Virtual Library

Abstract:
Aberrations of oncogenes, such as EGFR mutation; and ALK and ROS1 fusions, function as a driver in the development of lung adenocarcinoma (LADC) and are established therapeutic targets. We previously identified RET fusion present in 1-2% of LADC (Kohno, Ichikawa, Nat Med, 2012). Its activity as an oncogenic driver in lung carcinogenesis was validated by a study of transgenic mice expressing KIF5B-RET cDNA in their lungs (Saito, Carcinogenesis, 2014). RET fusion is likely to be another target of therapy using tyrosine kinase inhibitors, as represented by a high response rate of RET-fusion positive LADC to vandetanib (LURET study, Yoh et al., Lancet Resp Med, 2016). Our genome-wide sequencing study revealed that ALK, RET and ROS1 oncogene fusion-positive LADCs carry less numbers of mutations in cancer-related genes than others (Saito, Cancer Res, 2015), indicating a small mutation burden in the development of the formers. On the other hand, >30% of LADC and most of other types of lung cancers are negative for the oncogene aberrations above, therefore, other therapeutic targets are needed for precision lung cancer medicine. We have revealed frequent inactivation of chromatin-regulating genes, such as SMARCA4/BRG1 and CREBBP, in lung cancers negative for oncogene aberrations (Ogiwara et al, Cancer Discovery, 2016). We propose a synthetic lethal therapeutic method for chromatin regulator-deficient lung cancers based on inhibition of paralog proteins. LADC driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). We recently revealed that variations in HLA-class II loci underlie the risk of the disease, by conducting a genome-wide association study of 3,173 EGFR-LADC patients and 15,158 controls (Shiraishi et al., Nature Comm, 2016). The result indicates that LADC develops in vivo through interaction between somatic oncogene mutations and germline variations that modulate immune reaction. We would like to discuss here precision lung cancer medicine based on information on cancer and the host genomes.

Abstract:
The implementation of mutation-directed therapy has revolutionized systemic treatment of non-small cell lung cancer (NSCLC). In particular in lung adenocarcinoma targetable driver mutations can be found in a substantial proportion of patients allowing therapy with specific tyrosine kinase inhibitors (TKI) with higher efficacy and better tolerability compared to chemotherapy. Such personalized treatment approaches partly have already become first line standard therapy (EGFR, ALK, ROS1, BRAF V600), other driver mutations are currently evaluated in clinical trials (MET, RET, HER2, NTRK). Also with these new treatment options, however, we are still far away from cure and, mostly after a median progression free survival (PFS) of 10 – 12 months, resistance develops and the patients suffer from relapse. Different mechanisms may underlie primary as well as secondary resistance, which can be subdivided in two major groups: (I) pharmacological resistance, caused by reduced absorption or increased metabolism of the drug or, as a particular challenge in patients with CNS-metastases, by inadequate CNS penetration; (II) biological resistance by molecular changes in the target molecule (resistance mutations or gene copy number gain) or by activation of oncogenic bypass pathways (1). Impressive progress in treating NSCLC patients resistant to TKI therapy has been achieved by a deep understanding of the molecular mechanisms underlying biological resistance, in particular in EGFR mutated and ALK positive NSCLC. In about 60% of patients with acquired resistance (AR) to first- or second generation EGFR-TKIs resistance is caused by the secondary EGFR point mutation T790M leading to reduced TKI binding affinity and conferring growth advantage to the cancer cells. The resistance mechanisms include activation of bypass pathways e.g. by amplification of CMET or HER2 and transition to small cell carcinoma (2). Osimertimib, a third-generation EGFR-TKI, can overcome resistance caused by the T790M mutation and, based on its high clinical activity and favorable tolerability, now has become standard treatment for patients with T790M positive AR to EGFR-TKIs (3). However, resistance also occurs under osimertinib therapy and the molecular mechanisms, which are partly different to those conferring reistance to first generation EGFR inhibitors, are increasingly understood on the molecular level. They include occurrence of the EGFR C797S mutation, activation of the RAS/RAF/MEK/ERK pathway, CMET amplification and HER2 amplification (4,5). Dependent on the molecular mechanism underlying resistance to third generation EGFR inhibitors treatment strategies include the development of next generation inhibitors with activity against C797S positive cancer cells (6) as well as the evaluation of combination therapy approaches e.g. EGFR-TKI plus MET- or MET-inhibitors. These combination approaches are evaluated in the clinical setting of manifest relapse (to overcome resistance) but also as first line treatment (to prevent or postpone relapse). Similarly, also osimertinib is being evaluated in the first line setting and a substantial higher PFS has been reported in this clinical situation. A particular challenge for molecular diagnostics as well as for the development of resistance-overcoming therapeutic strategies is clonal heterogeneity, i.e. the occurrence of different driver mutations within the same patient (7). Also in ALK positive patients substantial progress has been achieved in understanding and overcoming the molecular mechanisms underlying resistance to therapy with ALK-directed TKIs. Similarly to AR to EGFR-TKIs also in AR to ALK-TKIs resistance can be caused by resistance mutations in the ALK receptor itself or by the activation of transforming bypass pathways. A series of resistance mutations has been identified and several next-generation ALK-inhibitors are either already approved or in clinical evaluation. These ALK inhibitors differ in their activity against distinct ALK mutations providing a basis for moleculary guided sequential therapy (8). Already now, impressive prolongation of survival has been reported by the sequential use of the first generation ALK inhibitor crizotinib and the next generation ALK inhibitors alectinib and ceritinib (9,10). Also for other driver mutations like ROS1, BRAF V600 or CMET resistance to TKI therapy is increasingly understood on the molecular level enabling the development of resistance-overcoming treatment strategies for these patients. The development of molecularly guided treatment strategies in AR to TKIs also poses a challenge to molecular diagnostics. In view of the numerous mechanisms which might underly resistance, the implementation of rebiopsies and molecular multiplex diagnostics using next-generation-sequencing (NGS) technologies in clinical routine becomes increasingly important. In addition, the particular challenge of clonal heterogeneity might be addressed already in the near future by the development of highly sensitive NGS-based liquid biopsy diagnostics. References Camidge R et al. Nat Rev Clin Oncol 11, 473-481 (2014) Yu HA et al. Clin Cancer Res 8, 2240-2247 (2013) Mok TS et al. NEJM 7, 629-640 (2017) Thress KS et al. Nat Med 6, 560-562 (2015). Ortiz-Cuaran et al. Clin Cancer Res 19, 4837-4847 (2016) Jia Y et al. Nature 534, 129-132 (2016) Scheffler et al. J Thorac Oncol 10, 40-43 (2015) Gainor et al. Cancer Disc 10, 1118-1133 (2016) Gainor et al. Clin Cancer Res 21, 2745-2752 (2015) Duruisseaux et al. Oncotarget 8, 21903-21017 (2017)

