Virtual Library

Abstract
Salvage surgery after Radiation: Residual Tumor and Complications Definitive chemoradiotherapy is increasingly used in the treatment of patients with stage III non-small-cell lung cancer. Historically, local control and overall survival rates have been poor. To improve local control higher doses of radiotherapy are being investigated, with or without new chemotherapeutic agents. Dose-escalation appears to provide a modest benefit in terms of preventing local failure and improving overall survival, but the benefit comes at a price: The risk of both early and late toxicity appears to increase as well. Despite improved treatment remnants of vital tumor often persist. In many patients this has no clinical significance because prognosis is determined by the occurrence of distant metastases. However, some tumors do not metastasize and local recurrence becomes a problem. These patients are then referred for possible surgical resection. Because of this possibility of isolated local recurrence, doctors Increasingly perform early re-staging procedures after definitive chemoradiotherapy. In case of persistent tumor patients are referred for resection as “late-induction cases”. Another category consists of patients presenting with complications caused by high-dose irradiation. These late sequalae of radiotherapy are: bronchial stenosis, fatal haemoptysis, esophageal stenosis, fistula’s, cardiac complications and the occurrence of 2nd primary tumors. They may occur as early as 3 months, but an interval of one or more years is not uncommon (1) Some of these complications, such as fistula’s or bronchial stenosis , require urgent surgical correction, due to their severe symptoms. Late surgical resection in irradiated patients has been described with good success (2). However, the impaired wound healing capacity of irradiated tissue makes surgery hazardous and the liberal use of non-irradiated tissue flaps is recommended. We describe our experience of surgical correction of late complications after concurrent chemoradiotherapy: Fistulae: A tracheo-esophageal fistula or broncho-esophageal fistula is best treated by esophageal resection and tube-stomach replacement, because the esophagus is often stenotic and mere interposition of a muscle flap between airway and esophagus will not suffice. Stenosis: Bronchial stenosis requires resection, but re-anastomosis carries a high risk of dehiscence. We have seen two cases of dehiscence after 6 and 8 weeks, after the sutures had been absorbed, in spite of wrapping the suture line with an intercostal muscle flap. Tracheomalacia requiring temporary stenting has also occurred following partial tracheal resection. Hemoptysis: Necrosis and cavitation of an irradiated area may be complicated by a fungal infection (aspergillus), causing haemoptysis. These patients, who are often weak and malnourished, are treated by a staged procedure: First thoracic wall fenestration for adequate drainage of the infectied area together with insertion of a gastrostomy or jejunostomy catheter for nutritional support. We try to avoid nasogastric tubes in these patients, to avoid aspiration. At a second stage the cavity is filled with a pedicled muscle flap. Depending on the size and location of the cavity, a partial thoracoplasty is also performed. The interval between the two operations should be limited if the cavity extends towards the hilum, because erosion of a vessel wall may cause fatal hemorrhage. New treatments for lung cancer create new situations for the thoracic surgeon. Good skill, knowledge of old techniques such as thoracoplasty and the use of muscle flaps, and emphasis on nutritional support are mandatory to solve these problems.

Abstract
Managed care system, public accountability, cost containment, pay-for-performance and ranking culture demand Quality of care to be monitored through appropriate instruments. Outcome endpoints (i.e. morbidity and mortality) are still the most widely used quality indicators in thoracic surgery. Outcomes however should be reported in the most correct way to prevent risk-averse behaviours and misleading information. They need risk-adjustment, as different case-mixes at different institutions may influence outcome and those units operating on older and sicker patients would be penalized without an appropriate risk-adjustment. Therefore, risk-modelling must become the logical and necessary approach for provider profiling and comparative audit. The most important tool of any quality assessment endeavour is a database that is made up of a representative sample of the study group of interest. The gold standard for data should be a specialty-specific, procedure-specific, prospectively maintained, periodically audited, electronic database that contain, at the minimum, a core set of variables that has been demonstrated to be associated with outcome. The practical steps that should be planned and possibly recorded to construct a solid clinical database are a clear definition of the data sources and the creation of a list of variables (and their definitions) that will constitute the database. These steps will permit that 1) the database can be used even by subjects that did not participate to its construction, 2) the database can be audited by external data managers to assess quality of data, 3) changes in data collection or variables recording may be adequately planned. The importance of the source and the quality of data cannot be overemphasized enough. Most of the data that are of clinical interest derive from clinical records or other attached documents, such as laboratory exams or PFTs. One of the most critical aspects of the database construction is the extraction of the data from the medical record to the database. Wherever possible, data should be entered in real time, at the point of capture; to this end a networked database should be accessible in the operating theatre, the ward, the clinic and the multidisciplinary team meeting room. When possible this data should be used to generate documents such as operation notes, MDT report, correspondence, so that data capture becomes integral to routine patient care. The person in charge of capturing or transferring data into a database should be properly qualified and adequately trained. A Clinical Audit Lead should be selected within each unit who will be responsible for the accuracy and quality of data collection. The data should be periodically checked for discrepancies, inconsistencies, missing values, in order to ensure a high quality database. In fact no model or predictive equation can be better than the data upon which it is based. If any underperformance in data collection would be detected this should be reported to all persons involved in the process of data recording with the final objective of continuously improving the quality of the database. The European Society of Thoracic Surgeons (ESTS) appointed a Database Committee responsible to develop and maintain an online clinical Database with the aim to collect clinical data from thoracic surgery units across Europe. The ESTS Database is an online database, which is free to members and directly accessible from the link on the ESTS homepage. The main purpose of the ESTS database is for quality monitoring and improving activities. Several outcome and process indicators are included in the dataset. These indicators have been used to construct a Composite Performance Score, which is used as one of the parameters necessary for the European Institutional Accreditation System (EIAS). The EIAS is a process aimed at standardization of thoracic surgery practice across European units. It is currently based on the information submitted to the ESTS Database and focused on major lung resections for lung cancer, the prevalent activity in our specialty. In the construction of the CPS, indicators covering all three temporal domains of our practice (preoperative, intraoperative and postoperative) were selected. These indicators included risk-adjusted hospital mortality and morbidity (outcomes) and 3 process measures derived from published guidelines: the proportion of lung resection candidates with measured DLCO, the proportion of candidates to lung resection for NSCLC with clinically suspicious nodal disease submitted to preoperative invasive mediastinal staging and the proportion of patients with a intraoperative mediastinal staging according to the ESTS published guidelines. The final composite score combined 3 processes and 2 outcomes indicators into a single comprehensive quality score which was able to discriminate between the units entering in the comparison process. Units eligible for the accreditation process are then inspected by a team of auditors appointed by the ESTS to verify a sample of data submitted to the ESTS database and the structural, procedural and qualification characteristics of the unit and surgeons working in that unit. Most recently the ESTS Executive Committee revised the structural characteristics of general thoracic surgery unit in Europe with the aim to provide a comprehensive document in line with the quality initiatives of the Society and serving as a guide for harmonizing the general thoracic surgical practice in Europe. That document will be used as a reference for future quality initiatives and educational activities of the society

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The 7th edition of TNM for Lung Cancer, introduced in January 2010, was based entirely upon recommendations from the IASLC Staging and Prognostic Factors Committee. The enormous size of the data base, its international accrual of cases diagnosed over a relatively short time period and its inclusion of cases treated by all modalities of care, coupled with detailed analysis and intensive validation ensured that this version aligned stage with prognosis more accurately than ever before. This was achieved by introducing new size cut-points for tumour size, re-assigning some T and M descriptors and moving some T, N, and M combinations to new stage groupings. Inevitably there are questions as to whether there should be consequent changes to established treatment algorithms. These discussions will focus upon the following scenarios: a) Larger node negative tumours, > 5cms, are now included in stage II. In the past 10 years we have seen data showing that stage II cases benefit from adjuvant chemotherapy after complete resection. Do these "new" stage II cases benefit from adjuvant therapy? b) Cases in which there are additional tumour nodules in the tumour-bearing lobe and other ipsilateral lobes have with certain combinations of N category, been down-staged to IIIA. Selected cases of stage IIIA disease have benefitted from resection, usually in a multi-modality setting. Should these cases, now included in stage IIIA be treated with regimens including surgery? c) Tumours invading certain mediastinal structures that were classified as T4 in previous editions of TNM have not been re-assigned but when associated with N0 or N1 disease these cases have been down-staged to stage IIIA. Should they also be considered for surgery in a multi-modality setting? Whilst it is impossible to give dogmatic and unequivocal advice on the right answer to these questions the speaker hopes to give some insights into the factors which might influence the decisions made by the Multi-Disciplinary Team in such situations. Other issues raised by the 7th edition include: a) The distinction between pulmonary metastases and synchronous primary tumours has been clarified and the opinion of the pathologist has been emphasised in this distinction. Thus in cases in which there is more than one malignant nodule biopsy of additional lesions may be required if such a distinction would alter the treatment advised in any case. b) The IASLC nodal map and definitions of nodal stations and zones are now the recommended means of describing regional lymph node involvement in lung cancer. All members of the MDT should be familiar with this nomenclature. c) The definition of an R0 resection now requires that a defined minimum of lymph nodes/stations be removed by the surgeon and examined by the pathologist. Surgeons and pathologists need to comply with this requirement and other members of the MDT need to understand this expanded definition. d) The 7th edition of TNM and the new IASLC/ATS/ERS classification of Adenocarcinomas may influence the management of screen-detected lesions. The new T category of T1a tumours no larger than 2cms and the fall in prognosis seen in lesions above this threshold may influence the choice of approach to lesions around this watershed, one's policy of structured surveillance and the extent of surgical resection for lesions confirmed to be malignant. As LDCT screening becomes more widely available the MDT managing these cases will need to consider these matters when developing their investigative algorithms.

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The radiology report forms an essential component of any radiological examination, and an accurate radiology report requires two key components: the detection of abnormalities (if any), and subsequently their interpretation. However, for radiology reports to be useful to the clinician and patient, a third crucial factor is successful communication. In the setting of lung cancer reporting, radiologists rely on their perceptive ability to detect nodules or masses, while interpretation requires knowledge and experience of the appearances, staging and behaviour of lung carcinomas. Improvements in both of the factors have been achieved by developments such as the use of computer aided detection software or maximum intensity projections (MIPs), for example, to detect lung cancer; and the use of internationally recognized documents such as the IASLC lung cancer staging classification which aids radiological interpretation. By comparison, the communication of the radiology report has changed little over the years, and it could be argued that efforts to improve lung cancer detection and staging are diminished without satisfactory communication. Standardized reporting (SR) has been advocated as a tool that can improve the communication of radiology reports, and which may also have benefits in the detection and interpretation of radiological abnormalities. This presentation will review the definitions of SR, and examine its purported benefits and disadvantages. Studies investigating the impact of SR will be reviewed. In particular, its relevance to lung cancer imaging will be highlighted. There is no single definition of what a standardized report should look like, but a key principle is that standardized reports (SRs) follow a pre-defined format. At the most basic level this includes the use of brief headings within a report, such as “clinical information” or “impression”, each of which contains free-text. At the other extreme is the mandatory use of a check-list of itemised headings, and the selection from a list of only pre-defined terms (using standardized language) within these headings, rather than free-text. Itemised headings in a CT structured report of a patient with lung cancer might include tumour morphology, tumour location, tri-dimensional measurements, presence or absence of invasion of structures such as pleura or chest wall, the presence or absence of enlarged lymph nodes recorded for all of the nodal stations, and the presence or absence of metastatic disease in each of the body organs. The hypothesized advantages of SR is that it produces: i) reports that are more accurate, ii) reports that are easier to read and understand, and iii) reports from which it is straightforward to retrieve data for research purposes. It has also been suggested that SRs allow radiologists to better convey uncertainties and likelihoods to clinicians. This is standard practice in mammographic reporting, where abnormalities are given a score between 1(negative) and 5 (highly suggestive of malignancy) and could in theory be extrapolated to the description of lung nodules in a clinical or lung cancer screening setting. The main disadvantages of SR that are put forward include its negative impact on workflow and the interpretation process. Additionally, it is suggested that, in fact, free text can better capture the uncertainties within a radiological examination, as often findings cannot be simply categorized into negative or positive. Unlike standardized reporting, the subject of standardized protocols in lung cancer imaging is perhaps less controversial, but no less important. The protocols used for the imaging of lung cancer can have a significant impact on the accurate staging and treatment planning of lung cancer. Furthermore, the successful implementation of future lung cancer screening programmes will require consistent adherence to low-dose CT acquisition protocols. In the staging of patients with lung cancer, protocols such as the routine reconstruction of multi-planar reformats to better identify tumour invasion are becoming widely adopted. Less agreement exists on imaging pathways. For example, the role of routine brain MRI in lung cancer staging or the possible use of contrast-enhanced PET/CT as a “one-stop shop”.

