers can serve as a framework to understand, in general, which targeted therapy strategies are likely to fail both now and in the future. Comprehensive genomic analyses of squamous cell lung cancers have shown that these tumors are complex, with overlapping alterations in more than one oncogene and/or tumor suppressor occurring in most cases. This is particularly problematic for gene amplification targets, which are also plagued by questions of functional relevance apropos degree of amplification and association with protein expression. As borne out in the phase 1 trials of the pan-FGFR inhibitors, single-target inhibition is unlikely to generate the breadth and depth of responses seen with other drugs targeting other oncogenes. Issues surrounding pharmacodynamic efficacy and target inhibition may also play a role in limiting responses. Data from ongoing work will be presented identifying potential genomic and non-genomic modifiers of response to FGFR1 inhibition. References 1. Björkqvist A-M, Husgafvel-Pursiainen K, Anttila S, Karjalainen A, Tammilehto L, Mattson K, et al. DNA gains in 3q occur frequently in squamous cell carcinoma of the lung, but not in adenocarcinoma. Genes, Chromosomes and Cancer. 1998;22:79-82. 2. Paik PK, Shen R, Won H, Rekhtman N, Wang L, Sima CS, et al. Next generation sequencing of stage IV squamous cell lung cancers reveals an association of PI3K aberrations and evidence of clonal heterogeneity in patients with brain metastases. Cancer Discovery. 2015. 3. TCGA. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519-25. 4. Paik P, Shen R, Ferry D, Soria J-C, Mathewson A, Kilgour E, et al. A phase 1b open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers: Preliminary antitumor activity and pharmacodynamic data. J Clin Oncol. 2014;32:suppl; abstr 8035. 5. Nogova L, Sequist L, Cassier P, Hidalgo M, Delord J-P, Schuler M, et al. Targeting FGFR1-amplified lung squamous cell carcinoma with the selective pan-FGFR inhibitor BGJ398. J Clin Oncol. 2014;32:suppl; abstr 8034. 6. Bahleda R, Dienstemann R, Adamo B, Gazzah A, Infante J, Zhong B. Phase 1 study of JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2014;32:abstr 2501.

Abstract not provided

Abstract:
For some health professionals, communicating bad news is one of the most frequent tasks of their daily work. Conversations on new diagnosis of a dismal disease, discontinuation of therapy due to disease progression or end-of-life care goals are some examples of discussions that oncologists and other health professionals are responsible for everyday with patients and caregivers. However, despite the frequency of these conversations, few health professionals are properly trained in how to conduct difficult conversations in an effective and yet compassionate manner. Navigating through these difficult conversations with thoughtfulness are crucial moments on the patient-physician relationship. The way in how these conversations are delivered have a direct impact on how the patient will perceive and react to the situation and it might make the difference between failure and success of this relationship. Communicating bad news demonstrates personal courage and integrity and when conducted in the right way, increases patient’s confidence and trust on the oncologist and his ability to make the right decisions during the patient’s journey. In addition, empathic communication can influence patient’s satisfaction with care, quality of life and ultimately patient’s outcome. Some studies have reported that the most valued qualities in nurses and doctors communicating bad news –from the patient’s perspective, are: recognition (how the oncologist respond to the gravity of the news), guiding (what patient would like to get after news are delivered) and responsiveness (oncologist’s ability to sense patient’s need). Learning how to communicate bad news effectively with patients and family members is an essential requirement on becoming a successful and contemporary health professional. During this lecture we will review some communication strategies on how to efficiently lead these conversations with our patients. References: Baile WF, et al. Curr Opin Oncol 2005, Jul;17(4):331-5 Fujmori M, et al. J Clin Oncol 2014 jul 10;32(20):2166-72 Back AL, et al. Oncologist 2011;16(3):342-50 Baile WF, et al. Oncologist 2000; 5(4):302-11 Girgis A, at al. Aust N Z J Surg 1997 Nov;67(11):775-80

Abstract:
Background: Emotional reactions are natural and expected in individuals experiencing cancer and confronting the end of their lives, the differentiation between a normal and appropriate reaction to dying versus a psychiatric disorder such as major depression can be clinically difficult to differentiate. Depression is a common mental health problem in palliative cancer patients, unfortunately misunderstood, underdiagnosed, and undertreated. Depression is a major cause of suffering among patients with advanced disease or terminal illness like cancer. Depressive syndromes are correlated with a reduced quality of life, greater difficulty in managing the course of the patient's illness, decreased adherence to treatment, and earlier admission to inpatient or hospice care. It amplifies pain and other symptoms, and causes worry in family members and friends. Patients with advanced illness who suffer from depressive syndromes are also at high risk of suicide and suicidal ideation, and they have an increased desire for a hastened death. The recognition and diagnosis of patient depression, is often delayed in the course of the disease. Prevalence and risk factors: The reported prevalence of major depression in individuals with cancer varies from 3 to 38 percent. This wide variability is explained by the lack of agreement as to appropriate diagnostic criteria to be used in the setting of advanced illness, differences in patient populations, and variation in assessment methods. In general, rates are higher in populations with advanced cancer, greater levels of disability, and/or unrelieved pain. In several studies, younger cancer patients have higher rates of depressive disorders and self-reported distress. While depression is twice as common in women as compared to men in the general population, gender is not consistently reported to be a risk factor for depression in cancer patients. A prior history of depression is a risk factor for major depression in cancer patients. The presence of uncontrolled symptoms, particularly pain, is a major risk factor for depression and suicide among patients with cancer. The incidence of depression also depends upon the patient's particular illness. Among cancer patients, those with head and neck and pancreatic cancers are at a particularly high risk. Certain factors associated with the patient's illness or its treatment may be associated with depression. Central nervous tumors or metastasis to the central nervous system can cause depression. Other causes of depression in cancer patients include toxins created by the tumor, autoimmune reactions, and nutritional deficiencies. Depression can also represent an adverse effect from certain treatments, including glucocorticoids, chemotherapy drugs (vincristine, vinblastine, interferon and tamoxifen) as well as radiotherapy to the brain or head and neck. Patients who have high levels of spiritual well-being tend to be less depressed. The beneficial aspects of religion related primarily to spiritual well-being rather than to formal religious practice. Screening and diagnosis: Screening for depression should be carried out in all palliative care patients given the high prevalence of symptoms. Expert recommendations state that every patient with cancer should be screened for depression at initial diagnosis and thereafter as clinically indicated, especially with changes in cancer status or treatment. There are many tools to identify vulnerable patients by screening, Patient Health Questionnaire (PHQ-2) and PHQ-9 can identify deserving cases a deeper interview. Depressed mood, sadness, grief, and anticipatory feelings of loss are all appropriate responses to advanced disease and dying, however, feelings of hopelessness, helplessness, worthlessness, guilt, lack of pleasure, and suicidal ideation are indicators of depressive syndromes in these patients. Although most used criteria for diagnosing major depression in non- oncology patients is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the most widely used for cancer patients is the substitutive approach of Endicott. This scale replaces four of the DSM-IV somatic criteria thought most likely attributable to medical illness or its treatment (ie, change of weight/appetite, sleep disturbance, loss of energy/fatigue, difficulty thinking or concentrating) with cognitive substitutes (depressed appearance, social withdrawal, brooding/self-pity/pessimism, and lack of reactivity in situations that would normally be pleasurable) Treatment: Unfortunately, some data suggest most cancer patients with depressive syndromes are undertreated. The first step in treating depression is to relieve uncontrolled symptoms, particularly pain and potentially reversible general medical cause of depressed mood. If depression persists once these are identified and controlled, specific therapy is warranted. Treatment should be tailored to the individual needs of the patient. In addition to drug therapy, effective psychosocial interventions include individual or group psychotherapy, cognitive-behavioral therapy, existential therapy, and self-help groups. There are no randomized trials that specifically address the benefit of psychotherapy for palliative care patients with depression. As a result, therapy for depression in these patients is generally based upon the larger evidence on effective treatments in patients of primary care populations with either no physical illness or less severe medical conditions. The agents used most commonly in palliative care patients are psychostimulants, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs), these drugs are an important option for treatment of depression at the end of life because they take effect quicker than other classical drugs. Other advantages as their more favorable side effect profile and the markedly lower danger with overdose, led to the recomendation of the American College of Physicians in the 2008 clinical practice guidelines for initial treatment of depression in primary care patients, to initiate an SSRI, serotonin and norepinephrine reuptake inhibitors SNRI, or atypical antidepressant in this group of patients. Meyer HA. et al. Palliat Med 2003; 17:604 Portenoy LK. et al. Qual Life Res 1994; 3:183 Wilson KG. et al. J Pain Symptom Manage 2007; 33:118 Akechi T. et al. J Clin Oncol 2004; 22:1957 DeFlorio ML. et al. Depression 1995; 3:66 Endicott J. Cancer 1984; 53:2243 Andersen B. et al. J Clin Oncol 2014; 32:1605 Qaseem et al. Ann Intern Med. 2008;149(10):725

Abstract:
ln the UK, lung cancer has one of the lowest 5 year survival rates of all cancers (8.8% of men and 11.1% of women are alive 5 years after their diagnosis) whilst only 30% of people live for more than one year following their diagnosis (Macmillan, 2014). This poor outlook can have a profound impact on the quality of life of those affected by the disease (LCA, 2015). However, helping people and their families cope with the impact and consequences of the disease and its treatment can make a substantial difference to the quality of their lives. In this context coping might be regarded as a means of understanding and regulating the emotions in response to stress but it might also be viewed as solving problems and adapting lifestyles and behaviour through goal setting and seeking information and help. By adopting a structured and planned approach to care, the healthcare professional can enhance the coping capability of the person with cancer and their families and thereby directly contribute to their quality of life. This approach can be seen in the Recovery Package. Data from the London Cancer Alliance reveals that the top ten concerns for the person with lung cancer are a mix of physical and psychological issues including breathlessness, fatigue, anxiety, weight loss, sleeping, finances, walking, pain, eating and transport. People with lung cancer have the highest number of unmet needs out of all cancer patients, mainly due to higher psychological support and physical/daily living support needs (Li et al, 2006). Depression levels tend to be higher for people with lung cancer compared to cancer patients with other types of cancer (Fischer et al, 2010). Self reported sexual concerns are common in people with lung cancer and are related to shortness of breath and emotional distress (Reese et al, 2011) whilst people with lung cancer experience higher levels of pain compared with patients with other types of cancer (Fischer et al, 2010) Link et al (2005) discuss the work of Lazarus and Folkman, and their ‘Transactional model of distress and coping’ which suggests that people respond to stressful situations by a primary appraisal (where they evaluate the significance of the stressor) and a secondary appraisal (where they evaluate their ability to change the situation and manage their emotions). It is at these key junctures that effective interventions might be best employed. The Recovery Package allows the identification and selection of suitable interventions which can be tailored to meet the specific needs of people with cancer and their families. In the UK the report ‘Taking Action to Improve Outcomes (NCSI, 2013) envisaged that care should be designed with the following key aims: Providing information and support from the point of diagnosis Promoting recovery Sustaining recovery Managing the consequences of treatment Supporting people with active and advanced disease These key aims underpin The Recovery Package which is a series of key interventions which, when delivered together, can greatly improve outcomes for people living with and beyond cancer. The Recovery Package is made up of an assessment of holistic needs and the development of a care plan to address these issues; a treatment summary that explains to the General Practitioner and individual what treatment has taken place; a cancer care review by the General Practitioner within 6 months of diagnosis; attendance at a health and wellbeing educational event. The Recovery Package The success of the Recovery Package depends upon the creation of a partnership with the individual and the focus of care is on supporting self-management after a cancer diagnosis. This is underpinned by effective assessment. Holistic needs assessment acknowledges that coping strategies are mediated by social context and that the quality and quantity of the person’s support can be quite variable. The assessment works by gathering and discussing information in order to develop an understanding of what the person living with and beyond cancer knows, understands and needs. It is focused on the whole person and the entirety of his/her needs including the physical, emotional, spiritual, mental, social, and environmental needs of the individual. The process culminates when the assessment results are used to inform a care plan. Holistic assessment tools offer front-line health service staff a structured yet collaborative way to elicit people’s concerns and, with adequate training and informational resources, respond to these concerns effectively, efficiently and humanely. By integrating the assessment of very understandable emotional concerns within a holistic treatment review there is less likelihood that psychological difficulties become pathologised by professionals or seen as a source of shame for those living with and beyond cancer (Brennan et al, 2012). Lung cancer is often characterised by rapid deterioration and a complex interplay of symptoms, concerns and worries and health care professionals can play a critical role in choice of coping strategy (which can be used to help people to more actively participate in their care) (Link et al, 2005). This can be helped by a structured and planned approach to care such as The Recovery Package.