Abstract:
Heterogeneity is a universal phenotype across different cancer types, including non-small cell lung cancer (NSCLC). Tumor heterogeneity is present not only between different tumors from different patients or within the same patients (inter-tumor heterogeneity), but also between different cells within the same tumor (intra-tumor heterogeneity, ITH). ITH results from tumor evolution and in the meanwhile servers as a substrate for tumor evolution. ITH may be influenced by the host antitumor immune surveillance as well as anticancer therapies. Delineating cancer evolution and ITH may provide pivotal insight to our understanding of cancer development, progression and therapeutic resistance, and may eventually help us design more effective preventive and therapeutic strategies. Pioneering studies by multi-region profiling and by comparing paired primary and relapsed tumors have shed light on cancer genomic evolution and suggested the potential impact of genomic ITH on cancer biology and patient outcome. Tracking Non-Small Cell Lung Cancer Evolution through Therapy (TRACERx) is by far the largest study on genomic ITH of NSCLC using multi-region sequencing approach. The results from the first 100 patients enrolled in TRACERx were recently published in the New England Journal of Medicine. In this elegant study, 327 tumor regions from 100 tumors were subjected to high-depth whole exome sequencing (WES). Extensive genomic ITH was demonstrated at both nucleotide and chromosomal levels: a median of 30% of somatic mutations and 48% of copy number alterations (CNAs) were subclonal. Early clonal mutations were associated with smoking signatures in the majority of tumors, while subclonal mutations were significantly enriched for genomic signatures related to spontaneous deamination of methylated cytosines and APOBEC suggesting different mutational mechanisms in play at different times during cancer progression. A high proportion of subclonal CNAs was associated with an increased risk of recurrence and shorter disease free survival (DFS). However, no significant association with DFS was observed between the groups when stratified by proportion of subclonal mutations. The rich data from TRACERx and previous studies are provocative for the future translational and clinical research. Herein, we outline some of the concepts. First, TRACERx provided another piece of evidence that genomic heterogeneity is associated with survival of patients with localized NSCLC. However, it is somewhat surprising that more commonly regarded ITH in point mutations was not found to be associated with survival in this patient cohort, which is in contrast with previous reports in NSCLC and other malignancies. Given the relative small sample size, short postsurgical follow up (median follow up of approximately 18 months with 80% patients less than 2 years) and only 20 relapses, any imbalance in major prognostic factors such as stage, age, histology, smoking, and adjuvant therapy may have masked an actual association between mutational ITH and survival. Our group has recently completed multi-region deep WES on 30 stage IA NSCLC -15 patients relapsed within 3 years post-surgery (cases) and 15 patients have not relapsed with a minimum of 5-year postsurgical follow up (controls). Cases and controls are matched for stage, tumor size, gender, age, histology, smoking history etc. and none of the patients received neoadjuvant or adjuvant therapy. In this well-balanced case-control study, higher degree of point mutation ITH was found to be associated with shorter overall survival and shorter DFS. Nevertheless, the association between CNA ITH and DFS reported in the TRACERx study remained significant after adjusting for known prognostic factors suggests that chromosomal ITH may have greater impact on patient outcome than somatic mutations. This is probably because gain or loss of chromosomal segments or even whole chromosomes could affect hundreds or thousands of genes that may thus disrupt multiple key molecular processes, while point mutations usually affect single genes or pathways. Second, subclonal driver mutations are often detected by multi-region sequencing, which introduces a challenge to our current personalized oncology approach based on sequencing driver genes from single biopsies. Multi-region sequencing is not practical for patients with metastatic diseases or unresectable tumors. However, ctDNA is not spatially limited to certain tumor regions and may have the advantage in detecting subclonal mutations compared to single biopsies. With the rapid progress being made in liquid biopsy and sequencing technologies, sequencing ctDNA could become a practical alternative for multi-region tumor sequencing. Third, majority of studies on NSCLC ITH are based on primarily resected tumors. How chemotherapy, targeted therapy, radiation or immune therapy would impact ITH architectures remains unknown. One can hypothesize that residual tumor cells that survive neoadjuvant therapies could represent the subclones resistant to the these therapies. Therefore, investigating the residual tumors post-neoadjuvant treatment may provide valuable information on mechanisms of drug resistance. As such, well-designed window-of-opportunity neoadjuvant clinical trials would be invaluable for studying drug resistance. Forth, in addition to serving as a potential prognostic biomarker, ITH itself could become a potential therapeutic target. Given the important role of genomic instability in tumor evolution, modulating genomic stability such as targeting APOBEC family, a common cause of subclonal diversification of NSCLC, or inhibiting DNA repair pathways could become a novel therapeutic strategy. This strategy has been recently highlighted by the efficacy of PARP inhibitors in homologous recombination-deficient tumors. Last but not least, the majority of studies on ITH have mainly focused on the genomic ITH. However, ITH can be present at different molecular levels (genetic, epigenetic, gene expression etc.) of cancer cells and also of tumor microenvironment constituting of epithelial cells, blood and lymphatic vessels, cytokines, infiltrating immune cells etc. ITH of any of these components may impact tumor evolution and patient outcome. Our pilot study has demonstrated that a higher level of methylation ITH was associated with larger tumor size, advanced patient age and increased risk of postsurgical recurrence in NSCLC patients. Furthermore, we recently reported substantial T cell repertoire ITH in NSCLC with the majority of T cell clones restricted to individual tumor regions and that a higher degree of T cell repertoire ITH was associated with an increased risk of postsurgical recurrence and shorter DFS. Tumor evolution is a complex process, during which cancer cells accumulate molecular alterations that change their phenotypic features by interacting with the tumor microenvironment. In order to systematically understand the tumor ITH and evolution, future studies are required to depict the overall molecular (genetic, epigenetic, gene and protein expression) ITH of cancer cells as well as the tumor microenvironment components, ideally from longitudinally collected samples with or without treatments to dissect the evolutionary history of NSCLC and other malignancies leading to novel diagnostic, preventive and therapeutic strategies.

Abstract not provided

Abstract:
It is required to improve patient-physician communication and that patients be offered participation in informed decisions regarding their care ethically in the context of serious and life-limiting illnesses, citing effects of good communication on quality of care and life. Many patients with advanced cancer and caregivers seek empathetic communication from physicians. Inadequate communication about prognosis and treatment choices is common and is associated with unrealistic patient expectations regarding curability, provision of aggressive treatment that is not concordant with patients’ wishes and enrollment in hospice too late to deliver discernable benefit. Conversations related advance directive and advance care planning typically do not happen, or happen in hospital shortly before a patient’s death. In order to complete advance directives and prepare an appropriate advance planning, it is necessary to promote physicians’ empathic communication. Therefore, we developed the 2-day communication skills training (CST) for physicians based on patient preferences and confirmed the effectiveness for both patients’ psychological distress and physicians’ empathetic communication behaviors through a randomized controlled trial. After confirming the effectiveness at RCT, CST was conducted for doctors nationwide as a clinical implementation as a consignment project by the Ministry of Health, Labor and Welfare. Meanwhile, we developed question asking prompt list (QPL) for patients who were newly advanced lung and gastrointestinal cancer use in consultations and confirmed the usefulness through a randomized controlled trial. However, the QPL did not affect the number of actual question from the patient to the physician. It was needed to develop apamphletn intervention with QPL. Furthermore, the evaluation of caregivers is also needed. This presentation aims to determine the effectiveness of an integrated communication support program for promoting empathetic communication between rapidly progressive cancer patients, families and doctors, and to estimate the intervention effects on distress and QOL of patients and caregivers, faith in their physicians. These evidence of an effective intervention to promote communication and decision-making process based patients’ values and preferences between patients, caregivers and physicians with reducing physicians’ burden will be created. Based on the results, we will reflect clinical guideline regarding communication between patients and physicians in cancer care and develop a train-the-trainer workshop program with related academic society. It is also expected that providing supportive therapy at cancer hospitals will be standardized and subsequently the quality of life of cancer patients will be improved.

Abstract:
Patients with advanced, incurable cancer, and also their family members, typically struggle between hopes to have long lives or even get cured and the concious, unconcious or denied reality of limited life time due to cancer. This struggle becomes more pronounced in modern oncology, making predictions of response to anticancer treatments or survival increasingly difficult. Adressing existential issues and uncertainties is an often feared theme for cancer clinicians (doctors, nurses, other professionals) in clinical practice: concerns about destroying hope, hesitation about own professional role (e.g., authentic, paternalistic, servant for patients autonomy), doubts about involvement of family members, incertitude about decisional processes on anticancer treatments, or prudence on patients emotional condition (e.g., stress, trauma, anxiety, depression, anger) may constitute real challenges. Adequate communication skills including empathetic communication and concepts of shared decision making are necessary, but often not suffcient to perform as an accountable, understanding, educating, empowering, self-reflective, and competent clinician guiding patients and families to address the reality of limited live time, death, dying and bereavement. Preparation for illness-deterioration and end-of-life encompasses continuous engagement in a) patients illness understanding (e.g., causes and impact of pain, fatigue, or cachexia); b) decisional processes for or against anticancer treatments (e.g., concrete goals, significance of burdens, characterization of patients values and expressed definition of own quality-of-life); c) worst and best time range scenarios of life expectancy (never say a concrete mean estimate !) These communicative, educational and counselling interventions are part of early integrated palliative care, supported by high quality evidence to improve patients quality-of-life and symptoms. To integrate palliative care early services may adapt the name (supportive) but not the content. Advanced care plans (ACP) shall include most relevant elements to prepare for the end-of-life period, but often they are limited to power of attorney and life-sustaining treatment choices (e.g., POLST, Advanced Directives); evidence suggests that such limited processes may not alleviate existential distress, but still are important. ACP shall encompass a structured process delivered in several encounters of patient and family members with cancer clinicians, built on a trustful relationship invigorated in good decisions, patients values and life concept including spiritual aspects and patients and families’ adequate illness- and prognosis understanding. Evidence supports that ACP do not deteriorate hope and that even in cultures not used to ACP patients welcome them. Key elements of ACP encompass patients’ life values, expressed understanding and preferences of management of typical complications and disease deteriorations, concrete professional support (nurses, specialized palliative care nurses, physicians, other professionals, 24/7), timeschedule of family members offering support, preferred place of death, adressing premortal grief with important people, adressing premortal preparation for postmortal roles, preferences for funeral arrangments, legacy work, finish business including legal & financial issues and words of love, excuse, forgiveness and love, use time left conciously, prepare for prolonged live and lazarus effects. To engage in ACP clinicians may self-reflect about own accountability to have an opinion, offered in a humble, reliable, and attentive way. Also clinicians may embrace concepts of healthy denial and the power of the double way: the reality of death and dying together with promises of modern oncology. In summary it is less the issue of what to say, but how to support the process, offer advice and continuous, accountable support.