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As the prognosis of cancer patients gets better, more individuals are at risk to develop a local recurrence or a new primary tumour in previously irradiated organs. New radiation techniques, better imaging and more knowledge of dose volume relationships have fuelled re-irradiation to high doses. The aim of high-dose re-irradiation is to give the patient a chance for long-term disease-free survival and even cure. Re-irradiation is only expected to be beneficial when a high-dose can be delivered. In order to do this safely, knowledge about the dose-response relation for the organs at risk (OAR) is needed. Here, the first problem starts. Even in patients that have never been irradiated, in-depth individual knowledge about dose-response relations for all AORs is lacking. As is clear from e.g. the QUANTEC reviews, even for widely used parameters such as the mean lung dose (MLD) or the V20, the accuracy of the model to predict subsequent development of radiation pneumonitis is very moderate, with AUC values under the ROC curve of 0.60-0.65. For other organs like the heart, current models score even worse. Functional, imaging and genetic parameters are an area of intensive research, but not usable in standard practice yet. In case of re-irradiation, only limited data coming from retrospective studies with small numbers at risk for late complications are available. Keeping all caveats in mind, it seems that the aorta can tolerate cumulative physical doses of up to 120 Gy (given in 2 Gy fractions), above which dose level lethal bleeding may occur (Evans et al. Radiother Oncol 2013). In other retrospective series, grade 4-5 stenosis, fistula and bleeding occurred only when re-irradiation included central structures (Peulen et al. Radiother Oncol 2011). Even when stereotactic body radiotherapy (SBRT) is used for re-irradiation, the risk for radiation pneumonitis seems to be more than 20 % with cumulative V20 values over 30 % (Liu et al. Int J Radiat Oncol Biol Phys 2012). This points to the importance to obtain composite plans, which should include non-rigid deformation. Whether alpha/beta values that are used for primary irradiation are safe in the re-irradiation setting is not investigated thoroughly, as is the repair of OARs over time, the influence of co-morbidities, medication and anti-cancer drugs. Nevertheless, one prospective ( Wu et al. Int J Radiat Oncol Biol Phys 2003) and several retrospective studies (Okamoto et al. Int J Radiat Oncol Biol Phys 2002; Kruser et al. Am J Clin Oncol 2013; Tada et al. Int J Clin Oncol 2005; Ebara et al. Anticancer Res 2007; Peulen et al. Radiother Oncol 2011; Meijneke et al. Radiother Oncol 2013) have been published. In most series, the median radiation dose of the first treatment was about 60 Gy and that of the second 40-50 Gy in 4-5 fractions in case of re-treatment with SBRT or 60 Gy in 2 Gy daily fractions. The median interval between the first treatment and the second was in most studies between 12 and 24 months. All series indicate that re-irradiation is “feasible”, with after a median follow-up of about one year approximately 25 % of the patients having grade 3 or more toxicities. It comes as no surprise that the median overall survival after re-irradiation is low, ranging from 6-15 months. Because apart from one prospective trial with 23 patients only small, retrospective studies have been presented, it is not clear what the prognostic factors for survival are. Thorough staging, a good performance status, a small GTV and the possibility to give a high dose of radiotherapy seem obvious. In view of all uncertainties and the observation a significant proportion of patients with important toxicity, the time is right to launch prospective studies, randomised or not. These studies should focus on prognostic factors both for survival and toxicity, in order to ultimately be able to identify a subgroup of patients with truly curable disease or in which systemic treatment can be delayed significantly without undue toxicity. In the meantime, an individual patient should clearly understand the limitations and doubts of re-irradiation with regard to survival and toxicity. In case of a limited recurrence in an otherwise good performance patient, SBRT is reasonable if central structures can be avoided and 2 Gy per day, 5 days per week in other cases. A biological dose of at least 60 Gy should be given, taking into account the OARs. Probably the most suited patients are those with a long delay, possibly of more than one year, between the first irradiation and the recurrence.

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The past 15 years has seen dramatic developments in radiotherapy (RT) technology and techniques many of which are being applied to patients with lung cancer. The most important of these are PET imaging for RT planning, 3D conformal RT, Intensity Modulated RT, stereotactic body RT (SBR), Image Guided RT and techniques to compensate for respiratory movement such as gating. These are now in widespread use and becoming the ‘standard of care’ in developed countries. But significant questions remain about how fully they have been evaluated and whether or not they have actually led to improvements in clinical outcomes, let alone whether they are in fact cost effective innovations. In this presentation I will address the following questions: · Why are new RT technologies difficult to evaluate for anything beyond efficacy and safety? · Should they be subjected to the same rigorous evaluations as new pharmaceuticals through randomised controlled trials (RCTs) before entering wide clinical practice? · What strategies could be used to assess ‘value for money’ in the absence of high quality evidence? The model for assessing new technologies is derived from pharmaceutics where the new drug is first evaluated for safety and dosage (Phase I), then for efficacy (Phase II) and finally for clinical effectiveness compared to standard therapy (Phase III) before (in some health systems) being assessed for cost effectiveness. New non-pharmacological technologies are not subject to the same regulatory regime and, other than meeting routine requirements for radiation safety, RT technologies can be introduced into routine practice without evidence of clinical effectiveness – improving outcomes. Novel RT technologies are difficult to evaluate formally because: · They often develop incrementally over time with new refinements, especially in associated computer software. · There may be competing manufacturers with slightly different products. · There is often a ‘learning curve’ before they are used most effectively. · There are demonstrable improvements in planned dose distributions, imaging and accurate dose delivery which lead to a reasonable belief that clinical outcomes will be better. · There is always a need for capital investment, sometimes substantial, which means that only centres that already have the technology can participate in comparative clinical trials and those clinicians may be reluctant because they may already be convinced that their new technology is better. · The important clinical outcomes, local control, survival, late radiation toxicity take years to evaluate. · Funding for such research may be hard to find. Does this really matter? It can be argued that demonstration of better-looking computerised plans and apparently more accurate and consistent delivery of radiation dose is a good in itself and one should always try to use the best tools available. That is true – up to a point. But there are two important considerations. First does this apparent improved ‘accuracy’ give false reassurance and result in in unsafe margins and poorer local control? This problem can be partly addressed by careful and well planned prospective follow up studies. Secondly these innovations come with a real cost in capital investment, staff time and, often, longer individual treatment times and lower throughput. How much is that cost and could that money be used in another area to deliver more health benefit? In other words are these innovations cost effective? There are increasing concerns everywhere about the escalating costs of healthcare and whether the payer is the state, an insurance system, a health maintenance organisation or an individual, health professionals have a responsibility to deliver cost effective care. Given the difficulty of carrying out RCTs in this area, what can be done to help those deciding on the best use of resources? One option is to undertake modelling studies not only of dosimetric and clinical consequences but also of costs and consequences. It may then be possible to make to some high level decisions about whether the benefits are likely to large enough and the costs low enough to justify introduction into routine clinical practice, whether comparative research (ideally an RCT) is needed or whether further evaluation of efficacy and safety is needed in institutions experienced in such research. I would therefore argue for better coordinated efforts, preferably at an international level, to address this difficult problem and provide more information about how best to use these new and important resources.

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Resource Constraints is an important barrier to Lung Cancer Management. In order to understand this issue in Developing Nations, the questionnaires was set up and send to an experts in Asian countries to find out the fact about this issues. Data gather from the questionnaires will be present at the meeting. Specific information in the questionnaires are Drug lagging period, time to get new cancer drug approval, the important of economic analysis during the approval of new anticancer drug. The other information related to man power including specialist in all related subspecialties and the availability and accessibilty to diagnostic and treatment will be captured by questionnaires. Pattern of Health Insurance and other cost was also the information gathered at the same time.

Abstract
The chronic disease burden of developed countries is increasing as the postwar “baby boomers” enter their senior years. The cost of managing these chronic diseases is compounded by the increasing availability and use of expensive technologies. Cancer drug costs are a key driver of health care costs and the expenditure on cancer drugs is rising faster than spending in most other areas of healthcare. Because of this and the fiscal constraint most developed countries have put in place a rigorous drug review process. The United Kingdom’s National Institute for Health and Care Excellence (NICE), amongst others has led the way in establishing drug review processes. These reviews are generally viewed by the pharmaceutical industry, healthcare providers and the public itself as a barrier to access. The pan-Canadian Oncology Drug Review (pCODR) evaluates the clinical benefits and safety of new cancer drugs, as well as their cost-effectiveness and alignment with patient values using a standardized clinical and economic review process, an expert panel, a deliberative framework and broad public engagement (1). Commonly, recommendations are conditional on the drug price being lowered because the drug is not felt to be cost-effective. The determination of incremental cost-effectiveness or cost-utility is critical to drug funding approval in most jurisdictions except the United States. This is determined by assessing the incremental cost of the new drug or regimen over the standard treatment and dividing by the incremental benefit usually measured as years of life gained. In Canada, $50,000 per life year gained or less was generally accepted as cost-effective. As drug costs have increased, this "threshold" has crept higher and $100,000 per LYG is increasingly accepted as “reasonable”. To take account of morbidity from the disease and its treatment, the quantity of life gained is weighted by the quality of that life into a single multidimensional measure (i.e. the quantity adjusted life year or QALY). The availability of other resources, not related to the cost of drugs, can be a barrier to access. In 2008, Cancer Care Ontario began to measure concordance with guidelines developed through its Program in Evidence-based Care and to report this information through a Cancer System Quality Index (CSQI) (3). In 2010- 2011, it was noted that only 41% of resected stage II/IIIA patients received guideline recommended adjuvant chemotherapy (AC) at Ontario’s regional cancer centres. There was also substantial variation in guideline adherence between centers ranging from 42.9% to 72.1%. Men were significantly less likely to be treated with AC (38.2% compared to 52.7% for women) (p=0001), as were patients over age 65 (65% < 65 yrs. vs. 34% > 65 yrs.)(p=.0001). Patients from regions with the highest tercile of immigrants were significantly less likely to be treated: 14.3% for the highest, 46% for the middle and 51% for the lowest tercile. Similar variations were seen for the uptake of the guideline recommendation for the use of combined modality therapy in the treatment of stage III NSCLC. To better understand the reasons for these variances, a survey and key informant interviews were undertaken with clinicians and administrators. The perception of respondents was that the most common barriers to implementing practice guidelines were the slow referral process of patients to the treatment centers, lack of support from the organization’s leadership to implement the recommended regimens and the difficulties that patients had in getting to the treatment centers. These results suggested that greater efforts are required to communicate best practices to providers, (including primary care physicians), to improve the efficiency of clinic processes and to arrange patient transportation. For aboriginal and immigrant populations, culture and language are known barriers. Resources to lower language barriers, to assist patients in health system navigation and to educate health providers in the provision of culturally sensitive care may be necessary to ensure equitable access to appropriate care. Some developed countries have experienced resource constraints that have delayed access to cancer surgery and to radiation treatment. Excessive wait times result from inadequate capacity and/or inefficiencies in the health system. To resolve these issues first requires recognition of the problem, the development of a plan of action, appropriate funding to address capacity issues, process improvements to increase efficiency and incentives to providers to prioritize cancer treatments. In a recent review of access to cancer care services in Canada, Maddison et al. noted that inequity of access occurs across the continuum of care for different disease sites (4). The review suggested that access to cancer services is most inequitable at the beginning (i.e. screening) and at the end (i.e. end-of-life care). Income level appeared to have the most influence on screening while age and geography were most influential on access to end-of-life services. As the results of the NLST are implemented as population-based screening programs, low dose CT will compete for diagnostic service resources and other services. Smokers at risk from lower socioeconomic levels, in particular, may encounter barriers to access. At the other end of the cancer spectrum, access to palliative care resources varies widely in developed countries. Conclusions: Access to optimal lung cancer care across the continuum from screening and early detection through treatment and end-of-life care can encounter numerous resource barriers, which are not all monetary in nature. Although the cost of new drugs is the most significant potential resource barrier, numerous other barriers can exist in developed countries related to the resources available for screening or diagnosis, radiation and surgery, access to knowledge specialists, supportive care services and accessible end-of-life care in the home or community. References: 1. Pan-Canadian Oncology Drug Review (pCODR) (website). Toronto, Ontario. (Accessed August 1, 2013) Available at http://www.pCODR.org 2. Cancer System Quality Index (CSQI) (website). Toronto, Ontario: Cancer Quality Council of Ontario (accessed August 6, 2013). Available from: http://www.csqi.on.ca 3. Maddison AR, Asada Y, Urquhart R. Inequity in access to cancer care: a review of the Canadian literature. Cancer Causes Control 2011; 22:359-366