Abstract:
The majority of patients with lung cancer present in advanced stages, and small biopsy and cytology specimens most frequently provide the only tumor material for diagnosis. Furthermore, the same sample is also needed for molecular studies that guide treatment and management. Lung carcinomas often are diagnosed by minimally invasive techniques and specimens are obtained by bronchoscopic or transthoracic approaches. The choice of the procedure depends on the location, accessibility of the mass and other clinical parameters. Since most adenocarcinomas are peripherally located, the transthoracic approach is often chosen to provide diagnostic samples. Squamous cell carcinoma is most frequently centrally located and the bronchoscopic approach is more common. If cytology specimens, including pleural fluids, are obtained, cell blocks should be prepared. Despite the best efforts, the lesional tissue or the most representative area of the tumor may not be obtained in some cases due to sampling issues. Even when the tumor is sampled, poor tumor differentiation or insufficient characteristic morphological features in the tumor sample will cause the difficulty in rendering a specific diagnosis and would prompt pathologists to use immunohistochemistry. Use of immunohistochemistry greatly reduced the number of lung carcinoma cases classified as non-small cell carcinoma, NOS to only 3%. .In addition to immunohistochemistry, cytology samples should be interpreted in conjunction with histology of small biopsies whenever possible. Immunohistochemistry should be limited only to cases when classification is uncertain and every effort should be made to preserve as much material as possible for molecular studies. There are few strategies besides limited immunohistochemistry panels how this could be accomplished. One approach is to cut unstained slides from a paraffin block after initial hematoxylin-eosin stain sections were obtained. It is essential that histology technicians limit facing of the block and place only one tissue section per slide. Another approach is to have each core biopsy tissue fragment placed into separate blocks during specimen processing so only one block can be used for immunohistochemistry and all of the blocks can be used for molecular studies. Same laboratories in order to avoid tumor microdissection from the unstained slides prefer to core paraffin blocks by 1-mm needles after diagnostic work up. Formalin-fixed, paraffin-embedded tissue samples and cytology aspirates can be used for various testing platforms including next generation sequencing. Each molecular laboratory should establish criteria for specimen adequacy for molecular studies taking into account the specific testing platforms, while surgical pathologists should assess the specimen adequacy. Although PCR-based methods can detect mutations from a single cell, a low copy number DNA template can generate sequence artifacts leading to false results. Therefore, the assessment of adequacy is essential to avoid assays failures and false positive/negative results. Estimates of tumor content from H&E stained sections vary between pathologists and there is no true standard. Acceptable specimens should have a sufficient amount of tumor cells, but also a small proportion of admixed non-neoplastic cells, and no necrosis.[116] If the specimen is inadequate, a new specimen needs to be procured although in this situation decision regarding specimen type is often difficult and depends on many factors including the patient’s health. Alternate non-invasive highly sensitive methods so called “liquid biopsies” have been developed to detect the presence of cancer specific mutations in circulating DNA in blood samples. This approach may result in significant changes in the management of lung cancer patients and may replace invasive procedures. Until then, it is essential that each institution develops its own strategy that addresses the collection and processing of lung cancer samples. At the same time, pathology departments must implement the procedures that would precisely define how to spare the tumor tissue for molecular testing, and how to provide clinically acceptable turnaround time for molecular testing results. It is also essential to define how to integrate diagnostic interpretation and molecular results in a single pathology report. References: Travis WD 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):668-84. Lindeman NI. et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from CAP/IASLC/AMP. J Thorac Oncol 2013:8(7):823-59. Francis G, Stein S.Circulating cell-free tumor DNA in the management of cancer. Int J Mol Sci. 2015;1 (6):14122-42

Abstract:
With 1.6 million new diagnoses and 1.4 million annual deaths worldwide, 230,000 annual cases and 160,000 deaths in the US, lung cancer is the oncologic scourge of the present age. It accounts for 23% of worldwide, and 28% of US, cancer deaths.1 Four decades of advances in diagnostic and treatment modalities, including the current ‘molecular’ decade of rapid-fire discovery of breakthrough therapeutics, have seen aggregate US 5-year survival improve from 12% to 17%.2 Although the deployment of effective population-based tobacco cessation and lung cancer screening programs can change these statistics, there remains the danger of blunted impact because of relatively little progress in the coordination of care, and major deficits in the use of curative-intent therapy. Lung cancer care is complicated. The disease is common and lethal; the primary at-risk population is ravaged by cumulative age- and tobacco-related comorbidities; the lungs and mediastinum are relatively inaccessible; multiple approaches and techniques for diagnosis, staging, and treatment exist, each requires different, highly-trained specialists (radiologists, pulmonologists, surgeons, medical oncologists, radiation oncologists, pathologists, palliative care specialists), using high-cost equipment, to perform high-risk procedures, any one of which may or may not be needed for specific patients. Determining which specific specialists and management approaches are needed for individual patients requires objective evaluation and careful coordination, in order to tailor management to patient needs. Prevailing nihilism about lung cancer care further complicates matters: ‘statistics suggest the patient will die anyway, so what’s the point?’, ‘he brought this on himself by smoking, whose problem is this?’ Care delivery must be better coordinated before we can achieve meaningful improvement in population-level survival statistics. All lung cancer care begins with an abnormal chest x-ray or CT scan. From then, it flows through certain ‘nodal points’: histologic confirmation, radiologic staging, histologic staging, selection of treatment, and (ultimately) outcomes. Each nodal point includes a myriad of options. Diagnosis is usually made by percutaneous (interventional radiologist), bronchoscopic (pulmonologist), or surgical (thoracic surgeon) biopsy ; radiologic staging often involves a PET/CT scan (nuclear radiologist), and brain MRI scan (neuro-radiologist); histologic staging requires an invasive biopsy procedure, which can be transbronchial needle biopsy during conventional bronchoscopy, endobronchial ultrasound-guided (EBUS) biopsy (pulmonologist), endoscopic ultrasound-guided (EUS) biopsy (gastroenterologist), percutaneous image-guided biopsy of a distant stage-defining lesion (interventional radiologist), mediastinoscopy, or other approaches to various parts of the mediastinum (surgeon). Treatment increasingly requires combinations of surgery, radiation therapy, chemotherapy and palliative care. Therefore lung cancer care demands a high degree of coordination. Major, well-described geographic, socio-economic, racial, and age-based disparities in diagnosis, staging, treatment, and outcomes suggest that healthcare systems fail to provide the required level of care coordination. The proportion of patients who make it to surgery, the most important curative treatment modality, varies from 9% in the UK, to 29% in the US.3 Use of invasive staging tests and surgical resection is significantly lower in African Americans than in Caucasians.4,5 Elderly patients are less likely to receive chemotherapy than younger patients.6 Although partly driven by patient choice, improvement in care coordination narrows or eliminates most disparities.7,8 Beyond disparities, access to high-quality care is generally low. ‘Trimodality’ staging (CT, PET/CT scan and invasive staging in combination) although associated with a 2-fold survival improvement was used in only 5% of US patients.9 In a high lung cancer mortality zone of the US, only 17% of curative-intent resections were preceded by invasive staging, including only one-third of patients with clinical N1, N2 or N3 disease (Osarogiagbon, unpublished data). Low rate of histologic confirmation of stage-defining lesions raises the danger of overuse and underuse of treatment modalities. At the extremes are primary surgical resection for patients with clinically evident mediastinal nodal disease, and palliative systemic chemotherapy for patients with false-positive radiologic staging tests or multiple primary cancers erroneously classified as stage IV. Avoiding misuse of diagnostic and staging modalities is equally difficult. The need to recognize and correctly act on non-diagnostic, false-negative and false-positive test results is great. Lung cancer care is often delayed when insufficient-quality diagnostic material or sampling error leads to erroneous reassurance that a high-risk radiologic lesion is benign. The problem is even greater in the use of invasive staging tests. More than half of US mediastinoscopy procedures fail to deliver lymph node tissue for pathology examination.10 This dismal statistic is probably worse with EBUS and EUS. The need for high-quality tissue rises as prognostic and response-predictive implications steadily increase our need for clear histologic categorization (and sub –categorization), and with the advent of molecular prognostication and treatment selection. The demand for high-quality tissue spans the stage spectrum. Therapeutic clinical trials now routinely demand tissue for molecular testing, surgical resection trials increasingly mandate a minimum quality of nodal staging. Patients’ eligibility for clinical trials and our ability to accelerate testing and deployment of novel treatments increasingly hinge on tissue procurement. Pathologists and interventionists who procure tissue must work collaboratively to increase tissue yield for the numerous purposes of treating clinicians. This must be achieved while maintaining patient safety and convenience. The countervailing forces of increasing adoption of minimally invasive diagnostic, staging and treatment modalities and ravenous hunger for high-quality tissue for prognostication and treatment selection collide within individual patients and healthcare systems. Only better coordination, involving all relevant clinicians in early strategic decision-making for each individual patient can prevent the delays, anxieties, exposure to harm, missed opportunity for better treatment outcomes, and looming medico-legal risk that the status quo in lung cancer care represents. Rising survival rates will only increase this conflict, as the need for re-characterization of disease rises, and lung cancer care evolves from a game of checkers to a chess match. REFERENCES 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. 2. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed May 28, 2015. 3. Moghissi K, Connolly CK. Resection rates in lung cancer patients. Eur Respir J 1996;9:5-6. 4. Bach PB, Cramer LD, Warren JL, Begg CB. Racial differences in the treatment of early-stage lung cancer. N Engl J Med 1999;341:1198-205. 5. Lathan CS, Neville BA, Earle CC. The effect of race on invasive staging and surgery in non-small-cell lung cancer. J Clin Oncol 2006;24:413-418. 6. Earle CC, Venditti LN, Neumann PJ, et al. Who gets chemotherapy for metastatic lung cancer? CHEST 2000;117;1239-1246. 7. Laroche C, Wells F, Coulden R, et al. Improving surgical resection rate in lung cancer. Thorax 1998;53:445-449. 8. Brawley OW. Lung cancer and race: equal treatment yields equal outcome among equal patients, but there is no equal treatment. J Clin Oncol 2006;24:332-333. 9. Farjah F, Flum DR, Ramsey SD, et al. Multi-modality mediastinal staging for lung cancer among Medicare beneficiaries. J Thorac Oncol 2009;4:355-363. 10. Little AG, Rusch VW, Bonner JA, et al. Patterns of surgical care of lung cancer patients. Ann Thorac Surg 2005;80:2051-6.