Abstract:
[Introduction] Dyspnea is one of the most frequent, refractory and distressing symptoms in lung cancer patients. It is reported that dyspnea interferes will to live in terminally ill cancer patients. Palliation of respiratory symptoms is important to improve quality of life (QOL) of cancer patients and their families. [Definition of dyspnea] 'Dyspnea' is defined as 'a subjective experience of breathing discomfort', while 'respiratory failure' is defined objectively as 'pulmonary dysfunction with hypoxia and/or hypercapnia'. Dyspnea and respiratory failure are different entities, and it is shown that the severity of those do not always correlate with each other. [Impact of dyspnea] Dyspnea experience is derived from interactions among physiological, psychological, social, and environmental factors, and may include secondary physiological and behavioral responses. Dyspnea often triggers panic, fear, anxiety, depression, hopelessness, sense of loss of control to patients. Dyspnea is closely associated with fatigue, pain, and depression, and interfering with general activities, mood and enjoyment of life. Dyspnea at rest is also known to correlate with survival, identified as a predictor of poor prognosis in cancer patients. [Clinical Assessment of Dyspnea] As for the assessment of dyspnea, multi-disciplinary team approach and paying attention to patients' own words are important. The assessment should focused on the following three dimensions; 1) quantities (intensity), 2) qualities, 3) symptom impact or burden. Several appropriate scales in each dimensions will be shown in this session. [Management of Dyspnea] Objectives of dyspnea management are to reduce its frequency and severity, minimize its physical, psychological and spiritual distress, and maximize patients' function and QOL. To achieve these goals, the first step is to identify all the underlying causes, and when they are reversible and modifiable, to treat them with specific modalities accordingly. It is, therefore, important for oncologists to judge treatability, including adverse effects, and to estimate patients' prognosis accurately. This session will provide the outline of palliative management of dyspnea with focus on pharmacological and non-pharmacological means. [Pharmacological interventions] The Japanese Society for Palliative Medicine (JSPM) published 'Clinical guidelines for respiratory symptoms in cancer patients' in 2016. These guidelines are unique because they are more directly focused on 'dyspnea' management specifically, based on the formal development process for clinical guidelines. Some of the important recommendations will be introduced in this session. *Note: Strength of recommendation: 1 (strong) = recommended, 2 (weak) = suggested. Level of evidence: A (High), B (Moderate), C (Low), D (Very low) 1) Opioids Systemic morphine is recommended to be used (1B). Systemic oxycodone is suggested to be used, as alternative to morphine (2C), while systemic fentanyl is suggested not to be used (2C). Systemic codeine/dihydrocodeine is suggested to be used (2C). 2) Benzodiazepine anti-anxiety Benzodiazepine is suggested to be used in combination with opioid (2C), while it is suggested not to be used alone (2C). 3) Corticosteroid Systemic corticosteroid is suggested to be used in patients with lymphangitis carcinomatosa, superior vena cava syndrome and major airway obstruction (2D). It is, however, suggested not to be used routinely without consideration of dyspnea etiology (2D). [Non-Pharmacological interventions] The effectiveness of non-pharmacological interventions for dyspnea in advanced cancer and non-cancer (mostly chronic obstructive pulmonary disease) has been reported in Cochrane reviews. Interventions supported by good evidence include breathing training, walking aids, and exercise. Those with some evidence include handheld fan, follow-up programs by nurses and acupuncture/ acupressure. [Conclusion] It is difficult to conduct high-quality clinical research on symptom control in advanced cancer patients because of patients' vulnerability as well as the ethical conflict. More clinical researches of good designs need to be conducted in this field, so that standard palliative care may be delivered to all the cancer patients anytime and anywhere, helping them live their own lives with dignity. [References] 1) Chan K, Tse DMW and Sham MMK. Dyspnoea and other respiratory symptoms in palliative care. In: Cherny NI, Fallon MT, Kaasa S, Portenoy RK, Currow DC. Oxford Textbook of Palliative Medicine (5[th] ed). Oxford University Press, 421-434, 2015 2) Yamaguchi T, Goya S, Kohara H. et al. Treatment Recommendations for Respiratory Symptoms in Cancer Patients; Clinical Guideline from the Japanese Society for Palliative Medicine. J Palliat Medicine. 2016, 19(9): 925-935 3) Bausewein C, Booth S, Gysels M, and Higginson I. Non-pharmacological interventions for breathlessness in advanced stages of malignant and non-malignant diseases. Cochrane Database of Syst Rev. CD005623, 2008 4) Non-invasive interventions for improving well-being and quality of life in patients with lung cancer. Cochrane Database of Syst Rev. CD004282, 2011

Abstract:
Lung cancer is the most deadly cancer disease in Denmark, one out of four cancer deaths, is due to lung cancer. 4656 Danes are living with a lung cancer diagnosis in late 2015. There are 4700 new cases each year. This means that lung cancer is responsible for 7,8 % of all deaths in Denmark and 24 % of all cancer deaths.[1]Getting lung cancer has major personal consequences - and major consequences for society. There are rehabilitation services for Danish lung cancer patients, and it has a great potential for improvement. The purpose of lung cancer rehabilitation is to support and assist lung cancer sufferers and their relatives, dealing with the changes in everyday life – including at work – that the disease causes. A lung cancer patient in Denmark meets a nurse in many contexts. Nurses are a necessity for the lung cancer patient and rehabilitation in Denmark. I will present a small sample of the rehabilitation possibilities a lung cancer patient meets in Denmark. My focus is, nurse involvement and whether they have sufficient education for the task. Copenhagen Centre for Cancer and Health provides rehabilitation programs including physical activities, education, and discussion groups or sessions. The rehabilitation programs are for cancer patients living in the City of Copenhagen. A referral from the patient´s GP or hospital department is required in order to participate. There are similar centers in many other cities in Denmark. These centers provide good opportunities for lung cancer patients and rehabilitation. At the Health Care Centre, the lung cancer patient meets nurses.[2] “Well, you know – you have symptoms of something and you come here and tell the others about it and they say “I know just what you are talking about, that is how I´m feeling” – it´s a nice experience and makes me feel that I am all right” - Statement from a man with lung cancer, Copenhagen Centre for Cancer and Health The Danish Cancer Society is the largest disease-fighting organization in Denmark. The organization has more than 430,000 members. They have 3 main work areas in the fight against cancer: #prevention of cancer #giving advice to and supporting cancer patient and their relatives #cancer research. Via this organization, the lung cancer patient can talk to nurses and gets the opportunity to receive information, counseling, social networking and you can be anonymous – if you want to.[3] A Danish lung cancer patient can become a member of the Patient Association for Lung Cancer. It is a nationwide independent association for people with lung cancer and mesothelioma, and their families. You can stay up-to-date on lung cancer treatment, health policy, networking and you can also be a part of a community. You can also help put lung cancer on the agenda. There are 500 members in Denmark.[4] In order for the lung cancer patient's possibilities / conditions to improve, there are many projects in Denmark. The Vision Project - a multidisciplinary working group with professionals across the country and dealing with all aspects of the disease, from surgery to palliative care. Action areas are formulated and concrete initiatives made. In this context, there will be a particular focus on rehabilitation that can improve the life quality of lung cancer patients during and after treatment.[5] Social inequality in cancer rehabilitation - The University Hospital in Copenhagen and the Health Care Center in Copenhagen are developing a concept for motivational conversations offered to vulnerable patients. The hospital assesses the need for cancer rehabilitation to those expected to be at risk of saying no to a rehabilitations process. It is a nurse who coordinates the project.[6] Proluca (the value of Postoperative Rehabilitation of Operation for cancer) is a research project in which the effect of early training after surgery for lung cancer is evaluated. The project aims to investigate whether training shortly after surgery for lung cancer can lead to an improved performance in the post-operation phase. It is as a nurse who coordinates the project in the health care center in Copenhagen.[7] Good lung cancer care is related to nurse education. In Denmark the Bachelore’s degree programme in Nursing has a duration of 3 and a half years; you can also get an Advanced Cancer Nurse Education – this requires 1 and a half year of training.[8] Taking care of a lung cancer patient can often be complicated and requires nursing care at a high level. On a global scale, Denmark has a lot to offer lung cancer patients, but there is obviously still room for improvement, since this group of patients faces so many different challenges in their everyday life. And it takes well-educated nurses to meet the complex demands of lung cancer patients. [1] www.lungecancer.dk/ [2] www.kraeftcenter-kbh.dk/ [3] www.cancer.dk/international/ [4] www.lungekraeft.com/ [5] lungecancer.dk/documents/F1BFDA1D-EBFD-409A-A26A-15FF5385F00A.pdf [6] www.kraeftcenter-kbh.dk/projekter/social-ulighed [7] www.kraeftcenter-kbh.dk/projekter/proluca [8] www.dsr.dk/

Abstract:
The onset of an MPE usually indicates a significant reduction in prognosis, with a median life expectancy of 3 to 12 months from onset. MPE associated with breast cancer is usually associated with a better than average prognosis whilst lung cancer has the worst prognosis. Confirmation of malignancy and determination of the cell type may be established by increasingly invasive techniques; pleural aspiration cytology, facilitated by ultrasound guidance if the effusion is small or loculated, pleural biopsy, blind or image guided, thoracoscopy (usually now video-assisted) under local or general anaesthesia. Whilst it is reasonable to start with the least invasive procedure suitable in the circumstances, in patients who are reasonably fit it is important to avoid an escalating cascade of failed procedures, each with the risk of causing pleural adhesions and clot formation, making effective palliation more difficult. There is much to commend early acceptance of an approach which combines the best chance of a tissue diagnosis with the best chance of effective palliation. This decision will be influenced by an assessment of prognosis. Prognosis once an MPE has been confirmed is dependent upon the extent of metastatic disease and associated co-morbidity. In a surgically palliated population in-hospital and 30-day mortality was statistically related to blood albumen levels, being 0% and 0.98% in those with normal albumen levels and 6.8% and 19% in those with hypoalbumenaemia (p=0.001) (1). In a series of 278 patients referred to the Department of Thoracic Surgery at the Royal Brompton Hospital over a 72 month period 195 underwent thoracoscopic talc pleurodesis, 39 had a pleuro-peritoneal shunt inserted, 38 had pleurodesis through an intercostal drain, 29 had pleural biopsy alone and 9 were treated with long-term pleural drainage, a total of 310 surgical procedures. Overall median survival was 211 days post operatively. Survival was not significantly different for tumour type or method of palliation but was related to leucocytosis (p<0.0001), hypoxaemia (p=0.014) and hypoalbumenaemia (p0.0001) (2). The summative effect of these factors is shown in the table below. Table 1