Abstract
Small cell lung cancer represents about 12% of new case of lung cancer in the USA. It has a unique presentation and natural history compared to other types of lung cancer and is highly responsive to first-line treatment. Unfortunately, the cancer typically relapses after a short period of time and exhibits resistance to cytotoxic and targeted therapeutic agents with a poor median survival. The last 2 decades witnessed significant improvement in our understanding of the molecular basis of small cell lung cancer with identification of several potential therapeutic targets leading to application and evaluation of novel chemotherapeutic, targeted and immunotherapeutic agents in a large number of clinical trials. In this presentation, we will summarize the data from the recent and ongoing clinical trials in this disease and understand the challenge that it poses. However, the results have overall been disappointing and the combination of a platinum compound with etoposide remains the most effective treatment for this patient population. Despite the advent of new cytotoxic and targeted agents, which have shown significant activity in other types of cancer including non-small cell lung cancer, their use in SCLC has not had any impact on survival. The differences in efficacy observed with agents such as amrubicin and irinotecan in patients from different ethnic or racial groups indicate the importance of the understanding the tumor genetic makeup and individualizing treatment regimens. The landscape of genetic alterations of SCLC is more complex than in other types of cancer. To date, no specific mutation, abnormal fusion protein secondary to chromosomal translocation or aberrant signal transduction pathway has been validated and proven to be critical for the continuation of the carcinogenesis process and survival of the SCLC tumor cells. SCLC remains one of the most challenging tumors to treat with our current standard of care. The recent advances in sequencing and high throughput technologies have started to yield useful information about the molecular abnormalities of SCLC. We need to refine the recently acquired knowledge of SCLC biology and apply that knowledge in innovative clinical trials to have a breakthrough in the treatment of SCLC.

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Whilst the incidence of small cell lung cancer (SCLC) has reduced over the last 20 years, the prognosis of the disease remains poor. Major advances in SCLC include improvements in radiotherapy (RT) techniques, the use of prophylactic cranial irradiation (PCI) for all stages of SCLC and the improved integration of chemotherapy and RT. It is unlikely that future advances in the treatment of SCLC will relate to standard chemotherapy. The role of thoracic RT is well established in the management of stage I-III SCLC [1,2,3,4]. There is increasing evidence in the literature in favour of early concurrent chemo-radiotherapy (CTRT), and a gold standard of care for patients with a good performance status is twice-daily thoracic RT (45 Gy in 3 weeks) with concurrent cisplatin and etoposide [5]. Although current clinical trials are exploring the efficacy of new chemotherapeutic strategies, essential questions related to the optimisation of thoracic RT remain unanswered. These questions include i) optimal total dose, ii) fractionation, iii) timing and sequencing of radiation, iv) volume of irradiation, v) concurrent chemotherapy/targeted therapy combinations, and vi) the importance of the time between the start of any treatment to end of RT. PCI reduces the incidence of brain metastases and improves survival in all stages of SCLC [6,7]. As a result of the implementation of best standard of care the 5 year survival of stage I-III SCLC patients has increased from less than 10% with chemotherapy alone to 25-30% with early concurrent CTRT and PCI. It is crucial that patients with SCLC are given the opportunity to participate in clinical research in order to continue to improve the survival of this disease. Clinical trials aiming to establish a standard dose/fractionation in the stage I-III setting include the European/Canadian CONVERT and the US intergroup (CALGB 30610/RTOG 0538) studies. The results of the CREST study investigating the role of thoracic RT in stage IV SCLC are eagerly awaited. Molecular studies are ongoing aiming to gain improved insight into the molecular biology of SCLC, discover and/or validate candidate biomarkers for response, resistance to or toxicity of systemic treatment and radiation. There is now a concerted effort within the research community to understand the molecular mechanisms that underpin the molecular pathways in cancer. It is hoped that this understanding will lead to the development of targeted therapies that will not only prove efficacious, but also less toxic than more conventional treatments. In combination with newer techniques such as conformal RT and better imaging, it is hoped that the rates of long term survivors will increase significantly in the future. References 1 Bayman NA, et al. Radiotherapy for small-cell lung cancer-Where are we heading? Lung Cancer. 2009;63(3):307-14. 2 Sørensen M, et al. ESMO Guidelines Working Group. Small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Supplement 5):v120–v125. 3 Stahel R, et al. 1st ESMO Consensus Conference in lung cancer; Lugano 2010: small-cell lung cancer. Ann Oncol. 2011;22(9):1973-80. 4 Pignon JP, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327:1618-22. 5 Turrisi AT, et al. Twice daily compared to once-daily thoracic radiotherapy in limited-stage small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265-71. 6 Auperin A, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341(7):476-84. 7 Slotman B, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;357(7):664-72.

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Abstract
Whenever a major alteration in histopathologic classification occurs, important ramifications for cytopathology follow. Furthermore, the recent recognition that associations of specific types of epithelial malignancies of the lung are associated with different prognoses and therapeutic complications also directly impacts diagnostic cytology. One important question is: how well can we distinguish adenocarcinoma, squamous cell carcinoma, and other nonsmall cell carcinomas (NSCLC) from each other in cytologic preparations? The answer is very well, with most recent data emanating from aspiration samples. Based purely on routine cytomorphology, approximately 90% of all specimens with NSCLC can be rendered by strict adherence to classic well indoctrinated cellular features. When the distinction cannot be rendered by morphology alone, the addtion of a small battery of immunochemical reactions raises the proportion of correct cell typing to nearlly 100%. Recommendations emphasize using a limited array of antibodies, eg. targets such as TTF-1, cytokeratin 5/6, and synaptophysin. In the infrequent case in which this does not make clear the cell type, a diagnosis of NSCLC, NOS is preferred over large cell carcinoma. Once a tumor is interpreted as adenocarcinoma, how well do we do in determining the predominant histologic subtype from the 2011 classification? The answer is poorly. This is related to both the small sample size with the recognition of the histologic heterogeneity within a sizeable tumor mass and the concept that the rather uniform manners in which neoplastic cells aggregate and present themselves in aspiration and exfoliative smears is typical of all types of adenocarcinomas and thus not representative of the histologic subtype. Current data supports the general notion that the predominant histologic subtype correlates with prognosis, and thus may serve as a morphologic grading surrogate. As just stated, it does not appear that cytology will permit such a parallel assessment. However, there is some evidence that certain nuclear attributes of adenocarcinoma cells in cytologic specimens are associated with prognosis and, hence, nuclear grading may be of value in this regard. Features which include nuclear contour, chromatin pattern, and the prominence of nucleoli can be used to formulate a meaningful nuclear grading system. This is likely better performed with alcohol-fixed Papanicolaou stained specimnes compared to air-dried Romanowsky stained samples. Note that mitotic figure counting is not a component of this proposal. It is crucial to recognize that cytologic samples provide a substrate for the molecular testing of therapeutically important mutations in adenocarcinoma cells which seem to be equal to histologic specimens. Thus, it is very relevant that sufficient cytologic material be collected at the very time of sampling and that it be utlized in an extremely judicious manner.

Abstract
There has been very little improvement in outcome from lung cancer over the last two decades but the identification of actionable mutations and structural rearrangements in subsets of patients with lung adenocarcinoma holds hope for the near future, particularly if these agents successfully move into the adjuvant setting. Detection of key molecular targets is central to this new understanding of lung adenocarcinoma and targeted therapy but poses significant challenges for implementation into routine clinical diagnostics. The importance of molecular testing in lung adenocarcinoma has been emphasized not only in the updated classification of adenocarcinoma but also in the recently released molecular testing guidelines for selection of lung cancer patients for EGFR and ALK Tyrosine Kinase Inhibitors produced by the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology this year with a central recommendation that tissue should be prioritized for EGFR and ALK testing. Recent molecular and genomic studies of lung adenocarcinoma in particular has resulted in the identification of other low incidence, novel driver mutations including structural rearrangements in ROS1 and RET-KIF5B as well as recognition of point mutations in BRAF and HER2 among others. It is apparent that “profiling” lung cancers for a range of important and potentially treatable driver mutations may offer significant advantages such as cost effective, rapid identification of actionable changes and efficient triage for clinical trials of novel agents. However performing molecular testing in lung cancer can be challenging given the majority of patients present with inoperable disease. This means histological and molecular diagnosis is generally performed on small biopsies including cytological specimens often with very limited material for testing. Furthermore much of this tissue has undergone formalin fixation and paraffin processing with subsequent DNA cross-linkage and fragmentation. There are additional problems of contamination with non-malignant tissue elements including stroma and inflammatory cells. There are also time pressures with the need for rapid results with current recommendations for results to be available within 10 working to allow appropriate triage for therapy. It is important to direct testing to appropriate clinical groups likely to benefit. While there are strong demongraphic associations of actionable mutations in lung adenocarcinoma, including non-smoking status, younger age, female sex and Asian ethnicity, these criteria are insufficiently robust to exclude patients without these characteristics from testing. Current recommendations in limited specimens are that molecular testing for EGFR or ALK gene changes be primarily undertaken in adenocarcinoma or cases with a component of adenocarcinoma. Fortunately cytology is emerging as a robust method for classification of lung cancer and these specimens are increasingly utilized for mutation testing. Large cell or histologically undifferentiated carcinomas with features suggestive of adenocarcinoma differentiation eg TTF-1 expression are also suitable for molecular testing. Molecular testing of limited biopsies may also be considered in cases showing squamous or small cell histology guided by clinical features such as ethnic background and non-smoking status among others. There is good concordance between primary and metastatic sites for EGFR mutational status and specimens from either site are acceptable for testing with choice based on morphological assessment of optimal specimens for molecular testing There are a wide variety of molecular techniques available to assess for the presence of key driver mutations in lung adenocarcinoma, each with their own limitations and advantages, but there is no perfect technology that fulfills all clinical and laboratory needs, especially on the limited material usually available in lung cancer mutation testing. Virtually all techniques for EGFR testing depend on PCR amplification, which is a major issue where limited DNA template is present raising the possibility of both false negative (due to sensitivity issues) and false positive results (eg due to amplification of formalin artifacts). In our own practice we have found that standard methods for DNA quantification such as spectrophotometry significantly overestimates the amount of DNA available for testing in comparison to more specific methods such as DNA fluorometry or estimates of amplifiable DNA copy number. We currently perform routine diagnostic mutation testing via multigene mutation profiling using a commercial panel, Oncocarta v1.0, on the massARRAY Sequenom platform in combination with fragment analysis for EGFR exon 19 and 20 insertions and deletions. This allows simultaneous determination of key mutations in EGFR and KRAS status as well as identifying rare but potentially actionable changes in BRAF, PIK3CA and HER2. In parallel, we perform immunohistochemistry for ALK and ROS1 to allow rapid triage for FISH testing if mutation profiling is negative. However not all cases have sufficient material for this approach and we are currently validating a new custom panel which can be performed reliably with less DNA. While cytological specimens are problematic in the generally small amount of tumour material available for testing, they have the advantage of often containing a relatively pure population of tumour cells, with a marked reduction in stromal contamination especially in FNAB specimen. Earlier studies suggested cytological specimen were less preferred to small tissue biopsies but a number of more recent publications have highlighted the suitability of these specimens. While the most recent recommendations suggest that cell block specimens allowing pretest morphological assessment are preferred to fresh smears, fresh material offers generally better quality and quantity of DNA. FISH testing for ALK gene rearrangement on cytological specimens is feasible and increasingly widely performed. Generally FISH testing requires less cellular material than mutation testing and the direct visualization of the molecular assay in tumor cells gives greater confidence that a negative result is far less likely to reflect problems with sensitivity as for EGFR testing. Expert morphological assessment is critical to ensure malignant cells are being assessed in this setting. In summary, cytology specimens are a commonly tested lung cancer diagnostic specimen and offer a number of advantages over more invasive small biopsies. Expert cytological assessment of specimens should be undertaken prior to molecular testing to maximize the quality and accuracy of testing.