Abstract not provided

Abstract:
The personalized treatment of lung cancer begins with an accurate histologic diagnosis. Lung cancer is a heterogeneous disease and recent advances in understanding the genetic underpinnings of cancer coupled with the development of targeted therapeutics have added to the complexity of the diagnostic evaluation. The previous simple division of lung cancer into small cell and non-small cell histology is no longer adequate, and evaluation of tumors for specific genetic changes and their expression is essential for the precise and accurate diagnoses required for optimal treatment and patient management. In 2011, the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) published a new pathological classification of lung adenocarcinoma.[1] This new system established uniform terminology and diagnostic criteria for both resection specimens and small biopsies. Based on advances in the understanding of lung tumor biology, the correlation between specific tumor histology and outcomes with selected chemotherapy agents, as well as the successful development of novel targeted therapies, this new classification system emphasized the importance of a multidisciplinary approach to the diagnosis of lung cancer in order to best guide management decisions. In the IASLC/ATS/ERS system, several changes to pathological classification of adenocarcinoma were proposed.[1] The term “BAC” (bronchioloalveolar carcinoma) was discontinued and new pathological subtypes were added, including adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma. For patients with invasive adenocarcinoma, the new system proposed comprehensive histological subtyping with classification based on predominant histological pattern (lepidic, acinar, papillary, micropapillary and solid). Mucinous tumors were classified as mucinous AIS, mucinous MIA or invasive mucinous adenocarcinoma based on extent of invasion. In subsequent validation studies, pathological subtyping using the IASLC/ATS/ERS adenocarcinoma classification system has been demonstrated to have both prognostic and predictive significance.[2, 3] Patients with AIS and MIA have close to 100% disease-free survival. In contrast, invasive adenocarcinomas with solid and micropapillary predominant histological subtypes were associated with worse overall survival.[2, 4] Because most patients with lung cancer will be diagnosed with advanced-stage disease, one of the most important distinctions between the 2011 IASLC/ATS/ERS classification system and the previous 2004 World Health Association (WHO) classification is the establishment of diagnostic criteria for small biopsies and cytology. Although the focus was on adenocarcinoma, diagnostic criteria for other histologies were also included with the primary focus on distinguishing between squamous cell carcinoma and adenocarcinoma. A limited diagnostic work up was recommended to preserve as much tissue as possible for molecular testing. In cases where the diagnosis can be established based on light microscopy alone, the WHO classification criteria were maintained and no additional confirmatory testing was recommended. In tumors without definite squamous or adenocarcinoma morphology, limited immunohistochemistry may be used to refine the diagnosis. Most tumors can be classified using a single adenocarcinoma marker (i.e. TTF-1 or mucin) and a single squamous marker (i.e. p40 or p63.[5] The acknowledgement that one needs to “preserve as much tissue as possible” for biomarker testing reflects the changing uncertainty in which biomarkers need to be assessed and what techniques might be available for testing. With the identification and validation of actionable molecular targets that can guide therapy in patients with advanced adenocarcinoma, institutions are encouraged to develop consistent strategies for obtaining and managing tissue samples that are optimized for molecular testing. Because this approach has not been validated for squamous histology, tumors with equivocal morphology or IHC findings should be classified as NSCLC-NOS so as not to exclude patients from histology-specific chemotherapy or molecular testing. In 2013, the College of American Pathologists (CAP), IASLC and Association for Molecular Pathology (AMP) published a molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors that included 37 recommendations addressing 5 principal questions, including: (1) When should molecular testing be performed? (2) How should EGFR testing be performed? (3) How should ALK testing be performed? (4) Should other genes be routinely tested in lung adenocarcinoma? And, (5) How should molecular testing be implemented and operationalized?[6, 7] In addition to EGFR and ALK, a number of other molecular alterations have been described that are potentially treatable with targeted agents. Because the data were insufficient to support routine testing of other targets when the CAP/IASLC/AMP guidelines were finalized, the recommendation was to prioritize EGFR and ALK testing over other molecular markers in order to reserve tissue for these analyses.[6] The type and number of molecular alterations being evaluated ultimately determine how a limited specimen should be used. Immununohistochemical (IHC) and Fluorescent In Situ Hybridization (FISH) are the standard approaches for the detection of protein expression and chromosomal rearrangements and amplifications. Specific single nucleotide polymorphisms (SNPs) that are recognized mutations influencing response to specific therapies demand nucleic acid based tests utilizing a PCR based approach or, in the extreme, DNA sequencing. Most of these assays are typically developed as singleton tests for one specific SNP. As the number of necessary biomarkers increases, efficiency demands multiplexing these singleton assays or adopting a different technology, e.g. Next Gen Sequencing (NGS).[8-10] However, the timeliness for reporting results vary depending on the platform and the number of genes. It needs to be understood that none of these technologies can detect all of the types of genomic alterations of interest and that all of these methodologies must remain in the armamentarium available for proper specimen evaluation. With this in mind, efficient use of limited tissue demands clear communication between oncologists, surgeons, interventional radiologists and pathologists with regard what is needed for patient care and an understanding of available resources, either in house or through an appropriate reference laboratory. A further complexity is the timeliness in obtaining a result. While good practice suggests establishment of institutional protocols, individual patient needs ultimately dictate how best to proceed, emphasizing the importance of good interdisciplinary communication References: 1. Travis, W.D., et al., International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol, 2011. 6(2): p. 244-85. 2. Hung, J.J., et al., Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification on death and recurrence in completely resected stage I lung adenocarcinoma. Ann Surg, 2013. 258(6): p. 1079-86. 3. Song, Z., et al., Prognostic value of the IASLC/ATS/ERS classification in stage I lung adenocarcinoma patients--based on a hospital study in China. Eur J Surg Oncol, 2013. 39(11): p. 1262-8. 4. Gu, J., et al., Prognostic significance of the IASLC/ATS/ERS classification in Chinese patients-A single institution retrospective study of 292 lung adenocarcinoma. J Surg Oncol, 2013. 107(5): p. 474-80. 5. Travis, W.D., 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): p. 668-84. 6. Lindeman, N.I., 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. J Thorac Oncol, 2013. 8(7): p. 823-59. 7. Leighl, N.B., et al., Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the study of lung cancer/association for molecular pathology guideline. J Clin Oncol, 2014. 32(32): p. 3673-9. 8. Rekhtman, N., et al., Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing. J Thorac Oncol, 2011. 6(3): p. 451-8. 9. Sholl, L.M., et al., Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience. J Thorac Oncol, 2015. 10(5): p. 768-77. 10. Gailey, M.P., et al., Multiplatform comparison of molecular oncology tests performed on cytology specimens and formalin-fixed, paraffin-embedded tissue. Cancer Cytopathol, 2015. 123(1): p. 30-9.

Abstract:
Usually NSCLC tumors that have invaded the central/mediastinal vascular structures are considered unresectable, and staged as T4 locally-advanced NSCLC and are treated with concurrent platinum-based chemotherapy and thoracic radiation with curative intent (60+Gy). However, subsets of good functional status patients with limited involvement (clinically node-negative; T4N0) have been selectively treated with surgical resection before or after additional therapy. This has been most commonly employed for tumor invasion at the base of one of the pulmonary veins with extension into the proximal left atrium or for right upper lobe tumors with segmental involvement of the superior vena cava. Smaller series exist for resection of lung tumors having primary extension into the cardiac chambers and aortic arch. There are no prospective trials, only manuscripts that detail decades-long retrospective single institution series. This presentation will review the literature and surgical approaches to NSCLC involving the great vessel with and without circulatory support. Surgical management of lung cancer invading the aorta or the superior vena cava. Misthos P, Papagiannakis G, Kokotsakis J, Lazopoulos G, Skouteli E, Lioulias A. Lung Cancer. 2007 May;56(2):223-7. Epub 2007 Jan 16. Extended resection of the left atrium, great vessels, or both for lung cancer. Tsuchiya R, Asamura H, Kondo H, Goya T, Naruke T. Ann Thorac Surg. 1994;57(4):960-5 Results of superior vena cava resection for lung cancer. Analysis of prognostic factors. Spaggiari L, Magdeleinat P, Kondo H, Thomas P, Leon ME, Rollet G, Regnard JF, Tsuchiya R, Pastorino U. Lung Cancer. 2004 Jun;44(3):339-46. 15 years single center experience with surgical resection of the superior vena cava for non-small cell lung cancer. Shargall Y, de Perrot M, Keshavjee S, Darling G, Ginsberg R, Johnston M, Pierre A, Waddell TK. Lung Cancer. 2004:357-63 Superior vena cava resection for lung and mediastinal malignancies: a single-center experience with 70 cases. Spaggiari L, Leo F, Veronesi G, Solli P, Galetta D, Tatani B, Petrella F, Radice D. Ann Thorac Surg. 2007 Jan;83(1):223-9; discussion 229-30 Left atrial resection for T4 lung cancer without cardiopulmonary bypass: technical aspects and outcomes. Galvaing G, Tardy MM, Cassagnes L, Da Costa V, Chadeyras JB, Naamee A, Bailly P, Filaire E, Pereira B, Filaire M. Ann Thorac Surg. 2014 May;97(5):1708-13 Results of primary surgery with T4 non-small cell lung cancer during a 25-year period in a single center: the benefit is worth the risk. Yildizeli B, Dartevelle PG, Fadel E, Mussot S, Chapelier A. Ann Thorac Surg. 2008 Oct;86(4):1065-75; Twelve-year experience with left atrial resection in the treatment of non-small cell lung cancer. Ratto GB, Costa R, Vassallo G, Alloisio A, Maineri P, Bruzzi P. Ann Thorac Surg. 2004 Jul;78(1):234-7. Review. Survival after extended resection for mediastinal advanced lung cancer: lessons learned on 167 consecutive cases. Spaggiari L, Tessitore A, Casiraghi M, Guarize J, Solli P, Borri A, Gasparri R Petrella F, Maisonneuve P, Galetta D. Ann Thorac Surg. 2013;95(5):1717-25 Superior vena caval resection in lung cancer. Lee DS, Flores RM. Thorac Surg Clin. 2014 Nov;24(4):441-7