No of factors	n	Median survival (days)	95% CI	p
None	39	702	473-931	.00001
One or two	74	200	111-289
Three	23	42	23-61

How might this information be used to personalise treatment options in patients for whom effective systemic therapy does not exist. Those whose prognosis is judged to be less than 2 months (having all 3 adverse prognostic factors) palliation may be achieved by repeated pleural aspiration. If prognosis is judged to be greater than 2 months, and especially if the patient is in a poor general condition, adequate palliation could be achieved by the insertion of an indwelling pleural catheter under local anaesthesia. In fitter patients with an estimated survival greater than 6 months VATS insufflation of talc or the insertion of a pleuro-peritoneal shunt should be considered. The choice of talc or shunt will be dictated by the adequacy of lung expansion during positive pressure ventilation. In many respects these 2 techniques are complementary but having both of these techniques available at thoracoscopy allows affective long-term palliation to be achieved in 95% of patients (3). However pleuro-peritoneal shunts can be complicated by occlusion within 4 months in 15% of cases but spontaneous pleurodesis has usually been achieved by this time (4). Pleurectomy is rarely indicated in the palliation of MPE. Reference List (1) Pilling JE, Dusmet M, Ladas G, Goldstraw P. Predictors of early mortality and morbidity follwoing surgical palliation of malignant pleural effusion. Journal of Thoracic Oncology 2[8], s430. 2007. (2) Pilling JE, Dusmet ME, Ladas G, Goldstraw P. Prognostic Factors for Survival after Surgical Palliation of malignant Pleural Effusion. J Thorac Oncol 5, 1544-1550. 2010. (3) Petrou M, Kaplan D, Goldstraw P. The management of recurrent malignant pleural effusions: The complementary role of talc pleurodesis and pleuroperitoneal shunting. Cancer 75, 801-805. 1995. (4) Genc O, Petrou M, Ladas G, Goldstraw P. The long-term morbidity of pleuroperitoneal shunts in the management of recurrent malignant effusions. European Journal of Cardio-thoracic Surgery 18, 143-146. 2000.

Abstract:
Dignity has been defined as the “quality or state of being worthy, honored or esteemed”[1]. While dignity-conserving therapy is popularly defined as assisted suicide in the setting of terminal illness, it may also be considered as a larger goal of palliation and achieving a “good death”. Chochinov has defined 8 subthemes in the conservation of dignity at the end of life, including continuity of self, role preservation, maintenance of pride, hopefulness, autonomy/control, generativity/legacy, acceptance and resilience or fighting spirit [1]. Based on how patients and their caregivers define dignity, different interventions may be used to target or support physical and/or psychological distress, a patient’s level of independence, patient perspectives and interactions with others. Dignity Therapy as developed by Chochinov involves a brief therapy session, which may be delivered at the bedside, transcribed and shared with friends and/or family, to support the patient in his or her desire to live in the moment, maintain normalcy as best as possible and to seek spiritual comfort. More commonly, however, dignity conserving therapy refers to physician-assisted death. This has been legalized in at least 8 countries, including the Netherlands, Belgium, Switzerland, Germany, Luxembourg, Columbia, Canada and 6 states in the USA [2]. In Canada, recent legislation decriminalized medically assisted death. Li et al have reported the University Health Network (UHN, Toronto, Canada) experience of establishing a hospital-based physician-assisted program of medical assistance in dying (MAiD) [2]. Three teams were developed including a clinical team, an assessment team and an intervention team. The clinical team is involved in the usual care of the patient, including nurses, allied health professionals, consulting physicians and the physician most responsible for the patient’s care. Upon patient request, the most responsible physician refers the patient to the hospital MAiD program. At this point, full palliative consultation and support is offered if not already in place. An assessment team of two physicians, with expertise in the assessment of prognosis, patient suffering and capacity or ability to provide informed consent, evaluate the patient (MAiD medical specialist, palliative care physician, psychiatrist). To be eligible for MAiD through the UHN program, a person is required to have health care services covered through the Canadian public healthcare system, to be at least 18 years old and capable of making his or her own health care decisions, and to have a grievous and irremediable medical condition. This includes a serious and incurable illness, disease or disability, to be in an advanced state of irreversible decline in capability, such that the illness or state of decline causes enduring physical or psychological suffering that is intolerable to the person and cannot be relieved by means that the person considers acceptable. Natural death must be reasonably foreseeable based on medical circumstances, the request for medical assistance in dying must be voluntary and the person is required to voluntarily provide informed consent after being informed of alternative means to relieve suffering including palliative care. Disagreements between assessors are resolved through discussion involving leaders of the MAiD program. Once deemed eligible for MAiD, the patient completes a request form for the procedures, followed by a mandatory reflection period of at least 10 days unless death or loss of capacity is imminent. The intervention team, comprised of physicians and/or a nurse practitioner, conducts a final evaluation of the person and ensures they retain capacity before obtaining final informed consent and providing the intervention. Psychosocial professionals are available to provide support to family as needed and to conduct debriefing sessions for staff before and after the intervention. A multidisciplinary quality committee provides oversite and reports to the hospital Medical Advisory Committee. Since the program’s inception in March 2016, 111 inquiries have been received, 39% information-seeking only [Dr. Madeline Li, personal communication]. Of these, 71% have a cancer diagnosis, commonly lung cancer. Other diagnoses include neurologic disorders such as ALS (14%), cardio-respiratory chronic disease including CHF, COPD, and interstitial lung disease (9%). Assessments have been conducted for 41 individuals, 7 were found ineligible, 35 have been approved and 24 have completed interventions. Many of these were already receiving specialty palliative care services. The most common reason for not proceeding with the intervention was clinical decline or loss of capacity. Those that received MAiD cited loss of autonomy as the main reason behind their request [2]. Preserving dignity in the face of incurable lung cancer remains a challenge for patients, families and their health care providers. An individualized approach and involving a multidisciplinary support team including palliative care remains key. References: 1. Chochinov HM. Dignity-conserving care – a new model for palliative care. JAMA 2002;282:2253-60. 2. Li M, Watt S, Escaf M, Garedam M, Heesters A, O’Leary G, Rodin G. Medical assistance in dying – implementing a hospital-based program in Canada. New Engl J Med 2017;376:2082-8.