Abstract
Most lung cancers are readily diagnosed by using light microscope without attaining special stains [1], but at least 30% of NSCLC could benefit from immunohistochemistry (IHC) to unveil the cell differentiation lineages, especially when dealing with cytology and biopsy specimens [2]. Molecular methods, including micro-RNA expression analysis [3], are cumbersome and unlikely to be directly transferred into the everyday diagnostic workflow [2, 4]. IHC is not a perfect mathematic model, since there is a small (<5%) subset of NSCLC with ambiguous co-expression of glandular and squamous cell differentiation markers or negative reaction for any marker [5, 6]. a) What is the best combination of biomarkers to use? The coordinated expression for TTF-1 for adenocarcinoma and p40 for squamous carcinoma is currently emerging as the most reasonable and reliable biomarker duet in terms of sensitivity and specificity [2, 7-9]. Other promising biomarkers include napsin A for adenocarcinoma [10] and desmocollin-3 for squamous carcinoma [11, 12]. While TTF1 is the best marker for adenocarcinoma and p40 equivalent to p63 for squamous carcinoma, p40 is by far superior in terms of specificity since only rare adenocarcinomas are focally positive in comparison with p63 [2, 7-9]. b) Be aware of antibody clones and other technical issues. The monoclonal antibody 8G7G3/1 for TTF1 seems to be more specific for adenocarcinoma than other clones (such as SPT24) [8, 13], but it has also been recorded in gynecologic [14] and breast [15] carcinomas. Monoclonal antibody to napsin A for adenocarcinoma is less sensitive, but more specific than polyclonal antiserum [16]. The single best marker for squamous carcinoma is a polyclonal rabbit antiserum against p40 [7-9][,17], but very recently a monoclonal antibody has been made commercially available. c) Practical hints to surgical pathologists. NSCLC-NOS upon morphology with negativity for p40 and some TTF-1 positivity should be equated to poorly differentiated adenocarcinomas, once large cell neuroendocrine carcinoma (LCNEC) by relevant markers (e.g., synaptophysin) has been excluded. NSCLC-NOS upon morphology showing double negativity or with only erratic labeling for p40 in < 5% tumor cells in absence of TTF-1 should be considered as poorly differentiated non-squamous carcinomas corresponding, in most instances, to poorly differentiated adenocarcinoma once metastatic cancer has been reasonably excluded, keeping in mind however that the same immunoprofile may be shared by sarcomatoid carcinomas (excludible by morphology and vimentin IHC) [17] and LCNEC (excludible by synaptophysin IHC). Poorly differentiated squamous carcinomas are instead highlighted by strong and diffuse p40 expression and TTF-1 negativity, hence lack of p40 exclude by definition this tumor according to the axiom “no p40, no squamous” [9]. When morphology fails to conclusively subtype NSCLC, it is recommended specifying in the pathology report the real contribution of IHC to render the final diagnosis according to the relevant cell differentiation lineages (e.g., NSCLC-NOS, favor adenocarcinoma or squamous carcinoma by IHC) [6]. References 1. Travis W, Brambilla E, Muller-Hermelink H, Harris C. Tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004. 2. Rossi G, Pelosi G, Barbareschi M, et al. Subtyping non-small cell lung cancer: relevant issues and operative recommendations for the best pathology practice. Int J Surg Pathol 2013;21:326-36. 3. Lebanony D, Benjamin H, Gilad S, et al. Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma. J Clin Oncol 2009;27:2030-7. 4. Rossi G, Papotti M, Barbareschi M, Graziano P, Pelosi G. Morphology and a limited number of immunohistochemical markers may efficiently subtype non-small-cell lung cancer. J Clin Oncol 2009;27:e141-2; author reply e3-4. 5. Travis W, Brambilla E, Noguchi M, 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;6:244-85. 6. Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med 2013;137:668-84. 7. Bishop JA, Teruya-Feldstein J, Westra WH, et al. p40 (DeltaNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol 2012;25:405-15. 8. Pelosi G, Fabbri A, Bianchi F, et al. DeltaNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: a novel two-hit, sparing-material approach. J Thorac Oncol 2012;7:281-90. 9. Pelosi G, Rossi G, Cavazza A, et al. DeltaNp63 (p40) distribution inside lung cancer: a driver biomarker approach to tumor characterization. Int J Surg Pathol 2013;21:229-39. 10. Turner BM, Cagle PT, Sainz IM, et al. Napsin A, a new marker for lung adenocarcinoma, is complementary and more sensitive and specific than thyroid transcription factor 1 in the differential diagnosis of primary pulmonary carcinoma: evaluation of 1674 cases by tissue microarray. Arch Pathol Lab Med 2012;136:163-71. 11. Monica V, Ceppi P, Righi L, et al. Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung. Mod Pathol 2009;22:709-17. 12. Righi L, Graziano P, Fornari A, et al. Immunohistochemical subtyping of nonsmall cell lung cancer not otherwise specified in fine-needle aspiration cytology: a retrospective study of 103 cases with surgical correlation. Cancer 2011;117:3416-23. 13. Rekhtman N, Ang DC, Sima CS, Travis WD, Moreira AL. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol 2011;24:1348-59. 14. Siami K, McCluggage WG, Ordonez NG, et al. Thyroid transcription factor-1 expression in endometrial and endocervical adenocarcinomas. Am J Surg Pathol 2007;31:1759-63. 15. Robens J, Goldstein L, Gown AM, Schnitt SJ. Thyroid transcription factor-1 expression in breast carcinomas. Am J Surg Pathol 2010;34:1881-5. 16. Bishop JA, Sharma R, Illei PB. Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Hum Pathol 2010;41:20-5. 17. Pelosi G, Melotti F, Cavazza A, et al. A modified vimentin histological score helps recognize pulmonary sarcomatoid carcinoma in small biopsy samples. Anticancer Res 2012;32:1463-73.

Abstract
According to the recent trend of increased frequency of CT screening for lung cancer, earlier stage of lung cancer is being detected and removed surgically. In applying the new classification to such lesions, it always becomes problematic to make a differential diagnosis among the three categories: adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and lepidic predominant adenocarcinoma. AIS is defined by a pure lepidic growth pattern with a continuous growth of neoplastic cells along the alveolar septa without disruption of the alveolar structures. MIA is defined as an adenocarcinoma with predominant lepidic growth with less than or equal to 0.5 cm area of sromal invasion. The definitions are summarized in Table. When the invasive area is more than 0.5 cm and lepidic growth is predominant, the tumor is diagnosed as lepidic predominant adenocarcinoma. The distinction is clinically important because AIS and MIA have been shown to have 100%5 year recurrence free-survival, whereas lepidic predominant adenocarcinoma can recur. However, the major difficulty for the differential diagnosis has in roots in the identification of stromal invasion and measurement of the invasive area. Histological stromal invasion is determined by tumor cell and stromal factors. Because the area where the tumor cells show invasive structure is regarded as an invasive area, it is important to recognize the differentiation of lepidic pattern from papillary or acinic pattern. However, the distinction is often difficult in practice. In terms of the stromal factor, it is also difficult to differentiate an invasive scar (myofibroblastic stroma) from a scar due to collapse. Physicians should know this room for discussion, and practical solutions should be shared with pathologists. Figure 1

Abstract
Background: The development of high-resolution chest imaging techniques and screening of smokers for lung cancer resulted in increased detection of multiple lung cancers. The challenge for pathologists and treating physicians is to determine whether multiple lung cancers represent separate primary tumors or metastasis, as this affects the stage, treatment and prognosis. The clinical and pathological criteria used to define multiple lung tumors were initially published by Martini and Melamed in 1975. These criteria are based on tumor morphology and location and may not predict prognosis. The AJCC 7[th] edition staging of lung adenocarcinoma recognized shortcomings of this proposal and incorporated changes in the staging of multiple lung cancer, but molecular genetic analysis was not recommended as a standard approach. Methods: PubMed available peer-reviewed original articles and experience of the author. Results: Distinction between primary tumors and intrapulmonary metastasis becomes challenging when tumors are morphologically similar. Since the original Martini and Melamed proposal, many molecular approaches have been utilized in the evaluation of clonal relationships between multiple lung nodules including DNA microsatellite analysis, PCR assays for common somatic mutations, aCHG, and gene expression analysis. Molecular classification of multiple lung cancers is concordant with pathological classification in about two-thirds of the cases. It is difficult to determine the precise percentage because of the relatively small number of analyzed cases, mixed analysis of synchronous and metachronous tumors, and use of different methods and interpretation criteria. Early studies used two types of clonality assays: a panel of variable number of polymorphic microsatellite markers and X-chromosome inactivation analysis (Am J Surg Pathol 2005; 29(7):897;Ann Diagn Pathol 2001;5(6):321; Clin Cancer Res 2000; 6(10):3994; J Natl Cancer Inst 2009;101:560) . Tumors with largely concordant results were considered clonal in origin (metastases), and those with discordant findings were considered to be independent primary tumors. The main weakness of earlier studies was a limited number of analyzed genes. Recently, more comprehensive approaches analyzing a large number of single nucleotide polymorphic loci in a single assay or large-scale DNA sequencing of tumors were used (Clin Cancer Res 2009; 15(16):5184; Lung Cancer 2012;77:281). Although more comprehensive molecular approaches were used, a proportion of cases with discordant molecular and morphological results remained similar. Furthermore, molecular profiling only slightly improved prognostic classification of multiple lung tumors. Standard practice is to test non-resectable adenocarcinomas for common actionable somatic mutations (e.g. EGFR) and gene rearrangements (e.g. ALK) as predictors of response to targeted therapies. This information can also be used for improved staging of multiple lung nodules (Eur Resp J 2012; 39:1437; Lung Cancer 2012; 77:281). Based on similar or different mutational profile synchronous tumors may be classified as independent primaries or intrapulmonary metastases. It is very likely that surgically non-resectable tumors with different mutational profiles such as EGFR and KRAS will show different treatment responses, further emphasizing the need for separate analysis of multifocal tumors. In contrast to morphologic classification, molecular profiling can be performed on the cytology specimens. This approach can be used in adenocarcinoma only, and currently no standard molecular testing in squamous cell carcinoma is in practice. Conclusions: Molecular approaches to classification of multiple lung tumors have not been standardized, and their performance in routine clinical practice remain to be established. Testing for common activating oncogenic mutations and translocations is likely to provide information about clonal relationship between multifocal lung tumors. Implementation of molecular information to current histologic staging could improve the accuracy of staging in patients with multifocal tumors and improve therapeutic decision making.