Abstract:
Chest wall involvement is rare in patients with non-small cell lung cancer (NSCLC), occurring in <8% of patients (1). Invasion of the chest wall accords a T3 designation in both the 7[th] and in the newly proposed 8[th] edition TNM staging systems (2). The overall five-year survival for patients with clinically staged T3N0 NSCLC is approximately 45% (2). With clinically suspected nodal disease, even limited to N1 stations, survival is markedly worse. While cT3N2 NSCLC patients are designated stage IIIA and typically given neoadjuvant therapy, optimal treatment protocols are less clear for cT3N0 or even for cT3N1 patients with chest wall tumors, despite the fact that cT3N1 patients are also classified stage IIIA. An en bloc surgical resection of the involved lung and of the chest wall with or without adjuvant therapy has historically been the treatment algorithm of choice for these patients. Little data exists to determine whether neoadjuvant chemotherapy or chemoradiation might be beneficial in this setting. In contrast, the preferred treatment algorithm for a unique subset of chest wall tumors, Pancoast tumors, has been clearly defined (1). These T3 or T4 superior sulcus tumors arise in the apex of the lung and invade the chest wall at the level of the first rib or above, often with involvement of the brachial plexus, subclavian vessels, or spine. For these patients with clinical T3-4N0-1 disease, two carefully conducted prospective, multi-institutional trials demonstrated that induction chemoradiation therapy was associated with high rates of pathological response, improved resectability, and increased survival over historical controls (3,4). In the Southwest Oncology Group Trial 9416 (Intergroup Trial 0160), following neoadjuvant cisplatin and etoposide with concurrent radiation (45 Gy), 61% of patients had either a pathologic complete response or minimal microscopic residual tumor (3). Among all patients undergoing surgery, 94% were able to undergo an R0 resection. Patients with pathologic complete response had a marked advantage in five year overall survival (median survival not reached for complete responders versus 30 months for those with residual disease). Overall survival of the entire cohort was 44%, but was 54% after complete resection. Similar results were found in a multi-institutional trial from Japan (JCOG 9806), in which 21% of patients experienced a complete pathologic response following neoadjuvant therapy with mitomycin, vindesine, and cisplatin and concurrent radiation of 45 Gy (4). Among surgical patients, 89% underwent an R0 resection. Overall five-year survival for the cohort exceeded 50%, with survival of complete responders again especially favorable. The successful adoption of neoadjuvant therapy followed by surgery for Pancoast tumors raised the question of whether a similar induction strategy should be used in patients with other T3 chest wall tumors outside of the superior sulcus. Previous reports have suggested that prognostic factors for survival in patients with chest wall tumors include lymph node status and depth of chest wall invasion, but also completeness of surgical resection and completion of chemotherapy (5,6). It seems logical that neoadjuvant chemotherapy or chemoradiation may facilitate an R0 resection and that such therapy may be better tolerated preoperatively in patients undergoing potentially morbid chest wall resections. Along those lines, a prospective phase II study of trimodality therapy was performed in Japan (CJLSG 0801) for patients with T3N0 or T3N1 NSCLC involving the chest wall (7). Fifty-one patients were entered into the study, among whom 49 (96%) completed neoadjuvant cisplatin and vinorelbine with concurrent radiation (40 Gy) and among whom 44 (92%) underwent complete resection. Similar to prospective studies in NSCLC patients with superior sulcus tumors, in resected tumors there was a high rate of complete pathological response (25%) and of only minimal residual disease (65%). Treatment was relatively safe. However, one patient did die during neoadjuvant therapy secondary to infection following neutropenia and seven additional patients (16%) experienced grade 4 toxicity. Despite this, 86% of patients completed the induction regimen. Among the 29 patients (66%) who went on to surgery, 5 patients experiencing major complications and there was 1 postoperative mortality. Although median follow up was only 16 months, the 2-year overall and progression-free survival rates were excellent at 85% and 71% respectively. While the results of CJLSG 0801 perhaps make a compelling argument to treat chest wall tumors with neoadjuvant therapy prior to resection, several caveats must be considered. From previous studies, it would seem that nodal disease is the strongest indicator of the need for systemic therapy. However, previously reported rates of nodal disease for chest wall tumors are generally only between 20-40% (5). The rate of nodal disease reported in a recently published review of a Japanese registry of chest wall tumors was only 27% (8). These patients without nodal disease will not clearly benefit from systemic therapy. Furthermore, as opposed to Pancoast tumors, the rate of complete resection of chest wall tumors outside the superior sulcus is high even without neoadjuvant therapy, 88% in the Japanese registry study (8). This ability to obtain an R0 resection calls into question the need to include radiation therapy in the preoperative treatment regimen for most cT3N0 patients, given the potential added morbidity. In conclusion, it would seem most reasonable to utilize neoadjuvant therapy in chest wall tumors with clinical N1 nodal disease. These patients are designated as stage IIIA and need chemotherapy as part of their treatment regimen. Neoadjuvant therapy prior to surgery makes sense, although care should be taken to avoid complications that may prevent surgical resection. For T3N0 patients, the treatment algorithm is less clear. Conceptually, large bulky tumors in which it is expected that difficulty in obtaining negative margins surgically would seem to be good candidates for chemotherapy and radiation preoperatively. Further studies need to explicitly compare neoadjuvant versus adjuvant chemotherapy for T3N0 chest wall tumors and need to better evaluate whether there is any beneficial role of radiation in this challenging group of NSCLC patients. 1. Kozower BD, Larner JM, Detterbeck FC, Jones DR. Special treatment issues in non-small cell lung cancer, diagnosis and management of lung cancer 3[rd] ed: American College of of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5):e3696S-e399S. 2. Rami-Porta R, Bolejack V, Crowley J et al. Proposals for the Revisions of the T descriptors in the forthcoming eight edition of the TNM classification for lung cancer. J Thorac Oncol 2015;10:990-1003. 3. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007;25:313-318. 4. Kunitoh H, Kato H, Tsuboi M, et al. Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group Trial 9806. J Clin Oncol 2008;26:644-649. 5. Riquet M, Arame A, Le Pimpec Barthes F. Non-small cell lung cancer invading the chest wall. Thorac Surg Clin 2010;20:519-527. 6. Lee CY, Syun CS, Lee JG, et al. The prognostic factors of resected non-small cell lung cancer with chest wall invasion. World J Surg Onc 2012;10:9. 7. Kawaguchi K, Yokoi K, Niwa H, et al. Trimodality therapy for lung cancer with chest wall invasion: initial results of a phase II study. Ann Thorac Surg 2014;98:1184-91. 8. Kawaguchi K, Miyaoka E, Asamura H, et al. Modern surgical results of lung cancer involving neighboring structures: a retrospective analysis of 531 pT3 cases in a Japanese Lung Cancer Resistry Study. J Thorac Cardiovasc Surg 2012;144:431-7.

Abstract:
Surgical resection offers the best chance of cure for most patients with localized non-small lung cancer (NSCLC). However, the risk-benefit deliberation for surgery becomes less clear in patients with more locally advanced tumors (T4), because the procedures are typically more dangerous (higher risk) and the patient’s prognosis is worse (benefit less clear). That being said, surgery remains a curative option for a significant proportion of patients with T4 tumors. In order to minimize risk and maximize benefit, surgeons should select patients with 1) T4 tumors that can be removed safely, 2) T4 tumors that can be completely removed (R0) and 3) patients that are less likely to experience early systemic failure. The group of T4 NSCLC tumors that have historically been amenable to safe surgical resection include those that invade the spine, trachea, esophagus great vessels, and atrium. The 7[th] edition of the lung cancer stage classification system expanded the T4 designation to include tumors that involve a nodule in a separate ipsilateral pulmonary lobe. The recently released proposal for the 8[th] edition of the lung cancer stage classification system has moved tumors greater than 7cm in maximum diameter and tumors that invade the diaphragm to the T4 category. We have previously stated that changes in staging nomenclature should NOT be taken as justification for changing the way a patient is treated (because the revision only considers prognosis without any regard to treatment). However, these additional members of the T4 staging group pose the same risk-benefit conundrum that the others members pose and are discussed. Global health should be assessed as this is a critical component to the surgical risk calculation for patients. This typically includes an assessment of comorbid condition severity, pulmonary function testing, exercise testing and cardiopulmonary stress testing in patients at risk for cardiac disease. Strategies for safe removal of T4 tumors typically center around preparation for the unexpected. The supporting services should be alerted to not only the planned elements of the case but also possible needs in the event of a more extensive resection. The anesthesia team should be prepared to deal with abrupt bleeding (e.g. appropriate intravenous access that is located away from vessels that are likely to be clamped), the need for alternate ventilation strategies (e.g. jet ventilation). Any surgical specialty that could support an extended resection (e.g. spine service) should be alerted to the possibility. Surgeons should adjust their surgical approach to not only address what is apparent, but possible occult involvement of neighboring structures. Incisions should be placed in a way that allows the surgeon the flexibility to extend the planned resection. If possible, entrance should preserve tissues that can be used to treat surgical complications (e.g. preserving muscle for later use as a muscle flap). The exposure should allow for proximal and distal control of neighboring vessels, the use of cross table ventilation and the urgent use of cardiopulmonary bypass. Complete resection (removing all gross and microscopic disease) is of paramount importance, as the survival of patients is severely compromised by a positive surgical margin. While positive margins are an unfortunate reality to cancer surgery, every effort should be made to estimate the likelihood that a negative surgical margin can be obtained. At times this involves an exploratory phase of the resection (occasionally a minimally invasive approach to start) in order to assess the extent of local involvement (because imaging is notoriously inaccurate for determining the extent of local invasion). Finally the multi-disciplinary team must attempt to select patients that are less likely to develop early systemic failure, as these patients will not benefit from resection. This is of course not knowable with any degree of certainty but an estimate is helpful. Patients should undergo a thorough staging evaluation (brain imaging, PET scanning). While not an absolute contraindication for surgical resection, surgeons should be cognizant of other staging parameters that further compromise the patient’s potential for long-term survival. Most notably this would include the patient’s mediastinal lymph node status. The presence of mediastinal lymph node metastases (N2) is a further indication of the patient’s risk for systemic failure, and is an overall poor prognosticator. While prognosis does not alone define treatment, the patient’s overall prognosis should be considered when attempting to justify surgical risk (which is typically increased for T4 tumor resection). For this reason, it is recommended that surgeons refrain from resecting of T4 tumors associated with N2 disease as their default approach, and rather develop a strategy that attempts to allow patients to declare their potential for early failure. One strategy would be to offer the patient curative-intent nonsurgical therapy (chemoradiation) and observe the patient for a “local only” recurrence. In conclusion, surgical resection of T4 tumors is reasonable and effective in highly selected NSCLC patients. The onus is on surgeons and multidisciplinary care teams to attempt to identify the patients most likely to benefit and least likely to be harmed by surgery.