Abstract not provided

Abstract not provided

Abstract not provided

Abstract:
Introduction Approximately 68 particle therapy facilities are in operation worldwide. Among them, only 11 offer carbon-ion treatment (5 in Japan, 2 in Germany, 2 in China, 1 in Italy, and 1 in Austria; 6 also offer proton), and the remainder offer proton treatment. More than 150,000 patients have been treated with particle therapy worldwide from 1954 to 2015, 87% of which were treated with protons and 13% with carbon-ions or other particles. (from the website of the Particle Therapy Co-Operative Group: http://www.ptcog.ch/). The National Institute of Radiological Sciences (NIRS) in Chiba, Japan, has been treating cancer with high-energy carbon-ions since 1994. The majority of patients curatively treated with carbon-ions worldwide were treated at NIRS (1). Through the data they have generated, carbon-ion radiotherapy (CIRT) for non-small cell lung cancer (NSCLC) has been suggested as safe and efficacious. Here, I review those results and discuss this modern technology. Characteristics of CIRT In comparison with photon radiotherapy, CIRT has better dose distribution to tumors while simultaneously minimizing dose to surrounding normal tissues. Moreover, CIRT offers potential advantages over protons, which have similar dose distribution benefits. Carbon-ions provide a better physical dose distribution, because lateral scattering is lessened, and offer a higher relative biological effectiveness with a lower oxygen enhancement ratio; desirable features for eradication of radioresistant, hypoxic tumors. This difference between densely ionizing nuclei and sparsely ionizing x-rays/protons further offers potential radiobiological advantages, such as reduced repair capacity in irradiated tumors, decreased cell-cycle dependence, and possibly stronger immunological responses. CIRT of early NSCLC Surgical resection with lobectomy has been the standard treatment of choice for early-stage NSCLC. From a Japanese lung cancer registry study of 11,663 surgical cases in 2004, overall survival (OS) rates at 5 years for stages IA and IB disease were 82.0% and 66.8%, respectively (2). Radiotherapy is an option for patients who are not suitable for surgery or refuse it. Recently, hypofractionated radiotherapy is regarded as an alternative for surgery in cases of localized NSCLC, employing x-ray stereotactic body radiotherapy, protons, or CIRT. Regarding CIRT, for peripheral stage I NSCLC, the number of fractions delivered per treatment at NIRS has been reduced through consecutive trials from 18 to 9, then 4, and finally to a single fraction (3-7). This latest result , conducted via dose escalation study, was recently reported by NIRS, demonstrating results comparable to those with previous fractionated regimens (8). The Japan Carbon-ion Radiation Oncology Study Group (J-CROS) has further reported that the results of a multi-institutional retrospective study of CIRT for stage I NSCLC were similar with the results of previous single institutional reports (9). The results of CIRT in stage IA NSCLC are similar to the best stereotactic body radiotherapy results reported worldwide. For stage IB disease, CIRT results appear tentatively superior to those reported for photon stereotactic body radiotherapy in terms of local control and lung toxicity, but will require randomized controlled trials to verify. Despite this high local control, however, disease-specific survival is much lower in stage IB than in stage IA, due to distant metastatic recurrence. A combination of CIRT with systemic therapy is therefore essential to improve survival. CIRT demonstrates a better dose distribution than both SBRT and proton therapy in most cases of early-stage lung cancer. Therefore, CIRT may be safer for treating patients with adverse conditions such as large tumors, central tumors, and poor pulmonary function. CIRT of locally advanced NSCLC There has only been one report regarding CIRT for locally advanced NSCLC. A prospective nonrandomized phase I/II study of carbon-ion therapy in a favorable subset of locally advanced NSCLC was reported from NIRS (10). They showed that short-course carbon-ion monotherapy (72GyE/16Fr) was associated with manageable toxicity and encouraging local control rates. Among them, cT3-4N0M0 patients were particularly favorable candidates for CIRT. However, there is a relative dearth of evidence for CIRT in the setting of locally advanced NSCLC, and more trials, including those combined with systemic immunological or chemotherapy agents, are required. Future directions We have organized a multi-institutional study group of carbon-ion radiation oncology in Japan (J-CROS) and have been conducting a number of trials involving a multitude of tumor sites. A number are emerging as particularly attractive for CIRT with possibility of new levels of achievable disease control, including in NSCLC, head and neck cancer, locally advanced unresectable pancreatic cancer, hepatocellular carcinoma, locally recurrent rectal cancer, as well as others. The outcomes of CIRT for stage I NSCLC in Japanese multi-institutional datasets were retrospectively analyzed. As a result, CIRT is considered a low-risk and effective treatment option for patients with stage I NSCLC. Confirmative multi-institutional prospective studies via J-CROS began last year, so as to validate these results. References: 1. Kamada T, Tsujii H, Blakely EA, et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol 2015; 16: e93-100. 2. Sawabata N, Miyaoka E, Asamura H, et al. Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. J Thorac Oncol 2011; 6: 1229-35. 3. Miyamoto T, Yamamoto N, Nishimura H, et al. Carbon ionradiotherapy for stage I non-small cell lung cancer. Radiother Oncol 2003; 66: 127-140. 4. Miyamoto T, Baba M, Yamamoto N, et al. Curative treatment of Stage I non-small-cell lung cancer with carbon ion beams using a hypofractionated regimen. Int J Radiation Oncol Biol Phys 2007; 67: 750-758. 5. Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week. J Thorac Oncol 2007; 10: 916-926. 6. Sugane T, Baba M, Imai R, et al. Carbon ion radiotherapy for elderly patients 80 years and older with stage I non-small cell lung cancer. Lung Cancer 2009; 64: 45-50. 7. Karube M, Yamamoto N, Nakajima M, et al. Single-fraction carbon-ion radiation therapy for patients 80 years of age and older with stage I non-small cell lung cancer. Int J Radiation Oncol Biol Phys 2016; 95: 542-548. 8. Yamamoto N, Miyamoto T, Nakajima M, et al. A dose escalation clinical trial of single-fraction carbon ion radiotherapy for peripheral stage I non–small cell lung cancer. J Thorac Oncol 2016; 12: 673-680. 9. Shioyama Y, Yamamoto N, Saito J-i, et al. Multi-institutional retrospective study of carbon ion radiation therapy for stage I non-small cell lung cancer: Japan Carbon Ion Radiation Oncology Study Group. Int J Radiation Oncol Biol Phys 2016; 96: S10. 10. Takahashi W, Nakajima M, Yamamoto N, et al. A prospective nonrandomized phase I/II study of carbon ion radiotherapy in a favorable subset of locally advanced non-small cell lung cancer (NSCLC). Cancer 2015; 121: 1321-7.

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Abstract:
Although Masaoka clinic-pathological staging system has been accepted as the global standard staging system for thymic epithelial tumors, several problems of this staging system have been pointed out because clinical practices in diagnosis, medical treatment and surgical procedure has enormously advanced during more than 30 years. Furthermore, there has not been a TNM classification system approved by UICC to describe a tumor’s clinical status adequately. To overcome these situations, International Thymic Malignancy Interest Group (ITMIG) established global database and proposed a novel staging system based on TNM definition in collaboration with IASLC staging committee in 2016. This is a great progress in clinical medicine in the field of thymic epithelial tumor, but as a matter of fact, stage grouping according to this novel TNM classification is mostly defined by tumor invasion to adjacent organs similarly to Masaoka staging system. Japanese Association for Research of the Thymus (JART) established by Akira Masaoka and colleagues contributed to the ITMIG project of global database, and several studies using JART database were performed and reported from Japanese researchers. Novel findings in the JART database study are reviewed and new insights in further modification in TNM staging system are addressed in the present article. The significance of involved organs as a prognostic factor has been a great interest, because some structures are easily resected while others are difficult to be completely resected. Actually, some previous studies showed prognostic significance of involvement of the great vessels. Based on the ITMIG database, involvement of the pericardium alone is defined as T2 in the UICC TNM classification while involvement of SVC and brachiocephalic vein is defined as T3 and involvement of the aorta, aortic branches and intrapericardial vessels is defined as T4. One of the JART database study focusing on the involved organs in Masaoka stage III tumors showed that invasion to the chest wall is an independent prognostic factor by multivariate analysis while involvement of the great vessels is not. The hazard ratio of involvement of the chest wall is 4.07. Invasion to the chest wall is defined as T3, but when invasion to the sternum is extended, resection of the chest wall including sternum is sometimes a difficult procedure, and complete resection is hard to be achieved. Lymphatic channels are distributed in the chest wall, of which involvement by the tumor can result in nodal metastasis. Thus, invasion to the chest wall might be considered as an important factor to determine the tumor spread, and therefore, as one factor in T definition. Involvement of SVC and brachiocephalic vein is defined as T3, but is heterogenous variable because some tumors invade to the outer surface of the vessel but others enter the lumen of the vessel, which can result in pulmonary metastasis. The extent in involvement of the great vessels could be a significant factor in T definition. Tumor size could reflect the time from initiation of the tumor and the larger tumor is more likely to be in an advanced status. Actually, tumor size is a critical factor in T definition in lung cancers. In thymic epithelial tumors, however, T definition does not reflect the tumor size. Using JART database, oncological significance of the tumor size was examined in thymoma and thymic carcinoma, separately. In thymoma, the rate of R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 94.4%, 91.3%, and 84.0%, respectively. Recurrence rate after R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 3.0%, 8.9% and 27.2%, respectively. In thymic carcinoma, the rate of R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 80.2%, 63.2%, and 62.5%, respectively. Recurrence rate after R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 28.2%, 53.7% and 62.5%, respectively. Thus, there was apparent difference in oncological behavior between tumors less than 5.0 cm and those more than 5.1 cm both in thymoma and thymic carcinoma. These observations suggest that tumors size also should be included in T definition in thymic epithelial tumors. Finally, the category of Masaoka stage IVA disease includes pleural dissemination, but the situation of pleural dissemination varies greatly from a single lesion to numerous lesions. Furthermore, some disseminations are resectable while others are not. JART study revealed that the number of disseminated lesions on the pleura In conclusion, T definition remains to be further evaluated in reference to tumor size, chest wall invasion and extent of involvement of the great vessels. M definition also remains to be further discussed in terms of extent of the pleural dissemination.

Abstract:
Background: Thymectomy via median sternotomy has been the standard surgical approach for patients with thymic malignancies. However, the last decade has seen an increasing interest in minimally invasive thymectomy for early stage tumors. By avoiding sternal split, video-assisted thoracoscopic surgery (VATS) has been reported to be associated with similar operating time but less blood loss during operation, shorter length of intensive care unit and hospital stays, diminished postoperative pain, and improved postoperative pulmonary function. A recent propensity-score matched study by the Chinese Alliance of Research for Thymomas (ChART) reported 100% complete resection rate in both VATS and open thymectomies for UICC stage I (T1N0M0). Both overall and disease-free survivals, as well as cumulative incidence of recurrence were similar between the matched groups. The role of minimally invasive surgery has thus been well established in early stage thymic tumors. Using the International Thymic Malignancy Interest Group (ITMIG) global database, a recent propensity-score matched study found that complete resection rate was comparable between minimally invasive and open approaches (96% vs. 96%, P=0.7), including 33 and 10 patients with Masaoka stage III and IV diseases. And surgical approach was not a predictor of R0 resection in that study. The results suggested that minimally invasive surgery may also have a role in some patients with locally invasive tumors. To prove this, it is necessary to show that VATS is associated with improved peri-operative results, while maintaining similar resection rate and oncologic outcomes as open surgery. We therefore carried out a propensity-score matched study comparing the results of VATS and median sternotmy in UICC T2-3 thymic tumors to see whether minimally invasive surgery might be an acceptable approach. Patients and Methods: Surgical patients with UICC stage pT2-3 thymic tumors were retrospectively retrieved from a prospectively maintained database at the Shanghai Chest Hospital. Those who undergone VATS resection were compared with patients receiving median sternotomy (Open). A propensity-score matched study was then carried out to compare resection rate, peri-operative outcomes, and follow-up results between the two matched groups. Results: During 2007-2017, 115 patients who undergone surgical resection of thymic malignancies turned out to have UICC pT2-3 tumors upon histological examination. In 29 patients, video-assisted thoracoscopic surgery (VATS) was attempted and completed in 26 cases. In 89 patients (including the 3 conversion cases due to extensive tumor invasion) the lesion was resected via Open median sternotomy. Comparing with the VATS group, the Open group has larger tumor size, higher T stage, and received more induction therapies. A propensity-score match was carried out according to concomitant autoimmune disease, co-morbidity, induction therapy, tumor size, and UICC pTNM stage in 1:2 ratio. This leaves 26 patients in the VATS group and 52 patients in the Open group (Table 1). Induction therapies were given in 7.7% and 9.6% patients in the two groups (p=0.779). The two groups were comparable in patients’ age, gender, tumor histology, as well as all the matching factors. Complete resection (R0) rate was comparable (76.9% in both groups), with higher primary tumor resection rate in the VATS group (96.2% vs. 86.7%, p=0.151). Because of local tumor invasion, pericardium, lung (wedge resection), phrenic nerve, and left innominate vein were resected together with the tumor in 21, 17, 3, and 3 patients, respectively. Postoperative morbidity rate was also similar between the two groups (15.4% vs. 17.3%, p=0.830). Comparing to the Open group, VATS patients had less intraopertaive blood loss (127 ml vs. 219 ml, p=0.005), shorter duration of chest drainage (3±1.2 day vs. 5±4.7 day, p=o.oo5) and length of hospital stay (5.9±3.1 vs. 9.6±5.1, p<0.001). During a median follow-up of 35 months, overall survival was 100% in the VATS group and 95.2% in the Open group (Figure 1, p=0.664), and 3-year recurrence rates were 0.052 and 0.167, respectively (Figure 2, p=0.554). Conclusions: In addition to UICC stage I thymic malignancy, VATS may also be an acceptable approach for locally advanced thymic tumors. Complete resection rate and follow-up results are comparable to open surgery in well selected cases. And better peri-operative results can be expected via VATS approach as compared to median sternotomy. Based on these results, VATS should be attempted in those patients with potentially resectable thymic tumors. And long-term follow-up is still necessary to confirm its oncological effectiveness. Table 1. Comparison of patient demographics, tumor characteristics, and peri-operative results between the VATS and Open groups.