Abstract
Overview of ultrasound imaging of the right and left bronchi using the radial probe The positional relationship between the peribronchial organs in EBUS images taken from the trachea corresponds to those in a reversed CT image (CT scans are cross-sectional images looking from the caudal direction). EBUS images taken distal to the bifurcation of the left and right main bronchi, however, are cross-sectional images of planes perpendicular to the long axis of the bronchus, and therefore have different positional relationship between the peribronchial organs to the CT images. To fully understand EBUS, it is essential to understand the positional relationship between the peribronchial organs during visualisation while the probe is being pulled out. 1. Right bronchi 1) Right lower lobe bronchi When the balloon is inflated in the right basal bronchus, the inferior pulmonary vein (V6) passes on the dorsal side of the bronchus, whereas anterior to the bronchus the pulmonary artery divides into A8, A9 and A10 positioned between 9 o’clock and 2 o’clock. As the probe is pulled back, A8, A9 and A10 meet at the 12 o’clock direction and the direction of the pulmonary artery changes gradually to the 3 o’clock direction. When the probe is pulled further back, it approaches the bifurcation of B6. Pulling the probe back further, the opening of the middle lobe bronchus, indicated by reflection of the ultrasound pulse, appears at 12 o’clock. The pulmonary artery has gradually moved round to the 2 o’clock position. 2) From the right intermediate bronchus to the right main bronchus As the probe is pulled from the distal intermediate bronchus to a point immediately below the origin of the upper lobe bronchus, the pulmonary artery crosses the bronchus from the right to the left. In the central section of the intermediate bronchus, the superior pulmonary vein can sometimes be seen anterior to the pulmonary artery. When the probe is pulled further back, the origin of the upper lobe bronchus is indicated by reflection of the ultrasound pulse at 3 o’clock. Pulling the probe back further, A1+3, originating from the pulmonary trunk, can be seen crossing horizontally anterior to the right main bronchus. Retracting the probe further, the origin of the left main bronchus at the carina is indicated by reflection of the ultrasound pulse at 9 o’clock. 2. Left bronchi 1) Left lower lobe bronchi When the balloon is inflated in the left basal bronchus, the inferior pulmonary vein (V6) passes on the dorsal side of the bronchus, whereas the A8, A9 and A10 branches of the pulmonary artery meet at 9 o’clock. As the probe is pulled back, it approaches the bifurcation of B6. Pulling the probe back further, the opening of the upper lobe bronchus, indicated by reflection of the ultrasound pulse, appears at 11 o’clock. The pulmonary artery is located below the origin of the upper lobe bronchus. 2) Left main bronchus The distal section of the left main bronchus is characterised by the left pulmonary artery at 10 o’clock, the descending aorta at 7 o’clock, and the left atrium from 1 o’clock to 3 o’clock. As we enter the central section of the left main bronchus, the left atrium disappears, and the oesophagus appears at 6 o’clock. The subcarinal (#7) lymph node is often visible medial to the oesophagus. Ultrasound imaging of mediastinal and hilar lymph nodes for EBUS-TBNA by the Convex Bronchoscope #7 LN: Subcarinal lymph node For approaching #7 LN, the convex bronchoscope is inserted into right main bronchus. While scanning at 9 o’clock direction, we can confirm the largest area of the #7 LN. While rotating right handed and scanning at 11 o’clock direction, we can watch the right main pulmonary artery. 11R LN: right intralobar lymph node (between right lower lobe bronchus and right middle lobe bronchus) For approaching #11R LN, the convex bronchoscope is inserted into right basal bronchus. While scanning at 12 o’clock direction, we can confirm the largest area of the #11R LN. While rotating right handed and scanning at 3 o’clock direction, we can watch the right pulmonary artery. 11R LN: right intralobar lymph node (between right intermediate trunk and right upper lobe bronchus) For approaching #11R LN, the convex bronchoscope is inserted into right intermediate trunk. On the bronchoscopic findings, right upper bronchus is locates at 12 o’clock direction from the intermediate trunk. While scanning at 12 o’clock direction, we can confirm the largest area of the #11R LN. While rotating left handed and scanning at 9 o’clock direction, we can watch the right main pulmonary artery. 11L LN: left intralobar lymph node For approaching #11R LN, the convex bronchoscope is inserted into left basal bronchus. On the bronchoscopic findings, left upper lobe bronchus is locates at 12 o’clock direction from left lower lobe bronchus. While scanning at 12 o’clock direction, we can confirm the largest area of the #11L LN. While rotating left handed and scanning at 10 o’clock direction, we can watch the right pulmonary artery. 4L LN For approaching #4L LN, the convex bronchoscope is inserted to the distal site of the trachea. On the bronchoscopic findings, the left side of the trachea is locates at 12 o’clock direction. While scanning at 12 o’clock direction, we can confirm the largest area of the #4L LN. While pushing the scope to distal site about 1-2cm, we can watch the left main pulmonary artery. While pushing the scope to proximal site about 1-2cm, we can watch aortic arch. 4R LN For approaching #4R LN, the convex bronchoscope is inserted to the distal site of the trachea. On the bronchoscopic findings, the membranous portion of the trachea is locates at 6 o’clock direction. While scanning at 2 o’clock direction, we can confirm the largest area of the #4R LN. While scanning 4R LN, we can watch superior vena cava (SVC) just below. While pushing the scope to proximal site about 1-2cm, we can watch aortic arch #4R LN.

Abstract
PET and PET/CT FDG PET scans have shown high sensitivity and specificity in detecting mediastinal nodal involvement. It works by detecting increased accumulation of F-18 fluorodeoxyglucose (FDG) in the neoplastic cells which have a deranged glucose metabolism. FDG undergoes similar uptake and metabolic pathway glucose molecules. The accumulation of positron emitting F-18 isotope can then be used to localise these hypermetabolic neoplastic tissue. Both 2003 and 2007 guidelines of the American College of Chest Physicians (ACCP) endorsed the use of PET imaging as a non-invasive staging tool for non-small cell lung cancer[1, 2]. FDG PET scan has become the standard of care in staging primary lung cancer. It is recognised as the most accurate non-invasive tool in the staging of lung cancer. It is also widely accepted that PET scanning improves detection of distant metastatic disease as well as unsuspected N2 or N3 disease particularly in the high-risk patients. Therefore, several series have shown that the use of PET imaging reduces unnecessary or futile surgical resection. Traditionally, a standard uptake value (SUVmax) of 2.5 or above is used as a threshold for malignancy, but this was initially based on the uptake of peripheral lung masses with diameter >2cm. Whether this can be applied to mediastinal nodes is questionable. The special resolution of a current generation PET scanner is approximately 7mm. Nonetheless, small or non-enlarged lymph nodes with highly aggressive tumour metastasis may be detected based on the higher intensity of uptake compared to the background. While FDG PET is clinically useful, it is an imperfect technique. The meta-analysis carried out by Silvestri et al [3]in the third edition of ACCP guideline demonstrated that the median sensitivity and specificity for detecting mediastinal metastases were 80% and 88% respectively. The findings demonstrate that PET is more accurate than CT scanning (median sensitivity 55% and median specificity 81%) [3]. However, it is important to know that neither technique is perfect. Interestingly, an increasing number of recent studies were performed using integrated PET/CT scanner. The meta-analysis by the ACCP showed a median sensitivity of 62% and median specificity of 90%[3]. The specificity is slightly higher although the sensitivity is lower. The reason for this observation remains unclear. Nonetheless, PET/CT hybrid cameras have superseded the role of stand alone PET scanners in nowadays. False negative results are more often seen with adenocarcinoma in situ, well-differentiated invasive adenocarcinoma, and typical carcinoid tumours. Small volume or micrometastasis can also be missed due to the finite spatial resolution of PET and perhaps by all imaging techniques. Studies have demonstrated that PET scanning is less sensitive for lymph nodes measuring <7-10mm diameter, and micrometastases have been detected in non enlarged lymph nodes without abnormal FDG uptake by invasive sampling[4]. Furthermore, in the presence of a central FDG avid lung cancer, N1 disease can be missed by FDG PET imaging in up to 25% of cases[5]. In the evolution of a peripheral T1A lesion particularly if the density of the nodule is ground glass or sub-solid. It is well known that these types of neoplasms have low incidence of mediastinal metastasis though the risk is not nil. It is important that the interpretation of a negative PET scan to be combined with clinical judgement as well as the pre-test likelihood of mediastinal metastasis. Furthermore the local availability and expertise in invasive biopsy procedures are also important factors. False positive findings are often due to infection or inflammation. Common causes include sarcoidosis, silicosis, reactive changes, fungal or mycobacterial infections. In summary, it is important to confirm N2 and N3 disease with tissue sampling to avoid delay or missing potentially curative surgery. In the presence of negative of PET and CT findings in the mediastinum, that the decision to operate or to have invasive tissue sampling requires careful consideration and clinical judgement. Combined with invasive mediastinal staging techniques Transbronchial biopsy has shown a median sensitivity of 78% and specificity of 100% in a systemic review. The sensitivity has been reported to be high in patients with positive CT or PET/CT findings. Occasional false positive results have been reported to be approximately 7%. The median negative predictive value in this systemic review is 77%. Endobronchial ultrasound with needle aspiration can achieve a median negative predicted value of 91%. This is further improved with combined EBUS and EUS which have a median negative predictive value is 96%[3]. For most patients undergoing PET/CT staging, the need of invasive mediastinal staging is not eliminated. It is important to confirm the presence of N2 or N3 disease in patients without evidence of metastatic disease to avoid withholding potentially curative surgery. FDG PET/CT can guide needle biopsy as to which nodal stations are considered high risk. Targeting lymph nodes with a higher pretest probability further decreases the inherent false negative rate of needle biopsy. The location of FDG avid nodal stations is important as to which technique will be most appropriate. For example, the identification of an FDG supraclavicular node (N3) can lead to ultrasound guided percutaneous biopsy. An FDG avid aortopulmonary lymph node may be sampled by using Chamberlain procedure, CT guided fine needle aspiration, or extended cervical mediastinoscopy. In cases with enlarged mediastinal lymph node with negative PET, confirmation by invasive techniques is also advised, as up to 21% of these can still have nodal involvement[4, 6]. There are two exceptions to the rule. First, it is known that in a patient with a peripheral T1 tumour (<3 cm), negative FDG uptake and no enlarged lymph node in the mediastinum carries a high negative predicted value with false negative rate being only 4%[3]. Therefore invasive staging is not recommended in these patients given the similar negative predicted value in a combined EBUS and EUS needle biopsy. Secondly, in lung cancer patients with infiltrative mediastinal mass on CT or PET/CT either from overt T4 disease or bulky nodal disease would not require invasive mediastinal staging. MRI and emerging Techniques MR imaging has mainly been used to evaluate non-small cell lung carcinoma when there is possible involvement of superior sulcus or brachial plexus. It is currently not a routine clinical tool in mediastinal nodal staging. New studies albeit with relatively smaller patient sample size have shown that MRI can detect nodal metastasis particularly using STIR and diffusion weighted imaging (DWI) [7, 8]. Several studies have shown comparable efficacy in relation to the PET/CT staging techniques[9]. Diffusion weighted imaging detect random thermal motion of water molecules, known as Brownian motion. Tissues with restricted diffusion will have a lower apparent diffusion coefficient (ADC) values. Hypercellular density, larger cellular nuclei and dense tumour cell membranes are known to cause restricted diffusion in malignant tissue. A study has confirmed the negative relationship between the SUV on FDG PET/CT scans and the lower ADC values on MRI[10]. Furthermore, MRI has the ability to differentiate tumour tissue from vasculature and mediastinal fat. It is therefore potentially useful to delineate direct tumour invasion of the mediastinum, chest wall, diaphragm or spinal column. More research is required in this field of MR mediastinal staging. The latest development in PET/MR imaging technique [11]using hybrid scanner will provide a fertile ground for future research in the use of non-invasive mediastinal staging. References 1. Silvestri, G.A., M.K. Gould, M.L. Margolis, et al., Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest, 2007. 132(3 Suppl): p. 178S-201S. 2. Physicians, A.C.o.C. and H.a.S.P. Committee, Diagnosis and management of lung cancer: ACCP evidence-based guidelines. American College of Chest Physicians. Chest, 2003. 123(1 Suppl): p. D-G, 1S-337S. 3. Silvestri, G.A., A.V. Gonzalez, M.A. Jantz, et al., Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 2013. 143(5 Suppl): p. e211S-250S. 4. de Langen, A.J., P. Raijmakers, I. Riphagen, et al., The size of mediastinal lymph nodes and its relation with metastatic involvement: a meta-analysis. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 2006. 29(1): p. 26-29. 5. Pozo-Rodríguez, F., J.L. Martín de Nicolás, M.A. Sánchez-Nistal, et al., Accuracy of helical computed tomography and [18F] fluorodeoxyglucose positron emission tomography for identifying lymph node mediastinal metastases in potentially resectable non-small-cell lung cancer. J Clin Oncol, 2005. 23(33): p. 8348-8356. 6. De Leyn, P., D. Lardinois, P.E. Van Schil, et al., ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 2007. 32(1): p. 1-8. 7. Usuda, K., X.-T. Zhao, M. Sagawa, et al., Diffusion-weighted imaging is superior to positron emission tomography in the detection and nodal assessment of lung cancers. Ann Thorac Surg, 2011. 91(6): p. 1689-1695. 8. Ohno, Y., H. Koyama, M. Nogami, et al., STIR turbo SE MR imaging vs. coregistered FDG-PET/CT: quantitative and qualitative assessment of N-stage in non-small-cell lung cancer patients. J Magn Reson Imaging, 2007. 26(4): p. 1071-1080. 9. Pauls, S., S.A. Schmidt, M.S. Juchems, et al., Diffusion-weighted MR imaging in comparison to integrated [¹⁸F]-FDG PET/CT for N-staging in patients with lung cancer. European Journal of Radiology, 2012. 81(1): p. 178-182. 10. Heusch, P., C. Buchbender, J. Köhler, et al., Correlation of the Apparent Diffusion Coefficient (ADC) with the Standardized Uptake Value (SUV) in Hybrid 18F-FDG PET/MRI in Non-Small Cell Lung Cancer (NSCLC) Lesions: Initial Results. Rofo, 2013. 11. Kohan, A.A., J.A. Kolthammer, J.L. Vercher-Conejero, et al., N staging of lung cancer patients with PET/MRI using a three-segment model attenuation correction algorithm: Initial experience. Eur Radiol, 2013.