Abstract:
After definitive CRT, approximately 25-30% of patients with stage III disease will fail at their primary site while the regional and systemic fields are under control. As a result, the question of whether some of these patients may potentially benefit from salvage resection of their primary site is often brought up at multidisciplinary tumor boards. The largest published series is from Duke who reported earlier this year on 31 patients in 17 years who underwent lobectomy after definitive radiation therapy (RT), 29 of whom had also received concurrent chemotherapy. Median dose of RT was 60Gy, ranging from 40 to more than 70. The median interval in between completion of the RT and the lobectomy was 18 weeks, ranging from 8 to 111. The majority of these resections were done open though, to their credit, 6 were done VATS without conversion. There was no operative mortality and 48% patients experienced some complications, only a third of these being major. There were no post op bronchopleural fistulae (BPF) despite only a third of patients having their stumps covered: 30/31 achieved an R0 resection, 19/31 had viable tumor in the specimen as histological confirmation of recurrence / persistent disease was not mandated before resection. Median follow-up (f-up) was 26 months and the median OS was 60 months: 20 months if persistent tumor was present in the resected specimen. For the patients who went to salvage resection for recurrent disease (n=3: DFIs being 240, 300 and 700 days) the OS was 9 months, significantly less than the 26 months of those who had persistent disease after RT. The 5 y survival was 31%, 0 if N1-2 disease was present at resection or if salvage was done for relapse, but very small numbers… (1) In 2013, the Yale group reported on 14 patients in 6 years who underwent salvage resection for biopsy proven persistent/ recurrent T disease after definitive CRT. Most underwent lobectomies (9), 2 pneumonectomies. 36% underwent stump coverage. There was no mortality at 90 days, 43% experienced some complication, including 1 ARDS and I BPF. Median post op survival was 9 months, mean 2 year survival was 49%.(2) Bauman in 2008 reported on 24 patients in 8 years who underwent salvage resection after RT, mean dose of 64 Gy (59 to 70), 22 had received concurrent chemo. The interval from completion of RT to surgery ranged from 5 to 94 weeks (median 21). Most underwent lobectomies but 10 were pneumonectomies, including 4 right sided. 19/24 had stump coverage, 16 by omentopexy. Median OR time was 5.5 hours. There was one post op death due to ARDS, 58% experienced some complications, no BPF. 80% of specimen had viable tumor, 2 had R1 resections, 11/24 had N1-2. Median f-up was 29 months, median OS was 30 months, 43 months if PET information/changes led to salvage resection. The estimated 3 year survival was 47%: 2 patients had were found to have brain metastases within 2 months of the salvage resection, neither had had brain imaging in the re-evaluation leading to salvage surgery.(3) Personal opinion (4): the preoperative evaluation of such candidates should always include fresh CT PET, brain MRI and PFTs including a DCO as well as a quantitative perfusion scan as the possibilities of pneumonectomy are not insignificant in this population. Smoking cessation is mandatory. The location of the tumor at presentation also matters: it may be technically much more difficult to perform a lobectomy for centrally radiated lesions. Though not the topic at hand, in my experience, the technical challenges to salvage after SABR pale in comparison as usually the hilar structures are relatively intact after SABR. These surgeries can be challenging and I would encourage that one obtain as much information as possible upfront before going to resection. This includes that one attempt to obtain histological confirmation of viable cancer before undertaking these surgeries. We now know that after RT, particularly after SABR, the PET information may be falsely positive. Along the same lines, I will get EBUS sampling of the mediastinal and hilar lymph nodes before resection. If negative, I will add mediastinoscopy evaluation even in those who had mediastinoscopy at presentation. (5) Intraoperatively, you need to communicate with anesthesia that these patients do not tolerate excess IV fluid well at all as a result of having had their mediastinum radiated. We prepare/ harvest the intercostal muscle bundle at entry. Early circumferential control of the proximal PA and PVs early on is also favored… just in case. Intrapericardial access to the PVs often helps when the hilum is fibrosed, in such instances, open division of the lobar bronchus will often help accessing the lobar PA branches, particularly with the RUL. We cover all of our stumps with the prepared intercostal bundle. Post-operatively, IV fluid restriction remains a priority. Patients whose left hilar dissection was difficult are kept fasting until the left recurrent nerve function is evaluated or judged to be intact. Any concern prompts immediate laryngoscopic evaluation and temporary medialization of any suspicious “lazy” vocal cord follows. The literature on the topic is sparse and all retrospective but we can conclude from its review that: in experienced hands, such resections can be performed safely with acceptable morbidity, such resections, particularly if one is attempting to perform less than a pneumonectomy can be technically challenging and that selection of the patients who may benefit the most from such surgery is not easy. References: Yang CJ, Meyerhoff RR, Stephens SJ, et al. Long-Term Outcomes of Lobectomy for Non-Small Cell Lung Cancer After Definitive Radiation Treatment. Ann Thorac Surg 2015; 99:1914–20 Kuzmik GA, Detterbeck FC, Decker RH, et al. Pulmonary resections following prior definitive chemoradiation therapy are associated with acceptable survival Eur J Card-Thorac Surg 44 (2013) e66–e70 Bauman JE, Mulligan MS, Martins RG, et al. Salvage Lung Resection After Definitive Radiation (>59 Gy) for Non-Small Cell Lung Cancer: Surgicaland Oncologic OutcomesAnn Thorac Surg 2008;86:1632–9 Page B, Blitz M, Louie BE, et al. Pulmonary Resection of NSCLC can be performed safely following definitive chemoradiotherapy. Oral presentation 13th World Conference on Lung Cancer, San Francisco, CA August 1[st] 2009, J Thorac Oncol. 4(9) Supplement 1:S301, September 2009 Louie BE, Kapur S, Farivar AS, et al. Safety and Utility of Mediastinoscopy in Non-Small Cell Lung Cancer in a Complex Mediastinum, Ann Thorac Surgery 92(1): 278-83, 2011

Abstract:
A 70 year old retired insulator presented to the emergency room with progressive shortness of breath limiting his ability to complete his daily 5 mile runs. Physical examination reveals minimal breath sounds and dullness to percussion on the right side. The patient denies chest pain or weight loss. There is no history of cardiac disease and he is a never smoker. Family histroy reveals a brother with cured uveal melanoma. Chest radiography reveals a completely opacified right hemithorax. WBC is 7000, platelet count 245,000, and his HgB is 13.2 gms. A thoracentesis reveals 3.5 liters of serosanguinous fluid, and post thoracentesis radiograph reveals complete expansion. Fluid is sent for culture and cytology, and the patient is discharged to home with a 2 day supply analgesics. The culture report at 5 days reveals no growth and the cytology reveals atypical mesothelial hyperpplasia. Two months after his thoracentesis he returns to see his PCP with similar complaints of shortness of breath with exertion without chest pain. 1. What is the proper further management of this patient? 2. What is unusual about his family history, and what are the possible implications?

Abstract:
Malignant Pleural Mesothelioma: A patient with unresectable disease It is generally accepted that only a minority of patient are candidates for combined modality treatment. Surgery or radiation alone is not able to achieve a complete pathological control of the tumor. Therefore most patients have to be considered for a systemic treatment. Since the nineties of last century only a slow progress has been achieved with the advent of chemotherapy. Single agents were tried but failed to achieve durable responses and did not achieve response rates over 20%. It was until the beginning of the current century that a standard therapy was defined using platin and an anti-folate. The response rate was 30-35% and the median survival increased from 9 to 13 months. Unfortunately 80% of the patients succumbed to the disease in the 2 years after chemotherapy. The new approaches that are currently available can be grossly divided into a maintenance; immunological and signal-pathway approach. For the case presented to our tumor board it is the challenge to decide which treatment is the most successful with acceptable toxicity. The choice of treatment strongly depends on the patients’ characteristics since cure is not very realistic. The standard of treatment consists of the administration of 4-6 courses of (cis)platin with pemetrexed given every 3 weeks. MPM is well known to respond slowly to chemotherapy and ongoing responses can be seen even after 6 courses of therapy. This has lead to the idea of maintenance therapy. In line with the results in NSCLC one can choose to continue with single agent pemetrexed but to date no randomized study has addressed this issue. Switch maintenance is currently under study with different drugs. The most mature phase III study is with bevacizumab (MAPS study), which showed an improvement in survival in the combination arm. This randomized study showed a very high survival in the control arm of 16 months. The addition of bevacizumab increased the OS to 18.8 months with statistical significance. The full data have not yet been presented and selection of the very best patients might account for this success. An ongoing randomized phase II study with defactinib tests the effect in a maintenance setting. The drug inhibits the Focal Adhesion Kinase pathway, rendering cells susceptible for apoptosis and it reduces the stem cells after chemotherapy. The results are expected in 2016. Since the disease recurs within 1 year, often second line therapy is offered. In table 1 a summary of different approaches is presented. Besides different chemotherapy regimens, inhibition of signal transduction pathways or immunotherapy has been tested. Until now no chemotherapeutic agent or oral TKI has been identified as promising agent. Immunotherapy however, is now one of the new and perhaps most promising developments of this decade. In this particular anti-PD-1 monoclonal antibodies and antibody drug conjugates have shown interesting results in phase I setting. There are a few issues to be resolved in the near future: How to select the best drug for each patient. How to compare study results in patients with different pathology/biological characteristics With a relatively small number of patients per year we must not embark blindly in to large phase 3 studies. We must try to personalize the treatment by increasing our TR efforts. Pre- and post-treatment biopsies can help to identify promising drugs at an early stage. Pre-treatment cell cultures can help to improve the selection of patients who might be good responders to certain chemical compounds. And finally we must improve our collaboration between centers to offer optimal service to our patients. Table 1

Agent group	line	Recommended Agents	LoE	Remark
Chemotherapy	1	cis/pem	I	Standard since 2003 (1)
	2	pem; vin	II	pem showed improved PFS (2)
Maintenance	1	bev	I	Reported at ASCO 2015 (3)
TKI	2	none	-	Many tested; no conclusive results
Immunotherapy	2	Immunotoxins	III	Phase I study of pseudomonas toxin (4)
		a-CTL4; a-PD1	III	Trametinib now tested in maintenance setting in phase III; pembrolizumab showed promising results in phase I (5)

cis: cisplatin; pem: pemetrexed; vin: vinorelbine; bev: bevacizumab; a-CTL4: anti cytotoxic lymphocyte 4; a-PD1: anti-programmed death; LoE: level of evidence; PFS: progression free survival Selected references 1.Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. J Clin Oncol 2003;21:2636–44 2, Jassem J, Ramlau R, Santoro A, et al. J Clin Oncol 2008;26:1698-1704 3. Zalcman et al. pASCO 2015 4. Hassan R, Miller AC, Sharon E et al. Sci Transl Medicine. 2013;5(208):208ra147. 5. Alley E et al. pAACR 2015