VATS N=26 Open N=52 P Value Gender male 17 (65.4) 34 (65.4) 1.0 Age year 58.5±13.0 57.7±10.1 0.781 Autoimmune diseases yes 5 (19.2) 8 (15.4) 0.667 Co-morbidity yes 8 (30.8) 14 (26.9) 0.722 Tumor size cm 5.7±2.0 6.4±1.7 0.161 Histology Thymoma 15 (57.7) 29 (55.8) 0.889 Thymic Carcinoma 11 (42.3) 23 (44.2) pT T2 8 (30.8) 14 (26.9) 0.722 T3 18 (69.2) 38 (73.1) pN N0 25 (96.2) 51 (98.1) 1.0 N1 1 (3.8) 1 (1.9) pM M0 21 (80.8) 45 (86.5) 0.506 M1a 5 (19.2) 7 (13.5) Operation time min 136±50 134±47 0.85 Blood lose ml 127±90 219±150 0.005 Chest tube drainage day 3±1.2 5±4.7 0.005 Length of hospital stay day 5.9±3.1 9.6±5.1 0.000 Morbidity yes 4 (15.4) 9 (17.3) 0.830

Figure 1. Overall survivals between the VATS and the Open groups after propensity-score matching. Figure 1 Figure 2. Cumulative incidences of recurrence after propensity-score matching in completely resected patients in the VATS and the Open groups. Figure 2

Abstract:
The argument for cytoreduction The argument in favor of cytoreduction is supported by several observations: First, several randomized trials support this procedure for other disease sites including advanced ovarian, colorectal and renal cell cancer. Second, most long-term survivors of MPM have had surgery as a component of their therapy, whereas there are very few long-term survivors who have been treated with non-operative strategies. Analyses of both the Surveillance Epidemiology and End Results (SEER) and the National Cancer Database have show longer survival of patients who have had ‘cancer-directed’ surgery compared to those whose treatment did not include surgery. Third, the median survival of patients in most recent phase III trials of chemotherapy is between 10 to 13 months, whereas in three multicenter trimodality phase II surgical studies median survival is significantly longer ranging 17 to 20 months. Nevertheless, the quality of evidence supporting a role for cytoreductive surgery for mesothelioma is low, and the only randomized study to performed date, the small, underpowered and highly controversial MARS 1 trial, failed to show benefit of extrapleural pneumonectomy compared to chemotherapy and supportive care. Cytoreductive surgical options There are two approaches to cytoreductive surgery for pleural mesothelioma: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (PD). The pendulum has swung back and forth over the last 40 years regarding the best operative approach and decisions are influenced by factors including tumor biology, patient physiology, surgical philosophy and availability of adjuvant therapies. A goal common to both EPP and extended PD/PD is macroscopic complete resection (MCR) of tumor, which is generally interpreted as <1cm residual tumor remaining after resection. The argument for EPP Extrapleural pneumonectomy (EPP) involves the en-bloc resection of the parietal and visceral pleura, lung, ipsilateral pericardium and diaphragm. The latter structures are usually reconstructed with prosthetic mesh, often polytetrafluoroethylene (Goretex), though use of polyglycolic acid (Vicryl), polypropylene and various biologic meshes has also been described. The procedure is associated with an operative mortality of 2 to 8% in experienced centers, however, a recent review of the Society of Thoracic Surgeon’s database reported a 30-day mortality rate of nearly 11%. 90-day mortality as high as 17% has been reported. Postoperative morbidity ranges from 30% to 80%, and major complications include bronchopleural fistula, empyema, hemorrhage, pulmonary embolus and ARDS/pneumonia. The potential value of EPP over PD is that it may offer a more complete cytoreduction in that tumor cells involving the lung and visceral pleura are completely removed. Indeed, most retrospective series show much lower rates of local failure after EPP (13%-35%) than PD (36%-100%). However, distant recurrence (most commonly in the contralateral chest or abdomen) are frequent (~50%). Median survival reported in 3 phase II trials that included EPP in the setting of neoadjuvant chemotherapy ranged between 17 to 20 months from initiation of treatment. Use of intrapleural adjuncts including photodynamic therapy (PDT), heated chemotherapy and other cytotoxic agents is controversial and has yielded varying results. Adjuvant radiation therapy is relatively easy to administer as there is no risk of ipsilateral lung toxicity (lung is removed) and though excellent local control has been reported in several phase II single arm studies, a recent randomized phase III trial showed no benefit to either disease free or overall survival. The argument for PD Pleurectomy decortication involves the resection of parietal and visceral pleura, and localized resection of any tumor involving the lung, diaphragm or pericardium. If the latter two structures are resected the term ‘extended’ PD (EPD) is applied. Several retrospective series have shown improved DFS and OS in patients undergoing either PD or EPD compared to partial pleurectomy (PP) although selection bias is likely to have influenced outcomes to some extent. Perioperative mortality rates following PD averages 3% and major morbidity ranges between 13% to 60%. A common complication after the procedure is prolonged air leak (14% - 58%). Rates of local recurrence after PD are higher than EPP most likely related to the larger surface area at risk for harboring residual microscopic tumor, however this does not appear to influence overall survival. Analysis of retrospective series reveals a median survival of approximately 20 months, similar to EPP, thought there have been notable recent reports of median survival as high as 36 months in patients who have received EPD with intrapleural therapies. Compared to EPP, adjuvant radiation therapy is more difficult to safely administer after PD, and though technically feasible, the benefit in terms of effect on local control (48% - 64%) is questionable. Comparisons of EPP and PD PD/EPD is associated with lower mortality and fewer and less severe postoperative complications than EPP. Additionally, retrospective comparisons of quality of life metrics tend to favor PD/EPD regarding global health, physical and social function and dyspnea[9]. Analysis of 9 retrospective series that have compared cancer related outcomes of EPP and PD/EPD reveals similar or improved survival in most cases with PD/EPD (Table). Differences in patient selection and prognostic factors such as tumor stage, volume and epithelioid histology make direct comparisons difficult, however. Nonetheless, there does not appear to be a survival benefit to performing EPP, and since the procedure is associated with greater risk of operative mortality, morbidity and functional deficit, it seems justified to recommend PD/EPD as the cytoreductive procedure of choice, where technically feasible[10]. The ongoing prospective, randomized MARS-2 trial currently accruing in the United Kingdom will better define the true role of cytoreductive surgery (PD) in the treatment of malignant pleural mesothelioma.