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Abstract
With the recent popularization of computed tomography (CT) screening, small malignant nodules are increasingly detected. In Japanese cases of lung cancer surgery, tumors in more than 60% of lung cancer patients were under 3cm in diameter. Stereotactic ablative radiotherapy (SABR) is a new treatment modality where narrow beams from several directions focus on the target while sparing the adjacent normal tissues with high accuracy. By SABR, the biological effect of radiation on tumors was increased and the overall treatment time was shortened. SABR has emerged as one of the radical treatment options for stage I non-small cell lung cancer (NSCLC), mainly in medically inoperable patients. First of all, Uematsu et al reported in 2001, that 3-year local control and overall survival rates of SABR (50-60Gy in 10 fractions) were 94% and 66%, respectively. Then Nagata et al reported in 2005, that 3-year overall survival rate of SABR (48Gy in 4 fractions) was 83% in stage IA and 72% in stage IB. In Japanese multi-centers large database of more than 2000 patients treated with SABR for stage I NSCLC, overall survival rate at three year (OS-3y) and disease-specific survival rate at three year of total patients was 72% and 85%, respectively. Locally progression free rate at three year of T1 and T2 tumors were 87% and 72%, respectively. In USA, Timmerman et al reported in 2010, that 3-year overall survival rate of SABR (54Gy in 3 fractions) was 55.8%. In Europe, Bauman et al reported in 2009, that 3-year overall survival rate of SABR (45Gy in 3 fractions) was 60%. According to a lot of previous studies demonstrating better results of SABR compared with conventional radiotherapy, a consensus that SABR is a standard radical treatment for inoperable patients with stage I NSCLC has been generally accepted. The overall survival rate for subgroup of medically operable patients who rejected surgery in retrospective and prospective studies was almost comparative to that of surgical series considering the same age range though its evidence level is not high. Onishi et al reported five-year overall survival of 87 patients with stage I NSCLC was 69% according to the multicenter retrospective study,. In the phase II trial of SABR with 48Gy in 4 fractions for stage IA (JCOG0403), Nagata et al reported three-year overall of 65 operable patients was 76%. For patients with stage I NSCLC, resection of full lobe and systemic lymph nodes represents standard treatment but can be associated with significant morbidity and even mortality, particularly because patients suffering from lung cancer are often elderly with high comorbidity rates. For such high-risk operable patients, SABR is considered as an alternative option of radical treatment. According to American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, SABR and surgical wedge resection are suggested over no therapy for patients with clinical stage I NSCLC who cannot tolerate a lobectomy or segmentectomy (Grade 2C), but surgical resection has the potential benefit of definitive histologic analysis and pathologic nodal information. In compromised patients for whom such information would not change management and also in patients for whom an adequate margin in unlikely with a surgical wedge resection, SABR is a preferred option. According to good results of these retrospective or prospective studies, some phase III prospective trials comparing SABR versus surgery (lobar resection) have been started, but the patient accrual seems to be difficult. Patient accrual of a trial exploring the efficacy and safety of sublobar resection for patients with smaller tumors has been completed by surgeon recently. SABR is a just local therapy, therefore it essentially should be compared with sublobar resection in high-risk operable patients for lobar resection with such small peripheral tumors. In the meantime, SABR represents a recent trend in radiation oncology also for oligometastases. Local aggressive therapy for oligometastases may improve outcomes, including survival in some cases. SABR has emerged as one option for local therapy against oligometastases in various body sites, most commonly in the lungs and liver. According to published papers of SABR for lung metastases, local control with SABR distributed from 70 to 90% with very low rates of serious toxicities. Although further investigation should be undertaken to clarify the benefits of SABR for the treatment of oligometastases, SABR may be worthwhile for patients who hope for treatment to acquire better local control and possible longer survival. Concerning toxicities, SABR for peripheral tumors is an almost safe and comfortable treatment. Rib fracture is a common adverse effect after SABR but the symptom is generally mild. But severe radiation-related pneumonitis occurs occasionally in the patients having pulmonary fibrosis. As the clear dose-constraint for mediastinal organs has not been demonstrated, the safety of SABR for cases with a central lesion has not been assured. When the tumor recurred only locally after SABR in operable patients, salvage radical surgery was mostly operated safely. Primary radiation therapy remains the primary curative intent approach generally for patients who refuse surgical resection or are determined by a multidisciplinary team to be inoperable or high-risk operable. However, good tumor control, less toxicity, and fewer treatment courses of SABR decrease the indirect costs of cancer care, including lost time and economic productivity secondary to treatment-related and cancer-related illness and death. On the other hand of promising results and advantages of SABR, it is imperative to assess its cost-effectiveness as well as its efficacy because SABR is becoming used in more clinical situations. SABR employing image guidance, high-precision dose delivery, more accurate target definition with better anatomical and biological imaging, and the possibility of dose verification during treatment via dose-adaptive radiation therapy permits a higher probability of tumor control. Such major technological progress certainly comes at a higher cost, and there are many concerns regarding the value of that progress. In the symposium, we will discuss what the benefits and disadvantages of SABR compared to surgical treatment in high or low risk surgical patients with early-stage NSCLC or pulmonary oligometastases are, and how we can decide best to proceed with treatment.

Abstract
Very recently, the revised international multidisciplinary classification of lung adenocarcinoma was published by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society, and European Respiratory Society.[1,2] This new classification is characterized by the creation/abandonment of some terminology for early and advanced adenocarcinomas and by a multidisciplinary approach for the application of the new classification in a clinical setting. In particular, the term "bronchioloalveolar carcinoma (BAC)" is no longer used and, instead, new concepts are introduced, such as “adenocarcinoma in situ (AIS)” and “minimally invasive adenocarcinoma (MIA)”. Invasive adenocarcinomas are classified according to the predominant pattern after comprehensive histologic subtyping with lepidic, acinar, papillary, micropapillary, and solid patterns. The term of mixed subtype adenocarcinoma is no longer used. The gold standard surgery for documented lung cancer has been lobectomy with lymph node sampling/dissection. The randomized, prospective study was performed between lobectomy and sublobar, limited resection in 1980’s by North American Lung Cancer Study Group (LCSG) and the results of this study justified the lobectomy as the standard surgical mode.[ 3] However, looking back this study from the present view point, it is obvious that the earlier forms of lung cancer, as mentioned above as adenocarcinomas of AIS or MIA, were not involved in the LCSG study, and its conclusion could not be applied for these tumors. The present-day issue of lung cancer surgery is to define the role of lobectomy or limited, sublobar resection in relation to newly defined pathological entities. The Japan Clinical Oncology Group (JCOG) has been focusing upon defining the most appropriate surgical approach for tumors of relatively early stages in recent series of clinical trials. JCOG 0201 was intended to define the radiological non-invasive lung cancer on the high-resolution CT image, and it has shown that a consolidation/tumor ratio (C/T ratio) on thin-section computed tomography (TSCT) ≤0.25 in cT1a (≤2.0 cm) could be used as a radiological criterion for a noninvasive pathology.[4] Further prognostic analyses have also indicated that according to this radiological definition of non-invasive lung cancer the 5-year overall survival rate at 97.1% could be achieved.[5] JCOG 0804 is a prospective phase II trial, targeting the radiological non-invasive lung cancers of a diameter of 2.0 cm.[6] Again, the radiological criteria of non-invasive lung cancer were defined as those with a consolidation/tumor ratio (C/T ratio) on thin-section computed tomography (TSCT) ≤0.25. For these tumors, the wide wedge resection or segmentectomy was performed. Targeted number of accrual is 340 patients, and accrual has been already over, awaiting the data maturation. JCOG 0802 is a prospective, randomized phase III trial between lobectomy and segmentectomy for peripheral lung cancers with a diameter of 2 cm or less in a non-inferiority setting.[6] The endpoints are overall survival (primary) and postoperative pulmonary function (secondary), and the targeted accrual is 1,100 patients. As of June, 2013, more than 800 patients were registered. In case that the prognosis of patients undergoing segmentectomy was not significantly inferior to that of those undergoing lobectomy and that the postoperative pulmonary function is significantly better for those undergoing segmentectomy, it can be definitively concluded that standard surgical mode for these early tumors are segmentectomy. The similar randomized trial is also underway in US (CALGB), and the sooner launch of these data is expected to change the daily practice of lung cancer surgery. Oligometastases are the state in which the patients show distant relapse in only a limited number of organs/sites. These distant, metastatic lesions are found both before and immediately after surgery, and obviously these indicate the systemic spread of the cancer cells as stage IV disease. The gold standard treatment for systemic disease has been systemic therapy (chemotherapy). However, it has been anecdotally reported that local treatment modality such as surgery for both primary and metastatic sites cure the patients. The present-day issue for patients with oligometastatic disease is the proper selection of surgical candidate who might benefit from such aggressive treatment in lung cancer. REFERENCES 1. Travis WD, Brambilla E, Noguchi M, 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;6:144-85. 2.Van Schil P, Asamura H, Rusch VW, et al. Surgical implications of the new IASLC/ATS/ERS adenocarcinoma classification. Eur Respir J 2012;39:478-86. 3. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615-22. 4. Suzuki K, Koike T, Asakawa T, et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-6. 5. Asamura H, Hishida T, Suzuki K, Japan Clinical Oncology Group Lung Cancer Surgical Study Group. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201. J Thorac Cardiovasc Surg. 2013 [Epub ahead of print]. 6. Nakamura K, Saji H, Nakajima R, Okada M, Asamura H, Shibata T, et al. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271-4. 7. Niibe Y, Hayakawa K. Oligometastases and oligorecurrence: the new era of cancer therapy. Jpn J Clin Oncol 2010;40:107-11.