Abstract not provided

Abstract:
The care of people with end-stage mesothelioma is complex due to the interplay of severe physical symptoms, intense psychological distress, and social factors related to mesothelioma being a fatal occupational disease. In comparison with people suffering from lung cancer, patients with mesothelioma experience more pain and greater negative impact on role and functioning and insomnia (1). Patients and family members should expect effective management of symptoms, support during the continuum of the illness and a rapid response to crisis. The high symptom burden experienced by patients with mesothelioma in the last year of life is shown in the table below (2):

Pleural mesothelioma: Symptoms in the last year of life
Breathlessness	96%	Social	16%
Pain	91%	Nausea	14%
Cough	41%	Fatigue	13%
Weight loss	41%	Dysphagia	11%
Anxiety	31%	Psychiatric	10%
Anorexia (loss of appetite)	25%	Constipation	8%
Depression	19%	Ascites	8%
Sweating	18%	Vomiting	5%
Emotional disturbance	16%	Painful metastasis	5%

Patients with incurable disease deserve and need to receive clear information and to share in the decision-making about each stage of their cancer journey. Once oncological treatments are exhausted, healthcare professionals hold the responsibility for helping patients and their families shift their expectation from “cure” to palliation of symptoms. A care plan for a good death needs to be sensitively eased into the clinical discussions, taking into account each individual patient’s preferences (3). In rare diseases such as mesothelioma a feeling of isolation tends to overwhelm the patient and their family. Unlike most cancers mesothelioma has an explained occupational and/or environmental cause. In many cases understanding that the fatal illness was caused by asbestos exposure due to neglect of health and safety precautions at work can lead to blame, anger, depression and inability to cope. The complicated processes concerning claims for welfare benefits and civil compensation litigation often exacerbate this psychological distress. Meeting the care needs of patients and their families in this situation requires a compassionate and specialised multi-disciplinary approach. Expert timely supportive and palliative care can address the burdens associated with advanced disease and guide the patient and family in accepting and planning for a good death. Transition to focus care on the family during the grief process completes the cycle in the care of the mesothelioma patient and family. Panel discussion will include the following areas: · Advanced education and the expanded role of a nursing team solely focused on mesothelioma (4). · The roles and availability of on-line, in person and telephone support groups · The need for early referral into palliative, supportive and hospice care References 1. Nowak AK, Stockler MR, Byrne MJ (2004) Assessing quality of life during chemotherapy for pleural mesothelioma: feasibility, validity, and results of using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Lung Cancer Module. J Clin Oncol. Aug 1;22 (15):3172-80. 2. Clayson H (2007) Thesis: The Experience of Mesothelioma in Northern England. University of Sheffield. Available online at etheses.whiterose.ac.uk/1775/ 3. Pass HI, Hesdorfer M, Lake SE, Lake SA. (2012) 100 Questions and Answers about Mesothelioma. Third Edition 4. Moore S, Darlison L (2011) Improving the nursing care of patients with mesothelioma. Nurs Stand May 25-31;25(38):35-8

Abstract not provided

Abstract:
The optimal management of locally advanced NSCLC is discussed controversially and depends from various aspects including the extend of N2 disease and/or T-stage as well as the patients risk profile and preference and the institutional experience. Therefore existing guidelines need a balanced modification during the tumorboard taking into account the different aspects relevant for the patient’s outcome and hence to define the best individualized treatment. Due to the lack of fully convincing randomized trials and the diversity of phase II studies and especially the heterogeneity of the study population, it is not surprising that the available evidence is interpreted differently and discussed controversially. Survival data may differ widely between studies and an explanation is often elusive. Patient selection is among other factors the key for differences in outcome. Unfortunately N2 disease is often imprecisely described. Several authors have proposed that N2 disease should be divided into subgroups. The question, whether N2 disease is resectable, cannot be answered easily in borderline situations since several co-founding factors play a role. The question includes at least four different aspects. The first aspect is resectability. The surgeon has to answer if the affected lymph nodes are completely removable. This question is a prerequisite and is typically answered by analysing images especially the CT or PET/CT by an experienced surgeon. The second and even more critical aspect relates to the question if local resection is useful for the patient since N2 disease may be the tip of an iceberg and indicate more than just locally advanced disease and rather a disease with systemic spread of tumor cells to other organs. The third aspect is the response rate of the tumor and mediastinal lymph nodes to neoadjuvant chemo- or chemo-radiotherapy. Finally the fourth consideration has to take into account the risk benefit ratio for the patient regarding the treatment. It is relevant for the decision making to evaluate to what risk the patient is exposed when a lobectomy or pneumonectomy is performed after neoadjuvant therapy. There are subgroups in stage IIIA (N2) which can be defined in which treatment recommendations are agreed among most oncologists, surgeons and radiotherapists. Microscopic N2 found unexpectedly during surgery and a radical resection of the tumor as well of the lymph nodes is possible and tolerated by the patient, surgery should be completed and adjuvant therapy is recommended. On the other hand in cases of bulky multilevel N2 at initial diagnosis and especially persistent after neoadjuvant therapy, surgery is not generally indicated since the patient will not experience a profit. The main controversy occurs in cases with initially diagnosed N2 disease at either a single or in some adjacent stations but surgically resectable. These patients are recommended to undergo neoadjuvant chemo- or chemo-radiotherapy followed by surgery most cases but direct surgery followed by adjuvant treatment is justified in single station N2 without extranodal disease. Definitive chemo-radiotherapy is reserved for those who are not completely resectable or with a high perioperative mortality. In general, these patients require a lobectomy with a complete mediastinal lymphadenectomy. In locally advanced stages, many surgeons still prefer to do these operations though a thoracotomy and in only a smaller percentage of patients can be operated minimal invasively by VATS. The invasiveness of the approach (VATS or open) is in any case of less importance than the completeness of the resection. Pneumonectomy should be avoided whenever possible and reconstructive techniques with bronchial-and or vascular reconstructions (sleeve resections) should be considered. These techniques can be done safely, even after induction chemo-or chemoradiotherapy. However, there are clear situation, when a pneumonectomy is necessary to achieve a complete resection and this should be considered, when the patient tolerates it functionally. Treatment of patients with locally advanced lung cancer is a challenge and requires the expertise of specialists from each discipline who respect the benefit and limitations of each individual technique in order to define the best individual treatment.

Abstract:

Abstract:
Overview Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with regard to tumor extent, prognosis and treatment options. Surgery is indicated in some patients, but the majority of patients receive radiotherapy and chemotherapy alone. The standard of care for unresectable stage III NSCLC patients with a good performance status consists of concurrent chemoradiation. The chemotherapy regimen usually consists of a platinum doublet and radiation doses of at least 60 Gy is standard. The prognosis for these patients remains dismal with a median survival time of 15-22 months and the need for improved treatment approaches is urgent. The optimal choice of chemotherapy and radiation dose and the schedules for these have been under investigation but is still not clearly defined. Radiation dose escalation studies have not resulted in better outcomes and with potentially harmful effects. Clinical studies of targeted agents in unselected patient groups, including therapies against epidermal growth factor receptor (EGFR) and angiogenic factors, have not been successful. The recent advances in molecularly targeted therapies together with technological advances in radiotherapy opens up for novel treatment strategies with potentially improved outcomes and less toxicity. This presentation will give an overview of randomized studies incorporating new approaches to combined modality therapy in stage III disease, including immune therapy with PD-1/PD-L1 inhibitors, inhibitors of EGFR and ALK as well as proton radiotherapy.

Abstract:
There is general agreement amongst biomedical researchers that stem cells exist in multicellular organisms. The most well characterized model of adult somatic stem cells is the bone marrow, in which serial transplantation in both immunocompetent and immunodeficient mice have clearly identified the hematopoietic stem cell (HSC). Using the same models, it is now generally accepted, even amongst cancer stem cell (CSC) sceptics, that most forms of myeloid leukemia are maintained by a self-renewing, transplantable HSC-like cell, even though the initial transformation event may have occurred in a committed progenitor. Given that nature tends to conserve processes across evolution, it is logical to hypothesize that a similar functional hierarchy exists in solid tumors. Over two decades, numerous papers have reported the presence of a functionally distinct, rare population of cells within solid tumors with stem-like properties based on the same criteria used to define the HSC and leukemic CSC. However, the idea that CSCs exist solid tumors remains controversial at best. The difficulties in reproducing results in highly complex models systems, and questions over the validity of CSC surface markers in solid tumors, have clearly contributed to these, often heated, arguments. If we assume for a moment that CSCs do not exist in solid tumors, they would constitute the only multicellular entity in nature without a hierarchical organisation based on self-renewal and differentiation. If this were true, then solid tumors would behave like colonies of bacteria or yeast, in which all cells were identical, where the capacity to self-renew in the face of an environmental challenge would be entirely determined by random genetic variants. In the setting of acquired resistance to targeted therapies, there is convincing evidence for such a “rare clone” hypothesis. For example, the source of acquired resistance to tyrosine kinase inhibitor (TKI) therapy in EGRF-mutant adenocarcinoma seems to be pre-existing clones that already possess a point mutation that confers resistance. But, can this genetic model explain other stemness phenotypes in non-small cell lung cancer (NSCLC)? In clinical terms, a pressing question is whether random genetic events can explain the rapid regeneration of NSCLC tumors after a long period of dormancy following curative surgery. Equally, can the “rare clone” hypothesis explain innate the innate chemoresistance of quiescent CSC-like NSCLC cells that have a greatly enhanced capacity for self-renewal. If the answer to either of questions is “not always”, then targeting CSCs based on function rather than genome remains a potential avenue for improving outcomes in NSCLC patients. The characterization of NSCLC CSCs is made difficult by the phenotypic and genomic heterogeneity of the disease, problems identifying robust surface markers, and in defining what experimental endpoints constitute CSC function. In addition, there is no general agreement on which markers are associated with CSC in NSCLC, although several studies suggest that the surface markers CD44 and CD133 can prospectively identify such cells. In therapeutic terms, elimination of CSCs in NSCLC would require such markers be reproducible and robust, but can also be therapeutically targeted in humans. An alternative approach is to target embryonic signaling pathways known to regulate self-renewal in development. This idea is the driving force behind clinical trials of Notch and Hedgehog inhibitors in several cancer types. Unfortunately, most of these clinical trials add the experimental agent along side standard-of-care chemotherapy rather than delivering the experimental agent following treatment in order to determine whether stem-cell targeting can “burn out” quiescent, undifferentiated residual disease. One promising candidate marker in NSCLC is ALDH1. In most published studies, expression of ALDH1 or ALDH1A correlates with reduced overall survival, consistent with the presence of enhanced regenerative capacity and innate chemoresistance in NSCLC. Moreover, experimental evidence supports the notion that expression of the ALDH1 protein, and its enzymatic activity, is associated with enhanced CSC functions in vitro and in vivo. Since secondary prevention studies in advanced NSCLC are impractical, it may be possible strengthen the case for targeting NSCLC, using ALDH1 as an example, using more practical preclinical and clinical approaches. Such an approach might be: 1. Concentrate on one subgroup of NSCLC- for example KRAS mutant lung adenocarcinoma. 2. Show that rare, single ALDH1+ cells give rise to tumors with the same ratio of ALDH1+ to ALDH1- cells as was seen in the parent tumor. 3. Using single cell genomics, determine whether ALDH1+ and ALDH1- cells share the same genotype. 4. In lung cancer patients treated with neoadjuvant chemotherapy, show that the percentage of ALDH1+ cells increases in the residual tumor removed at surgery. 5. In lung cancer patients with recurrent disease following surgery, show that the recurrent tumor contains the same ratio of ALDH1+ to ALDH1- cells as was seen in the parent tumor. References: Jordan CT. Cancer stem cells: controversial or just misunderstood? Cell Stem Cell, 2009; 4:203-5. Alamgeer M, Peacock CD, Matsui W, Ganju V, Watkins DN. Cancer stem cells in lung cancer: Evidence and controversies. Respirology, 2013; 18:757-764 Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, Schuster K, Shao C, Larsen JE, Sullivan LA, Honorio S, Xie Y, Scaglioni PP, DiMaio JM, Gazdar AF, Shay J, Wistuba II, Minna JD. Aldehyde Dehydrogenase Activity Selects for Lung Adenocarcinoma Stem Cells Dependent on Notch Signaling. Cancer Res, 2010; 70:9937-48. Shao C, Sullivan JP, Girard L, Augustyn A, Yenerall P, Rodriguez-Canales J, Behrens C, Shay JW, Wistuba II, Minna JD. Essential Role of Aldehyde Dehydrogenase 1A3 for the Maintenance of Non–Small Cell Lung Cancer Stem Cells Is Associated with the STAT3 Pathway. Clin Cancer Res; 2014; 20:4154–66. Alamgeer M, Ganju V, Szczepny A, Russell PA, Prodanovic Z, Kumar B, Wainer Z, Brown T, Schneider-Kosky M, Conron M, Wright G, Watkins DN. The prognostic significance of ALDEHYDE DEHYDROGENASE 1A1 (ALDH1A1) and CD133 expression in early-stage non-small cell lung cancer. Thorax, 2013; 68(12):1095-104. Alamgeer M, Ganju V, Kumar B, Fox J, Hart S, White M, Harris M, Stuckey J, Prodanovic Z, Schneider M, Watkins DN. Changes in ALDEHYDE DEHYDROGENASE-1 (ALDH1) expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer. Breast Cancer Res, 2014; 16:R44.