Author	Group	n	Epithelioid (%)	Node +ve (%)	T3 or T4 (%)	Stage III or IV (%)	Median survival (mo)	Median follow-up (mo)	Local failure (%)	Distant failure (%)
Flores, 2008	EPP	385	70%	nr	75%	75%	12	17 (all)	19%	38%
	PD	278	64%	nr	65%	65%	16*		31%	17%
Lang-Lazdunski, 2012	EPP	22	64%	46%	nr	87%	13	13	52%	56%
	PD	61	67%	30%	nr	63%	23*	16	nr	nr
Rena,2012	EPP	40	86%	0%	0%	0%	20	nr	47%	53%
	PD	37	84%	0%	0%	0%	25	nr	100%	44%
Nakas, 2012	EPP	98	78% (all)	nr	100%	100%	15	21	60%	40%
	PD	67		nr	100%	100%	13	16	56%	18%
Batirel, 2016	EPP	42	75% (all)	49% (all)	52% (all)	nr	18	23	68% (all)	21% (all)
	PD	66				nr	15	16
Infante, 2016	EPP	91	89%	44%	nr	80%	19	17	45%	50%
	PD	47	98%	30%	nr	62%	30	11	26%	24%
Sharkey, 2016	EPP	229	72%	53%	76%	86%	13	nr	43%	57%
	PD	133	76%	56%*	69%	80%*	12	nr	53%	41%
Korston, 2017	EPP	52	94%	nr	nr	65%	23	nr	nr	nr
	PD	26	94%	nr	nr	65%	32*	nr	nr	nr
Verma, 2017	EPP	271	34%	27%	43%	51%	19	15 (all)	nr	nr
	PD	1036	26%	20%	37%	47%	16		nr	nr

Table: Comparative studies of EPP and PD References 1. Nelson DB, Rice DC, Niu J, et al. Long-Term Survival Outcomes of Cancer-Directed Surgery for Malignant Pleural Mesothelioma: Propensity Score Matching Analysis. J Clin Oncol. 2017:JCO2017738401. 2. Flores RM, Riedel E, Donington JS, et al. Frequency of use and predictors of cancer-directed surgery in the management of malignant pleural mesothelioma in a community-based (Surveillance, Epidemiology, and End Results [SEER]) population. J Thorac Oncol. 2010;5(10):1649-1654. 3. Burt BM, Cameron RB, Mollberg NM, et al. Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. J Thorac Cardiovasc Surg. 2014;148(1):30-35. 4. Stahel RA, Riesterer O, Xyrafas A, et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol. 2015;16(16):1651-1658. 5. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. J Thorac Cardiovasc Surg. 2015;149(2):558-565; discussion 565-556. 6. Marulli G, Breda C, Fontana P, et al. Pleurectomy-decortication in malignant pleural mesothelioma: are different surgical techniques associated with different outcomes? Results from a multicentre studydagger. Eur J Cardiothorac Surg. 2017. 7. Friedberg JS, Simone CB, 2nd, Culligan MJ, et al. Extended Pleurectomy-Decortication-Based Treatment for Advanced Stage Epithelial Mesothelioma Yielding a Median Survival of Nearly Three Years. Ann Thorac Surg. 2017;103(3):912-919. 8. Rimner A, Zauderer MG, Gomez DR, et al. Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma. J Clin Oncol. 2016;34(23):2761-2768. 9. Rena O, Casadio C. Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. Lung Cancer. 2012;77(1):151-155. 10. Waller DA, Tenconi S. Surgery as part of radical treatment for malignant pleural mesothelioma. Curr Opin Pulm Med. 2017;23(4):334-338.

Abstract:
Multimodality therapy for malignant pleural mesothelioma (MPM) including radical surgery has been associated with prolonged survival and in selected patients, but the evidence for a long term survival benefit is inconsistent [1,2]. There is little evidence regarding the optimal timing of additional chemotherapy, with some advocating induction treatment or in the immediate post operative setting, and others choosing to delay until progression. We have analysed our experience of the effect of the timing of chemotherapy on the outcome of extrapleural pneumonectomy (EPP) or pleurectomy/decortication (PD) [3] . Induction chemotherapy The use of a standardized neo-adjuvant chemotherapy regimen has been reported to be feasible in patients treated by EPP and adjuvant hemithoracic radiotherapy [4] . This regime requires high levels of patient fitness and is associated with a median survival of 16.8-25.5 months. However, this decreases dramatically if patients are unable to complete the entire trimodality therapy protocol (9-14 months) [5]. This may select those who will not have a prolonged survival, thus avoiding futile but morbid therapy. There is also the potential for tolerance of an increased number of cycles prior to surgery than in the adjuvant setting. The drawbacks include the risk of progression during chemotherapy, or severe toxicity, leaving the patient unsuitable for radical surgery. It is possible that neoadjuvant chemotherapy may select out chemoresistant cells, and lead to more aggressive disease progression following the inevitable R1 resection. There is currently no evidence to show that there is any long-term benefit to a response to chemotherapy prior to radical surgery. In fact, a true, significant, pathological response to chemotherapy is very rare [5]. Adjuvant chemotherapy The apparent benefit with adjuvant chemotherapy may be due to selection bias; only the fittest can receive the full regime, and will therefore have a survival benefit independent of therapy. Nevertheless, the IASLC staging committee found that the provision of adjuvant therapy was an independent prognostic factor for survival in patients with MPM [6]. Adjuvant chemotherapy may be contraindicated due to low compliance as a consequence of the morbidity of surgery In the case of EPP, many patients are not able to tolerate adjuvant chemotherapy, however in the case of EPD, most patients recover from surgery and are able to commence therapy within 8 weeks [7]. There has been a change in practice over time with regards the number of cycles given in the adjuvant setting, from 4 to 6. Delayed (expectant) chemotherapy Oncologists may wish to reserve an active agent, pemetrexed, until assessable disease or symptom-related progression. It may be beneficial as treatment of low volume residual disease following R1 resection may select out clones with resistance to platinum therapy thus reducing the efficacy at re-challenge during relapse. We found no difference in overall survival when chemotherapy was given in the immediate adjuvant setting or only at progression. However, subgroup analysis revealed that in non-epithelioid MPM delayed therapy was an independent predictive factor for poor survival/progression free survival. This could be explained in part by the continued presence of a subpopulation of aggressive and chemo-resistant stem cells in the sarcomatoid element of biphasic disease following an R1 resection. These more aggressive cells are then able to proliferate, as compared with a more indolent group of stem cells in epithelioid disease, leading to a shorter time to relapse and a more aggressive tumour type if no chemotherapy is given in the adjuvant setting. This is often seen after chemotherapy treatment alone, where these aggressive resistant cells are selected for, giving rise to rapid progression, even after an initial response [8]. Similarly, in those with nodal disease delaying chemotherapy was also found to be detrimental. In these patients tumour cells have already developed the ability to metastasise and it is likely that systemic micrometastases are present following local resection. Intra operative chemotherapy Intraoperative instillation of platinum based chemotherapy into the pleural cavity after resection has been shown to be safe in selected experienced institutions, where favourable median overall and progression free survival outcomes have been reported [9]. We did not include this modality in our protocol but one such study showed an increase in time to progression from 12.8 to 27.1 months, and overall survival from 22.8 to 35.5 months in clinically matched patients [10]. Conclusion Our retrospective study [3] showed no significant overall survival benefit from any particular timing of chemotherapy with either neo-adjuvant, adjuvant, or expectant management. Interestingly, we found no benefit in giving neo-adjuvant chemotherapy, despite the intrinsic bias within this group of patients, as only those who did not progress proceeded to surgery. We suggest that it may be important to tailor chemotherapy in 4 clinical sub-groups. In the poorer prognosis groups, non-epithelioid cell type and/or with pathological lymph node disease, giving chemotherapy in the immediate adjuvant setting (within 3 months of surgery) rather than delaying it until progression gave a survival advantage. Conversely, there was no benefit found in giving therapy in the immediate adjuvant setting in better prognosis patients with epithelioid cell type and with no evidence of lymph node metastases at operation. It may therefore be preferable to reserve first line chemotherapy until there is radiological evidence of disease progression in these patients. Future results from the EORTC NCT02436733 trial : a randomized phase II study of pleurectomy/ decortication (P/D) preceded or followed by chemotherapy in patients with early stage malignant pleural mesothelioma [11] will inform this debate. We suggest that the randomization in the trial is stratified in to epithelioid versus non-epithelioid and clinical node positive versus negative. References 1.C. Cao, D. Tian, C. Manganas, P. Matthews, T.D. Yan, Systematic review of trimodality therapy for patients with malignant pleural mesothelioma., Ann Cardiothorac Surg. 2012; 1: 428–37. 2.Nakas A, Waller D. Predictors of long-term survival following radical surgery for malignant pleural mesothelioma .Eur J Cardiothorac Surg. 2014;46:380-5. 3.Sharkey AJ, O'Byrne KJ, Nakas A, Tenconi S, Fennell DA, Waller DA. How does the timing of chemotherapy affect outcome following radical surgery for malignant pleural mesothelioma? Lung Cancer. 2016 Oct;100:5-13 4.Stahel RA, Riesterer O, Xyrafas A, et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol 2015;16:1651-8. 5. L. Donahoe, J. Cho, M. De Perrot, Novel Induction Therapies for Pleural Mesothelioma, Semin Thorac Cardiovasc. Surg. 2014;26:192–200. 6.Pass HI, Giroux D, Kennedy C, Ruffini E, Cangir AK, Rice D, Asamura H, Waller D, Edwards J, Weder W, Hoffmann H, van Meerbeeck JP, Rusch VW; IASLC Staging Committee and Participating Institutions. Supplementary prognostic variables for pleural mesothelioma: a report from the IASLC staging committee. J Thorac Oncol. 2014 Jun;9(6):856-64 7.S. Bölükbas, C. Manegold, M. Eberlein, T. Bergmann, A. Fisseler-Eckhoff, J.Schirren, Survival after trimodality therapy for malignant pleural mesothelioma:Radical Pleurectomy, chemotherapy with Cisplatin/Pemetrexed and radiotherapy, Lung Cancer. 71 (2011) 75–81 8.L. Cortes-Dericks, G.L. Carboni, R.A. Schmid, G. Karoubi, Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed, Int. J. Oncol. 37 (2010) 437–444. 9.M. Ried, T. Potzger, N. Braune, R. Neu, Y. Zausig, B. Schalke, et al., Cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion for malignant pleural tumours: Perioperative management and clinical experience, Eur. J.Cardio-Thoracic Surg. 43 (2013) 801–807. 10.D.J. Sugarbaker, R.R. Gill, B.Y. Yeap, A.S. Wolf, M.C. Dasilva, E.H. Baldini, et al.,Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection, J. Thorac.Cardiovasc. Surg. 145 (2013) 955–963. 11. EORTC NCT02436733 trial : a randomized phase II study of pleurectomy/ decortication (P/D) preceded or followed by chemotherapy in patients with early stage malignant pleural mesothelioma. https://clinicaltrials.gov/ct/show/NCT02436733