Abstract
Lung cancer is the number one cancer killer worldwide accounting for more cancer deaths than colorectal cancer, breast cancer and prostate cancer combined. While the outlook is dismal in advanced lung cancer, when patients are diagnosed once they have become symptomatic, the prognosis is more favourable in early stage node-negative disease. Small lung cancers are increasingly diagnosed as incidental findings on cross-sectional imaging such as CT-coronary angiogram (CTCA), CT-pulmonary angiogram (CTPA), CT angiograms for vascular conditions or CT -intravenous pyelogram (CT-IVP). As many as 15% of patients with early stage NSCLC are not eligible for surgery due to comorbidities, usually poor cardio-respiratory reserve. This number doubles in the patient population 75y and older. Approximately 30% of patients dying of malignancy have pulmonary metastases at autopsy with some primary cancers metastasising exclusively to the lungs. In the setting of primary cancer site being under control, reasonably long disease free interval (DFI) and oligometastatic lung disease with metastases of reasonable size and in amenable positions, data shows a survival benefit for metastasectomy in a selected patient population. Metastasectomies, even if performed as sub-lobar or wedge resections, often carry a substantial morbidity and have a major impact on quality of life. Thermal ablations can be performed in an outpatient setting, they spare healthy tissue, are repeatable and are extremely well tolerated. Thermal ablation has been applied to lung tumours for over a decade and has managed to become an established minimally invasive therapy option for a selected patient population. It is used as a therapeutic means in primary and secondary lung cancer, both with a curative and palliative intent. Combination of thermal ablation with radiotherapy for NSCLC should be a viable consideration in the therapy planning pathway, with available radiofrequency ablation (RFA)/external radiation therapy (XRT) data showing convincing 5y cumulative survival rates of 39% at no additional toxicity. Microwave ablation (MWA) represents the most recent addition to the growing armamentarium of minimally invasive thermal ablation therapies. Advantages of microwave over RF energy are perceived to be many. RF heating requires an electrical conduction path and is therefore less effective in areas of low electrical conductivity and high baseline impedance such as lung parenchyma. Unlike RF and laser, microwaves can even penetrate through the charred or desiccated tissues that build up around all hyperthermic ablation applicators, resulting in limited power delivery for non-microwave energy systems. Further advantages of MWA over RFA are that the system does not require grounding pads, thus avoiding pad site burns, that implanted cardiac devices are less prone to malfunction during MWA than during RFA and that heating occurs faster with is less susceptibility to heat sink, allowing for larger and more homogenous ablation volumes. Multiple microwave antennas can be powered simultaneously to maximise the ablation volume when placed in close proximity to each other, or when widely spaced, to ablate several tumours simultaneously, particularly helpful in the case of multiple metastatic ablations. This presentation will focus on the indications for pulmonary thermal ablation, the limitations of the procedure and the advantages of MWA over RFA.

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Abstract
We have developed a novel transgenic mouse (MexTAg) where cellular transformation is driven by the SV40 (simian virus 40) large T antigen (TAg). In these mice, TAg is specifically targeted to the mesothelial compartment because it is expressed under the control of a tissue specific promoter. MexTAg mice uniformly develop mesothelioma after exposure to asbestos, with no spontaneous formation of other tumours. The key differences between MexTAg and wild type animals are the higher incidence and the shorter latency of the disease. Survival after diagnosis is not different suggesting that TAg does not drive a more aggressive disease. The model is comparable to human mesothelioma because of the eliciting carcinogen and because the location, pathology, molecular lesions and tumour response to therapy are similar (Robinson et al., 2006; Robinson et al., 2011). It is thought that asbestos fibres drive cellular transformation via the production of reactive oxygen species and the induction of chronic local inflammation. Accordingly, we have begun to test antioxidants and anti-inflammatory drugs as potential cancer prevention agents. We have reported that dietary supplementation with the antioxidants, vitamins A, E and selenium does not affect overall survival nor the time to progression of asbestos-induced mesothelioma in MexTAg mice (Robinson et al., 2012). We have extended our analysis to vitamin D and compared survival of asbestos-exposed MexTAg mice provided with diets supplemented (4500 IU/kg feed) or deficient in vitamin D (cholecalciferol). Survival of supplemented mice was significantly shorter than mice given standard diet (median survival, 29 and 32.5 weeks respectively). Mice deficient in vitamin D developed mesothelioma at the same rate as control mice. We conclude that vitamin D is unlikely to moderate the incidence of disease in asbestos exposed populations or to ameliorate the pathology in patients with established mesothelioma. Mesotheliomas in MexTAg mice respond to cytotoxic chemotherapy. Gemcitabine treatment from week 16 prolonged survival of asbestos-exposed MexTAg mice increasing the median survival from 33 weeks to 48 weeks. Interestingly, latency was not significantly prolonged, but animals survived for longer after the first signs of disease were noted. To understand the importance of the immune system in the pathogenesis of mesothelioma, we crossed MexTAg mice with immune deficient RAG KO mice. Perhaps surprisingly, MexTAg mice with no acquired immunity lived longer with a more indolent disease than their immunocompetent sibs. We compared cell lines derived from mesotheliomas from MexTAg mice and cell lines from wild type mice with human mesothelioma cell lines by expression array. TAg expressing mouse tumours were 90% identical to wild type mouse tumours. The key pathway that was different was cell cycle-associated. Human mesotheliomas commonly have a deletion of the cdkN2 locus, encoding the tumour suppressor genes p16 and p15. While wild type mouse tumours carried a homologous p16 deletion, TAg tumours did not. We hypothesize that TAg expressing mice develop tumours in an accelerated way following asbestos exposure because they are not dependent on deletion of p16 for tumourigenesis. Robinson, C., I. van Bruggen, A. Segal, M. Dunham, A. Sherwood, F. Koentgen, B.W. Robinson, and R.A. Lake. 2006. A novel SV40 TAg transgenic model of asbestos-induced mesothelioma: malignant transformation is dose dependent. Cancer Res 66:10786-10794. Robinson, C., A. Walsh, I. Larma, S. O'Halloran, A.K. Nowak, and R.A. Lake. 2011. MexTAg mice exposed to asbestos develop cancer that faithfully replicates key features of the pathogenesis of human mesothelioma. Eur J Cancer 47:151-161. Robinson, C., S. Woo, A. Walsh, A.K. Nowak, and R.A. Lake. 2012. The antioxidants vitamins A and E and selenium do not reduce the incidence of asbestos-induced disease in a mouse model of mesothelioma. Nutrition and cancer 64:315-322.

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Abstract
Malignant mesothelioma (MM) represents a significant clinical challenge. Not only can this tumour be difficult to diagnose but treatment options are limited. There is a desperate clinical need for biomarkers that can aid the diagnosis of MM, and/or predict survival and measure disease response to treatment. MM diagnosis is challenging as phenotypic differentiation of malignant mesothelial cells from benign reactive ones is notoriously difficult. No immunohistochemical marker(s) can uniformly define the cancer either. Invasive pleural tissue sampling for MM is more frequently negative than in any other cancer type [1]. A reliable diagnostic marker will present a major aid to clinicians. The median survival for the MM population is less than 12 months, however about 5% of patients live for several years and unusually long survivals of over 10 years have also been seen. But no reliable prognostic algorithm exists to predict survival in individual cases – a question of utmost concern for patients and their families. There is no cure for MM. Chemotherapy may improve survival, but only 30 to 40% of patients respond [2]. Thus finding a biomarker that may reflect disease burden and response to therapy, and hence prognosis, will be a significant advance. It has been nearly a decade since mesothelin [3] and MPF [4,5]were reported as candidate biomarkers for MM, both providing similar diagnostic accuracy [6]. A recent meta-analysis of serum mesothelin in the diagnosis of MM determined that having a sensitivity of 32% at a 95% specificity was too low for diagnostic use and highlighted the need for ongoing research for better biomarker(s) [7]. However, studies world-wide on a range of soluble markers including osteopontin, hyaluronic acid, CA125, CA15-3 and others have failed to improve upon diagnostic accuracy. More potential biomarkers such as fibulin-3 and the SOMamer panel have recently been identified [8,9]and the search to discover novel biomarker(s) for this disease using a variety of genomic, proteomic and immunologic approaches continues. For these candidate MM biomarkers to attain their professed clinical potential, independent externally validated studies with large, representative patient cohorts will be required. The next stage will then need studies to determine how to integrate promising markers into clinical diagnostic and/or management algorithms, a process essential to improve outcomes for MM patients. 1 Davies, H. E. et al. Outcome of patients with nonspecific pleuritis/fibrosis on thoracoscopic pleural biopsies. Eur J Cardiothorac Surg 38, 472-477, (2010). 2 Nowak, A. & Bydder, S. Management of malignant pleural mesothelioma: a review. Asia Pacific J clin Oncol (2007). 3 Robinson, B. W. et al. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 362, 4 Onda, M. et al. Megakaryocyte potentiation factor cleaved from mesothelin precursor is a useful tumor marker in the serum of patients with mesothelioma. Clin Cancer Res 12, 4225-4231 (2006). 5 Shiomi, K. et al. Novel ELISA system for detection of N-ERC/mesothelin in the sera of mesothelioma patients. Cancer Sci 97, 928-932 (2006). 6 Hollevoet, K. et al. Diagnostic performance of soluble mesothelin and megakaryocyte potentiating factor in mesothelioma. Am J Respir Crit Care Med 181, 620-625, (2010). 7 Hollevoet, K. et al. Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis. J Clin Oncol 30, 1541-1549, (2012). 8 Ostroff, R. M. et al. Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool. PLoS One 7, e46091, (2012). 9 Pass, H. I. et al. Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma. N Engl J Med 367, 1417-1427, (2012).