Abstract not provided

Abstract:
Lung cancer is a dismal disease, however, anticipated selective responses are observed in a subgroup of non-small cell lung cancer (NSCLC) patients where the disease is driven by epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur in 15 – 40% of lung adenocarcinomas, according to gender, smoking history and geographical region. Two types of EGFR mutations account for 90% of all lung adenocarcinoma-associated EGFR mutations and are related to sensitivity to treatment with oral tyrosine kinase inhibitors (TKIs), such as gefitinib, afatinib or AZD9291: (i) small in-frame deletions in exon 19 that lead to elimination of an LREA motif in the protein (DEL) and (ii) a point mutation in exon 21 that substitutes an arginine for a leucine at position 858 in the protein (L858R). Lung cancer patients bearing EGFR mutations show radiographic responses to TKIs in 60 – 70% of cases. Although the majority of patients achieve a significant therapeutic benefit, almost all invariably progress in less than 1 year. Therefore there is an unmet medical need for novel therapies in order to avoid resistance to treatment. We have employed a wide array of approaches (MTT, western blot analysis, PCR, Aldefluor assay and mouse models) to demonstrate that the combination of gefitinib, afatinib or AZD9291 with compounds targeting signal transducer and activator of transcription 3 (STAT3) can suppress the mechanisms of early adaptive resistance. STAT3 is a member of a family of proteins responsible for transmission of peptide hormone signals from the extracellular surface of the cells to the nucleus. STAT3 is a master regulator of several key hallmarks and enablers of cancer cells, including cell proliferation, resistance to apoptosis, metastasis, immune evasion, tumor angiogenesis, epithelial-mesenchymal transition, response to DNA damage and the Warburg effect. In addition STAT3 promotes an increase in the cell renewal of tumor-initiating cells or cancer stem cell subpopulation, mainly aldehyde dehydrogenase (ALDH). EGFR mutations cause receptor oligomerization and activation of intrinsic or receptor-associated tyrosine kinases, respectively. These activated kinases phosphorylate receptor tyrosine residues creating docking sites for recruitment of cytoplasmic STAT3. STAT3 docks to receptor phosphotyrosyl (pY) peptide sites through its Src-homology (SH2) domain which leads to its phosphorylation on Y705 followed by STAT3 tail-to-tail homodimerization (SH2 domain of each monomer binds to the pY peptide domain of each partner). STAT3 homodimers accommodate in the nucleus, where they bind to specific STAT3 response elements in the promotor of target genes and regulate their transcription. EGFR mutations and tyrosine kinase-associated receptor interleukin-6 (IL-6) lead to the activation of STAT3 that is not obliterated by EGFR TKIs. Even more, 2 hours after starting gefitinib treatment there is an increase in STAT3 activation in EGFR mutant cell lines (P. Ma, Cancer Research, 2011). Moreover, following erlotinib treatment there is an enrichment of ALDH+ stem-like cells through EGFR-dependent activation of Notch3. We have tested several small molecules that target STAT3. The combination inhibits cell viability in several human EGFR mutant cells and blocks STAT3 activation. However, neither the combination of EGFR TKIs with TPCA1 (repurposed as a STAT3 inhibitor), nor the combination of gefitinib with AZD0530 (a Src inhibitor) prevent the increment in the ALDH + cancer stem cell subpopulation. Therefore, we are exploring more in depth the crosstalk between EGFR and IL-6. As a whole, human EGFR mutant cell lines have increased levels of IL-6 which leads to STAT3 hyper-activation. Nevertheless, recent evidence indicates that IL-6-Src can induce YAP activation and NOTCH signaling. The downstream effectors of YAP and NOTCH ligands CTGF and HES1, respectively, are being examined in clinical tumor samples. We have examined the combination of Src, YAP and NOTCH inhibitors in addition to the use of STAT3 inhibitors. The triple combination of gefitinib plus TPCA1 plus AZD0530 had great synergism with a very low combination index and also eliminated the ALDH+ population (Figure). Furthermore, the overexpression of ALDH1A1 was decreased with the triple combination, however with only gefitinib plus TPCA1 or gefitinib plus AZD0530, ALDH1A1 mRNA was substantially increased in comparison with gefitinib alone (Figure). The western blot for the triple combination shows the inhibition of STAT3 Y705 phosphorylation as well as the phosphorylation of YAP (Ser397) and also from BMI1. We plan to confirm some of the data in clinical tumor samples to understand the contribution of IL6 and well established effectors-the SHP2-ERK, PI(3)K-Akt-mTORC1 and JAK-STAT3 modules and the interaction with YAP. Figure 1

Abstract:
Our long-term goal is to elucidate the role of stem cells in lung homeostasis as a prerequisite to the development of therapeutic strategies that can be used to prevent or attenuate lung disease and lung cancer. Our previous experience isolating the first stem cell population from the adult murine lung, termedbronchioalveolar stem cells (BASCs), and our demonstration of a role for these cells in lung cancer serves as a platform to address these questions. We have recently developed three-dimensional co-culture and subcutaneous co-injection assays that allow us to quantitatively assess the identity and the differentiation potential of lung stem cells. This approach led us to uncover a cross-talk between lung endothelial cells and lung stem cells via a novel signaling axis involving Bmp4, NFATc1 and Tsp1;this pathway drives BASCs to differentiate into the alveolar epithelial cell lineage. Our work in the intersection of stem cell biology and lung disease has expanded into new insights for understanding metastasis and non-small cell lung cancer (NSCLC). We previously showed the adenocarcinoma Kras/p53 mutant mouse model contains Sca1+ tumor-propagating cells (TPCs), the cells that recapitulate the tumor by transplantation. We recently showed multiple lung tumor sub-populations can give rise to metastatic disease, and that the Sca1+ CD24+ TPCs have the highest metastatic potential. We also showed the Hippo pathway mediators Yap/Taz are necessary andsufficient for lung cancer progression. Finally, in a new mouse model of lung squamous cancer, the second most common type of NSCLC, we identified a TPC population defined by the markers Sca1 and NGFR. These studies illustrate the utility of stem cell biology approaches to provide new avenues for lung cancer therapeutic targeting.

Abstract:
DNA methylation changes in lung cancer: Defining functional events and use of cancer specific changes for early detection. Epigenetic alterations in lung cancer represent early changes which are associated with tumor initiation and progression. Alterations in DNA methylation include the global loss of DNA methylation in non-promoter region and selective CpG island promoter region methylation leading to gene silencing. Previous studies have focused on individual loci identified through candidate gene approaches. However, recent improvements in technology allow the assessment of genome wide patterns of DNA methylation. The comprehensive genome wide analysis of molecular changes in cancer completed by The Cancer Genome Atlas (TCGA) includes determination of DNA methylation using the Illumina Infinium 450K array. Initial analyses have primarily focused upon defining methylation subtypes. However, this data can be used to determine novel cancer specific events which are associated with transcriptional silencing to identify candidate driver epigenetic alterations. New promoter region DNA methylation changes leading to transcriptional silencing are found in multiple signaling pathways critical for lung cancer development. In addition, a search for common tumor specific DNA methylation provides new markers for early detection strategies. These novel biomarkers can be combined with novel methods developed with extremely sensitive assays for the detection of hypermethylated DNA sequences. By combining these more sensitive methods of detection with highly prevalent methylation changes in lung cancer, utrasensitive detection of tumor specific changes in DNA methylation in blood and sputum samples is possible. This molecular detection can complement CT screening to address the important issue of early detection of lung cancer.

Abstract:
I will discuss opportunities and future directions in profiling lung cancer using mass spectrometry based proteomic technologies. This includes a proposal to perform deep integrated proteo-genomics studies on cancer subtypes to produce more complete views of the tumor architecture, allow contextual understanding of major drug targets, and discover new lung cancer subtypes. Alterations in the genomes of cancers ultimately get integrated and produce a cancer proteome that can be analyzed using modern state of the art mass spectrometry proteomic tools. For example, signaling pathways and networks involved in cancers are built using a ‘parts list’ of the cancer genome, such as through integrating mutated genes, genes altered through differential expression (i.e. copy number gain or loss), and through regulation by micro-RNA molecules. DNA sequencing-based atlases exist for major tumors allowing ‘part lists’ for cancers; however, these atlases lack integration with expressed proteomes and signaling architectures. By taking into account all these alterations in the cancer genome, cancer proteomics can annotate and prioritize proteins and pathways important for cancer growth and survival. Furthermore, microenvironmental influences, known to be important in drug response, are lacking from these DNA based studies. Proteomics can inform about active pathways driving cancers and lead to novel combination therapy approaches for targeting complex oncogenic networks. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is increasingly used to study cancer proteomes. This includes examining the ‘expressed proteome’ through shotgun proteomics, global signaling by annotating key post-translational events (phosphorylation, acetylation, ubiquination) events in cancers or assembling protein-protein interaction data that yield network views of cancer. This allows unbiased and global views of signaling events in cancer thus offering complementary views of cancer biology that are not considered by sequencing of genes or gene expression. By integrating DNA-RNA-proteome-network type data, the co-existing driver processes instilled by the genome that either surround or act in parallel to drug targets can be mapped directly onto cancer molecular machines that drive cancer progression and response to therapy. Discovery proteomics has become a widely used tool in our laboratory. This approach provides an unbiased view of the components in a sample, supporting the testing of multiple hypotheses and generating new leads. I will discuss examples integrating complementary mass spectrometry approaches to build molecular snapshots of cancer proteomes, including phosphoproteomics in tumors related to drug resistance (1, 2), drug affinity selection of proteins and identification of drug targets using mass spectrometry (3-6), and protein-protein interaction mapping(7-9). Literature Cited: 1. Yoshida T, Zhang G, Smith MA, Lopez AS, Bai Y, Li J, Fang B, Koomen JM, Rawal B, Fisher KJ, Chen YA, Kitano M, Morita Y, Yamaguchi H, Shibata K, Okabe T, Okamoto I, Nakagawa K, Haura EB. Tyrosine phosphoproteomics identified both co-drivers and co-targeting strategies for T790M-related EGFR-TKI resistance in non-small cell lung cancer. Clin Cancer Res. 2014. doi: 10.1158/1078-0432.CCR-13-1559. PubMed PMID: 24919575. 2. Bai Y, Kim JY, Watters JM, Fang B, Kinose F, Song L, Koomen JM, Teer JK, Fisher K, Chen YA, Rix U, Haura EB. Adaptive Responses to Dasatinib-Treated Lung Squamous Cell Cancer Cells Harboring DDR2 Mutations. Cancer Res. 2014;74(24):7217-28. doi: 10.1158/0008-5472.CAN-14-0505. PubMed PMID: 25348954. 3. Remsing Rix LL, Kuenzi BM, Luo Y, Remily-Wood E, Kinose F, Wright G, Li J, Koomen JM, Haura EB, Lawrence HR, Rix U. GSK3 alpha and beta are new functionally relevant targets of tivantinib in lung cancer cells. ACS Chem Biol. 2014;9(2):353-8. doi: 10.1021/cb400660a. PubMed PMID: 24215125; PubMed Central PMCID: PMC3944088. 4. Gridling M, Ficarro SB, Breitwieser FP, Song L, Parapatics K, Colinge J, Haura EB, Marto JA, Superti-Furga G, Bennett KL, Rix U. Identification of kinase inhibitor targets in the lung cancer microenvironment by chemical and phosphoproteomics. Mol Cancer Ther. 2014;13(11):2751-62. doi: 10.1158/1535-7163.MCT-14-0152. PubMed PMID: 25189542; PubMed Central PMCID: PMC4221415. 5. Li J, Rix U, Fang B, Bai Y, Edwards A, Colinge J, Bennett KL, Gao J, Song L, Eschrich S, Superti-Furga G, Koomen J, Haura EB. A chemical and phosphoproteomic characterization of dasatinib action in lung cancer. Nat Chem Biol. 2010;6(4):291-9. doi: 10.1038/nchembio.332. PubMed PMID: 20190765; PubMed Central PMCID: PMC2842457. 6. Chamrad I, Rix U, Stukalov A, Gridling M, Parapatics K, Muller AC, Altiok S, Colinge J, Superti-Furga G, Haura EB, Bennett KL. A miniaturized chemical proteomic approach for target profiling of clinical kinase inhibitors in tumor biopsies. J Proteome Res. 2013;12(9):4005-17. doi: 10.1021/pr400309p. PubMed PMID: 23901793; PubMed Central PMCID: PMC4127982. 7. Smith MA, Hall R, Fisher K, Haake SM, Khalil F, Schabath MB, Vuaroqueaux V, Fiebig HH, Altiok S, Chen YA, Haura EB. Annotation of human cancers with EGFR signaling-associated protein complexes using proximity ligation assays. Sci Signal. 2015;8(359):ra4. doi: 10.1126/scisignal.2005906. PubMed PMID: 25587191. 8. Li J, Bennett K, Stukalov A, Fang B, Zhang G, Yoshida T, Okamoto I, Kim JY, Song L, Bai Y, Qian X, Rawal B, Schell M, Grebien F, Winter G, Rix U, Eschrich S, Colinge J, Koomen J, Superti-Furga G, Haura EB. Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms. Mol Syst Biol. 2013;9:705. doi: 10.1038/msb.2013.61. PubMed PMID: 24189400; PubMed Central PMCID: PMC4039310. 9. Haura EB, Muller A, Breitwieser FP, Li J, Grebien F, Colinge J, Bennett KL. Using iTRAQ combined with tandem affinity purification to enhance low-abundance proteins associated with somatically mutated EGFR core complexes in lung cancer. Journal of Proteome Research. 2011;10(1):182-90. Epub 2010/10/16. doi: 10.1021/pr100863f. PubMed PMID: 20945942; PubMed Central PMCID: PMC3017669.

Abstract not provided

Abstract:
Study of genomics, epigenomics and proteomics may contribute to an understanding aetiology, prevention, early diagnosis, classification, treatment selection, and novel trial design in lung cancer. The clinical material available for analysis ranges from tumour biopsy to pleural fluid, bronchoalveolar lavage, saliva and even urine. The available techniques are in many cases sensitive (including PCR and mass spectrometry (MS)), and specificity can be optimised especially with reference to normal material such as germline DNA. The omic landscape of lung cancer has been extensively characterised (The Cancer Genome Atlas Research Network, 2014). This provides insight into disease biology via SNP/exome/whole genome sequencing, CpG DNA methylation, mRNA sequencing and protein expression profiling. Epigenomics is a key component since promoter hypermethylation occurs an early event in lung tumourigenesis (Belinsky, S. et al. 2015), targeting tumour suppressor genes. Indeed epigenomics and genomics are intimately linked, with CpG methylation leading to base substitution through 5-methylcytosine deamination, and enhancing the effect of exogenous carcinogens. Although the contribution of smoking to lung cancer aetiology has long been recognised, genomics is now providing insight into somatic mutagenesis as the mechanism of this causal interaction, as well as into tumourigenesis in non-smokers. However, this wealth of genetic and epigenetic information requires further analysis to establish which of these events really drive the phenotype, and which can be biologically validated as targets for therapy. Both genetic and epigenetic targets for therapy of lung cancer have been identified, in the form of both activated oncogenes and loss of tumour suppressor gene function. In some cases tumour genotype proves valuable as a predictive biomarker for patient selection. Several current biomarker-directed trials (such as Lung-MAP and MATRIX) are seeking to identify further successful genotype/therapy pairings. Despite impressive response rates in genomically stratified populations, regulators seem still to require validation of omics-driven treatment selection in a strategy-testing design, randomising to standard of care or personalised therapy. A further therapeutic application of genomics is characterisation of resistance mechanisms, an understanding of which has already led directly to next generation drugs in several drug classes including inhibitors of EGFR and ALK. It is genetic events that are at the origin of the hallmarks of cancer, but proteins, as the effectors of cellular processes, are key to a full understanding of the cancer phenotype. Some have argued that proteomic markers, as a surrogate for the genetic drivers, may be inferior to genomics. Certainly proteomic biomarkers are the less dynamic because their half life is measured in weeks, compared with a few hours for nucleic acids. Beyond the small number of actionable mutations already described in non-small cell lung cancer, the diagnostic, prognostic, and predictive potential of a large number of omic markers has been studied, and in most cases problems with reproducibility have limited their clinical impact. Indeed the utility of multi-gene predictive markers described to date, most likely to be of clinical value in therapy, is limited. An eight-peak MALDI-MS proteomic profile has been developed as a predictive tool (Taguchi, F. et al. 2007). Long suspected, the contribution of tumour heterogeneity to an analysis of tumour omics is now proven to be potentially problematic (Bedard, P. et al. 2013). The study of circulating genomic (eg circulating free DNA, cfDNA) and proteomic tumour markers provides an opportunity for integration of this heterogeneity. Nevertheless, further questions remain. For example, do primary and metastatic sites release similar amounts of DNA and protein into the circulation? However, potential advantages of these liquid biopsies are obvious, as they can be repeated over time without risk or inconvenience to the patient. Still to be fully clarified is the clinical utility of this approach. Possible applications include early discontinuation of toxic failing therapy, evaluation of an emerging resistance mechanism and selection of next therapy, and prognostication (for example, selection for adjuvant therapy). Earlier liquid biopsy methods required initial analysis of potential biomarkers in a tumour, to identify what to look for, followed by detection of this marker in blood samples. This approach requires personalisation for each patient. Newer techniques allow direct analysis, for example next generation sequencing of cfDNA. It is also possible to study the methylation status of cfDNA, so these liquid biopsies may in addition be relevant to the study of tumour epigenomics. cfDNA may be superior to circulating tumour cells (CTCs) as a biomarker since in some patients cfDNA but not CTC is detectable (Bettegowda, C. et al. 2014) The most prominent recent therapeutic advance in lung cancer is the validation of immunotherapy in the context of checkpoint inhibition. While this approach appears to target the tumour only indirectly, via host immunity, there is already good evidence that the genomic context of the target tumour is critically significant (Gubin, M. et al. 2015) The optimum strategy for selection of patients for clinical omic testing remains to be finalised. Should this be for all patients, from the time of diagnosis, or only after completion of standard care? And what material is ideal for testing (archival or contemporaneous biopsy, for example)? Guidelines on what, when and how to test are available (Lindeman, N. et al. 2013), but this advice quickly becomes out of date given the pace of change in the field. Further practical concerns include access to technology, turnaround time for testing, interpretation of molecular pathology results and bioinformatics, and clinical relevance. Fundamental questions arise about which changes are actionable, and the importance of any findings in the germline sequence (incidental or deleterious). Finally, quality control and regulation of omic technologies is demanding and not necessarily well served by existing approaches and infrastructure (Evans, B. et al. 2015), and these aspects must be developed alongside the emergence of these novel technologies. Progress in development of these techniques has been rapid, but maximum utility to patients is still to be developed. Omics have made major contributions to the understanding of lung cancer biology, and to the identification of a growing spectrum of therapeutic targets, but more work remains to be done. References Bedard, P et al. (2013). Tumour heterogeneity in the clinic. Nature 501; 355-364 Belinsky S, et al. (2015). Gene promoter methylation in plasma and sputum increases with lung cancer risk. Clin Cancer Res 11; 6505-11 Bettegowda, C et al. (2014). Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6, 224ra24 Evans, B et al. (2015). The FDA and genomic tests - getting regulation right. New Engl J Med 372; 2258-2264 Gubin, M et al. (2015). PD-1 blockade in tumors with mismatch-repair deficiency. New Engl J Med 372; 2509-2520 Lindeman, N et al. (2013). Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. J Thoracic Oncol 8; 823-59 Pastor, M et al. (2013). Proteomic biomarkers in lung cancer. 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