Abstract
Approval of most new agents for advanced non-small-cell lung cancer (NSCLC) has been based on prolongation of OS, representing a direct measure of clinical benefit, in randomized clinical trials. Recently, however, as we have more opportunity to obtain trial results showing “significant improvement in PFS without any OS benefit”, most investigators feel that the assessment of OS may become of limited use and that PFS must be surrogate endpoint for assessing the efficacy of an experimental agent in NSCLC. Originally, PFS is quite different from OS since it is subjective, but not a direct measure of clinical benefit. Progression is often asymptomatic, and it is not always clinically relevant. To use PFS as surrogate endpoint, its validity should be statistically evaluated. In the pooled analysis using individual patient data of randomized trials comparing first-line docetaxel with vinca-alkaloids, Buyse et al. showed relatively weak PFS-OS correlation [BMJ open 2013;3:e001802]. So far, there seem no other large-scaled validation studies investigating the surrogacy of PFS for OS endpoint with formal statistical approach. Thus, PFS has not yet been a statistically acceptable surrogate endpoint for OS in patients with metastatic NSCLC. Now, what could we interpret “significant improvement in PFS without any OS benefit”? Also, what would be the clinically meaningful endpoint in advanced NSCLC? The literature-based study was conducted to assess the PFS-OS relationship with the data of the phase III trials investigating molecular-targeted agents in advanced NSCLC [Lung Cancer 2013;79:20]. It showed a strong PFS-OS correlation only in trials where subsequent therapy was conducted less frequently, whilst trials with a higher proportion of use of subsequent therapy had weaker association. The study concluded that 1) the relationship between PFS and OS is originally strong enough to support potential surrogacy of PFS, but that 2) given the observation that increasing use of effective salvage therapies could affect the PFS-OS association, improvement in PFS without any OS benefit does not mean the experimental agent fails to have a true clinical benefit. That is, a potentially true OS benefit by an experimental agent would have been seen without any confounding if no subsequent therapy had been given. This theory is called “explanatory approach”, supporting the use of PFS as a clinically meaningful outcome. Rather, there is an opposite opinion, suggesting the observed difference in OS would be considered the measure of clinical benefit, regardless of subsequent therapies, provided that they follow the current standard of care. This is the pragmatic approach [JCO 2011;29:2439]. The observed difference in OS, of course, will be expected smaller by the subsequent therapy than one would see if it was not available, leading to the need of a large sample size to detect such differences. But, according to the pragmatic approach, such potentially attenuated but actually observed OS difference should be used for assessing the true clinical benefit of the experimental agent in the given clinical setting under reflecting the clinical reality of available subsequent treatments. Recently, ASCO discussed what would be clinical meaningful outcome in advanced NSCLC without EGFR or EML4-ALK mutations, and provided draft recommendations as follows: 1) survival after first line therapy is relatively short, and OS is a feasible endpoint although the effects of the experimental agent on OS can be clouded by treatments administered after the period of therapy, and 2) clinical trials should aim to improve OS by a minimum of 25% as compared with standard therapy. ASCO seems to support the importance of measuring OS rather PFS, in favor of the pragmatic approach. Even in the first-line metastatic colorectal cancer, though PFS has already been established as a surrogate for OS in the 90’s, its surrogacy was reappraised using individual patient data between 1997 and 2006 because of the advance in the treatment during the last decade and recent improvement of OS [JCO 2013 (suppl;abstr 3533)]. Surprisingly, the PFS-OS relationship was not as strong as was seen in the 90’s. The study concluded that in modern metastatic colorectal cancer trials where SPP exceeds time to first progression, the treatment effects on PFS do not reliably predict those on OS. It seems that even though PFS was once accepted as a suitable surrogate for OS, its validity should be assessed repeatedly along with the advances especially in the post-progression treatment, which also supports the concept of the pragmatic approach. Regarding the regulatory considerations, the FDA stated OS should be considered the standard clinical benefit endpoint and that it should be used to establish the efficacy of a treatment in metastatic NSCLC, although it can also consider PFS for regulatory decision of drug approval based on the population. Some of the abovementioned findings potentially support the rationale of the pragmatic approach, stressing the importance of a possibly attenuated, but actually observed OS difference. However, this theory is unlikely to be applied in more recent trials investigating specific targeted therapies including EGFR-TKIs or ALK inhibitors, because no OS difference would be arguably obtained due to a quite high level of crossover inevitably for the ethical reason. Thus, under the special situation where i) an experimental agent has theoretically been considered to target specific molecules, and ii) the earlier trials showed dramatic effect, this possibly high proportion of crossover can compromise the ability to assess clinical benefit, and also lead to the unrealistic sample size to detect significant OS difference. Rather, in this condition, whether both large magnitude of PFS advantage and great OS advantage compared with historical control can be obtained would be more important than the conventional assessment of OS difference between the arms. In conclusion, the goals of any new cancer treatment are to offer patients a true clinical benefit. PFS has not yet been formally accepted as a valid surrogate for the OS endpoint in advanced NSCLC, and its surrogacy will be addressed by each drug mechanism of action and patient population. Finally, OS remains the primary endpoint of clinical trials, except in a situation where agents targeting specifically driver oncogenes are being evaluated with anticipation of high level of crossover.

Abstract
A screening programme is a set of procedures that can be applied to an asymptomatic population to enable early detection and treatment of disease. The success of the programme is dependent on this early intervention reducing morbidity and mortality associated with the disease. There has been much research to develop and assess potential screening programmes for lung cancer. In particular, there are a number of major clinical trials such as the National Lung Screening Trial in the United States, the United Kingdom Lung Cancer Screening Trial and the Dutch-Belgian NELSON trial, that assess the effectiveness of screening a high risk population with low dose computed tomography scans to reduce mortality from lung cancer. The key elements of any screening programme are: (i) identification of the target population for screening, (ii) the screening test that will be used to classify patients as likely or unlikely to have the disease, (iii) the frequency of applying the screening test, (iv) the diagnostic test that will be used to determine whether people are truly diseased or not, (v) the treatment that will be available for those diagnosed early. These choices will impact on the statistical design. The research question may be whether to introduce screening, to determine the frequency of screening, to identify the appropriate target population for screening or whether to add an additional screening tool to an existing screening modality. Randomised controlled trials are the gold standard for assessing a screening programme as they overcome major biases specific to screening namely lead-time bias, length bias, over-diagnosis bias and selection bias. The usual trial design parameters are important but special statistical issues arise in relation to screening trials. Statistical inferences should only be made back to the eligible population defined for the trial so the choice of eligibility criteria is important. Screening interventions can cause harm to individuals that are potentially disease-free so the target population is usually those who are at high risk of disease. Interventions such as CT scans which have both a relatively high risk and high level of harm should be targeted at a high risk population whilst those that are low risk to the individual such as sputum cytology could be targeted at a wider population. Harms also include the inconvenience and psychological effects of a false positive result. A high risk population is usually defined in terms of pack-years of smoking and time since quitting and simple patient characteristics such as age. Statistical models that predict risk of disease could enhance the identification of a high risk population but the accuracy of prediction should be considered in relation to its impact on the trial. The primary outcome measure to assess benefit of a lung cancer screening programme should be lung cancer specific mortality. Duration of follow-up is an important design parameter. It needs to be long enough to allow for the time lag before the impact of screening becomes apparent and not so long after the cessation of screening as to include a period of time when screening would have lost its impact. Appropriate statistical analysis of the primary outcome measure is essential to properly evaluate the benefits of screening. Typically the screening intervention will be compared to the control arm in terms of its ability to reduce cumulative mortality. If this is calculated over the entire period of screening and follow-up then the benefit may be underestimated. Comparing time-specific mortality rates is the recommended approach [1]. The analysis is also complicated by the problems of non-attendance and contamination but methods have been proposed to adjust for these [2]. Sample size calculations involve key design parameters including hypothesised mortality reductions, expected compliance and contamination, number of screening rounds and length of follow-up [3]. The accuracy of the screening test to predict disease in asymptomatic people is not only important for the feasibility and ethics but will also impact on sample size as inaccurate predictions will dilute the potential benefit of screening. Screening tests, such as those that involve biomarkers measured on a continuous measurement scale, should be rigorously developed and validated before assessing their clinical utility within a randomised controlled trial environment. References [1] Hanley JA; Measuring mortality reductions in cancer screening trials; Epidemiologic Reviews 2011; 33: 36-45. [2] Baker SG, Kramer BS, Prorok PC; Statistical issues in randomised trials of cancer screening; BMC Medical Research Methodology 2002; 2: 11. [3] Prorok PC, Marcus PM; Cancer screening trials: nuts and bolts; Seminars in Oncology 2010; 37(3): 216-223.

Abstract
The growing number and rising costs of modern lung cancer therapies have brought the issue of cost and cost effectiveness to the forefront of clinical practice. While personalized medicine improves outcomes in specific subgroups, sparing others from ineffective costly treatment and toxicity, it can be challenging to incorporate into economic analyses. Defining the target population for the new treatment is key, and then evaluating the costs and benefits of the new intervention compared to the previous standard. However, the definition of molecular populations for targeted therapies has emerged as an important consideration when considering whether or not to adopt a new targeted therapy. The cost of biomarker testing can have a major impact on healthcare costs, and many countries are struggling with how to best incorporate the "hidden" costs of personalized medicine into adopting new targeted therapies. Focusing only on the target population, comparing the new treatment with standard comparators does not incorporate the costs of biomarker testing, or need for repeat biopsies for successful testing, but will be a better reflection of the benefit of the new treatment in that population. Comparing a test-and-treat strategy to a strategy without testing or the new therapy allows incorporation of the costs of testing, but has some important challenges. Biomarker frequency is a key driver in these analyses, with smaller populations as a particular challenge, such as ALK positive nonsmall cell lung cancer. Presenting the cost of both a test-and-treat strategy alongside an evaluation of the cost effectiveness of therapy in the target population may be a better way to illustrate the impact of a novel treatment, especially when the target population is small, while acknowledging the incremental financial burden of biomarker testing in cancer. This may allow new therapies to compete with current alternatives on a comparable footing, and not underestimate the impact of a new treatment in a small subgroup. It would also permit the development of more effective and cost-efficient screening methods for the desired target population. It is important to recall that technological methods and costs involved in biomarker testing and molecular analysis are rapidly changing, and should be revisited over time. The technological methods used to identify molecular abnormalities in cancer, such as sequencing and antibody development, are changing rapidly along with associated costs. Thus less expensive or more efficient methods (e.g. multiplex testing) may be more affordable compared to more labor-intensive methods used in initial clinical trials. For example, immunohistochemical techniques may replace more expensive methods, allowing more jurisdictions to take up testing and treatment of new therapies.

Abstract
Over the last several years, there have been a number of new classes of drugs approved for the management of lung cancer. Regulatory pathways are evolving in many ways – for example, to recognize that targeted therapies, such as the EGFR inhibitors, will require evaluation of the drug alongside a diagnostic test; or that the increasing specificity of targets may result in smaller and shorter trials with different endpoints; or that regulatory authorities might identify potential significant advances in therapy by the use of special evaluation pathways, such as the ‘breakthrough’ therapy designation from the US FDA. Sometimes the trials now also measure quality of life outcomes or patient preferences. But these trials are still fundamentally designed to ask the ‘regulatory’ question – can the new product work – as well as assessing the risk-benefit ratio. But where does this changing regulatory environment leave payers? The information set that is available to guide assessments of value of money generally seems to becomes more limited as the regulators increase the pace of their decision-making. Trials are truncated or treatment groups are crossed over to the new treatment at the earliest possible opportunity, often before there is a confident estimate of the effect size in terms of final clinical outcomes. The ethical imperative to offer access to possibly effective treatments outweighs ensuring adequate trial design to be confident in the estimate of effect. Statistical techniques to ‘adjust’ for limitations in design become more and more complex, and more prone to uncertainty. And at the same time, most countries are still struggling with faltering economies and diminishing health budgets. Patients still want access to the latest treatments, but are less and less willing to pay increasing prices. Payers then have to compare the limited information set available for new drugs with what is known about current treatments. Arguments over the value of differences such as a 1.4 months gain in overall survival compared to existing treatment become conflated with the cost of this gain. That is assuming, of course, that there is a gain in overall survival, which has not been often shown to date in the trials of the new drugs for lung cancer. When high prices and high prevalence are combined, the value-for-money question is rightly raised – why pay so much more for so much uncertainty? Arguments about incremental advances in therapy, innovation and technological developments then dominate the discussion, rather than the appropriate focus on health gain for communities and individuals. So what is the solution? Options suggested include ‘managed entry’ of new products with additional data collection as a condition of price negotiation, ‘paying for performance’ with outcome data collection, or ‘value-based pricing’ that allows a premium for ‘innovation’. However, given the high clinical need for effective treatments, the emphasis should be on getting the best health outcomes for an affordable price, to the community and for individuals.