Abstract:
Intensity-modulated radiation therapy (IMRT) is a highly conformal radiation technique that allows more effective sparing of normal tissues, providing an opportunity for safer, less toxic treatments and increased efficacy by enabling higher radiation doses to the tumor target. It comes with a much higher level of dosimetric control and certainty leading to better target coverage than conventional OR 3D conformal radiation techniques.[1] The higher precision of IMRT delivery when used in the adjuvant setting requires detailed knowledge of the intrathoracic anatomy, incorporation of all diagnostic imaging tools available, incorporation of the pathologic findings at the time of surgery, assessment of the respiratory tumor motion using a 4D scan, and image-guided treatment delivery. IMRT with integration of a boost to areas of gross disease is technically feasible but has not yet been tested in a larger series. The use of 18-fluorodeoxyglucose positron emission tomography (PET) for RT planning purposes may reduce the likelihood of geographic misses and detect radiographically occult lymph node involvement. Small series have suggested that PET may guide the delineation of an integrated boost volume or improve local control.[2] The recent decline in extrapleural pneumonectomies (EPP) in the surgical management of malignant pleural mesothelioma (MPM) due to reports suggesting a lack of survival benefit compared with lung-sparing pleurectomy/decortication (P/D) has posed a particular challenge for adjuvant radiation treatments: how to safely treat the pleural space for microscopic residual disease without exceeding the radiation tolerance of the underlying sensitive normal lung tissue. Older radiation techniques result in unacceptable toxicity and insufficient local control.[3] Thus, an IMRT technique targeting the hemithoracic pleural space including the diaphragm that simultaneously spared the ipsilateral lung, heart, liver, kidneys and abdominal contents was developed (Figure 1).[4] Typically these patients are treated with six to nine coplanar 6 MV beams equispaced over 200-240 degrees around the ipsilateral hemithorax were used. More recently, rotational techniques such as volumetric arc therapy or tomotherapy have been shown to allow for even more effective sparing of organs at risk.[5,6] The first report in 36 MPM patients with 2 intact lungs showed that hemithoracic adjuvant pleural IMRT (50.4 Gy in 28 fractions) could be delivered with a 20% (n=7) ≥ grade 3 pneumonitis risk; 1 patient had grade 5 pneumonitis.[4] The median survival in resectable patients was 26 months. A tomotherapy technique was published with similar toxicity outcomes (20% ≥ grade 2 pneumonitis, one fatal case of pneumonitis).[6] The radiation dose delivered was slightly higher with 50 Gy delivered in 25 fractions including a simultaneous boost to 60 Gy for areas of concern for residual disease based on FDG-PET. A matched analysis of P/D, chemotherapy, and IMRT vs. EPP, chemotherapy and IMRT found favorable median overall (28.4 vs. 14.2 months) and progression-free survival (16.4 vs. 8.2 months) with trimodality therapy involving P/D compared with EPP.[7] Local failure rates vary significantly among studies, ranging from 40 to 68% at 2 years. A systematic review of 67 patients still found a significant risk of local failures in the radiation field, mostly in unresectable patients and sites of gross residual disease, emphasizing the importance of a macroscopic complete resection, need for optimization of radiation targeting and experience with this complex radiation technique.[8] Increasing experience over time led to fewer marginal failures and decreased toxicity, suggesting the improvement in target delineation and RT planning. Most recently an association of radiation dose to the heart and overall survival was reported,[9] similar to observations in locally-advanced non-small cell lung cancer. These encouraging results have led to a 2-institution phase II trial of trimodality therapy using induction chemotherapy with cisplatin and pemetrexed, P/D, and adjuvant hemithoracic intensity-modulated pleural radiation therapy (IMPRINT).[10] Twenty-seven patients were treated and 29.6% developed radiation pneumonitis (6 grade 2; 2 grade 3). Median progression-free and overall survival was 12.4 and 23.7 months, respectively. In resectable MPM patients who received chemotherapy and IMPRINT, 2-year OS was 59%. Based on these findings a multi-institutional phase II study was initiated to demonstrate the safety and exportability of this complex IMPRINT technique in a multicenter setting involving institutions without prior experience of IMPRINT (clinicaltrials.gov: NCT00715611). All patients’ treatment contours and plans are centrally reviewed and revised for uniformity. The goal is to accrue 36 patients from 5 institutions. Given the promising outcomes this study may be succeeded by a randomized trial testing the effect of adjuvant IMPRINT vs no additional treatment after lung-sparing P/D and chemotherapy. Figure 1: Figure 1 1. Krayenbuehl J, Dimmerling P, Ciernik IF, et al: Clinical outcome of postoperative highly conformal versus 3D conformal radiotherapy in patients with malignant pleural mesothelioma. Radiat Oncol 9:32, 2014 2. Fodor A, Fiorino C, Dell'Oca I, et al: PET-guided dose escalation tomotherapy in malignant pleural mesothelioma. Strahlentherapie und Onkologie 187:736-743, 2011 3. Gupta V, Mychalczak B, Krug L, et al: Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. International Journal of Radiation Oncology Biology Physics 63:1045-1052, 2005 4. Rosenzweig KE, Zauderer MG, Laser B, et al: Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma. International Journal of Radiation Oncology Biology Physics 83:1278-1283, 2012 5. Dumane V, Rimner A, Yorke ED, et al: Volumetric-modulated arc therapy for malignant pleural mesothelioma after pleurectomy/decortication. Applied Radiation Oncology 5:24-33, 2016 6. Minatel E, Trovo M, Bearz A, et al: Radical Radiation Therapy After Lung-Sparing Surgery for Malignant Pleural Mesothelioma: Survival, Pattern of Failure, and Prognostic Factors. Int J Radiat Oncol Biol Phys 93:606-13, 2015 7. Chance WW, Rice DC, Allen PK, et al: Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma: toxicity, patterns of failure, and a matched survival analysis. Int J Radiat Oncol Biol Phys 91:149-56, 2015 8. Rimner A, Spratt DE, Zauderer MG, et al: Failure patterns after hemithoracic pleural intensity modulated radiation therapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 90:394-401, 2014 9. Yorke ED, Jackson A, Kuo LC, et al: Heart Dosimetry is Correlated with Risk of Radiation Pneumonitis after Lung-Sparing Hemithoracic Pleural IMRT for Malignant Pleural Mesothelioma. Int J Radiat Oncol Biol Phys, 2017 10. Rimner A, Zauderer MG, Gomez DR, et al: Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma. J Clin Oncol 34:2761-8, 2016

Abstract:
Thymic and Mesothelial Tumors are relatively rare. There are few therapies that have been established in prospective studies, so the conditions have poor prognoses. Cisplatin+pemetrexed is the gold standard for unresectable malignant pleural mesothelioma in that it has shown a significantly longer survival than cisplatin in a controlled Phase III clinical study. Moreover, adding on bevacizumab to this combination therapy can extend survival, and these two therapies are recommended as 1L by the NCCN guideline. There have recently been promising results reported with anti-PD-1 antibody and anti-PD-L1 antibody single agent therapies as well as combination therapies with anti-CTLA-4 antibody, and there are many ongoing prospective clinical studies on these now. There are not very many therapies for Thymic malignancies that have already been examined in prospective studies. Carboplatin + paclitaxel, ADOC (cisplatin + doxorubicine + vibncristine + cyclophasphamide) therapy, CAP(Cisplatin + doxorubicine + cyclophosphamide) therapy, and the like are currently used as a result of outcomes in Phase II studies and retrospective studies. Furthermore, there have been reports of responses with molecular targeting therapies such as Sunitinib that target Kit. It has been reported that Thymic tumors express PD-L1, and there are currently several ongoing studies examining the relatively frequency and effect of anti-PD-1 antibody on such. My presentation will provide an overview of the current gold standards, recent clinical study outcomes, and promising pipeline therapies for Thymic and Mesothelial Tumors.

Background:
Although stereotactic ablative body radiotherapy (SABR) is now well established as a treatment for stage I non-small cell lung cancer (NSCLC), there is limited evidence that it is as or more effective than conventional fully fractionated radiotherapy (CRT). We conducted a randomized trial to determine if SABR results in longer time to local failure than CRT.

Method:
This was a multicentre trial of the Trans-Tasman Radiation Oncology Group (TROG) and Australasian Lung Cancer Trials Group, registration number NCT01014130. Patients were eligible if they had biopsy proven stage I (T1- T2a N0M0) NSCLC based on PET and were medically inoperable or refused surgery. Patients had to be performance status ECOG 0 or 1, and the tumor had to be at least 2 cm or more from the bifurcation of the lobar bronchus. Patients were randomized 2:1 to SABR (54 Gy in 3 fractions, or 48 Gy in 4 fractions, depending on proximity to the chest wall, to the isodose covering the PTV) or to CRT (66 Gy in 33 fractions or 50 Gy in 20 fractions). The primary objective was to compare time to local failure between arms. Assuming that the rate of local failure at 2 years would be 10% in patients randomized to SABR versus 30% in patients randomized to CRT, 100 patients were required. All living patients were followed for a minimum of 2 years. Analysis was based on the intention to treat principle. Funding: In Australia: Grant #1060822 was awarded through Cancer Australia. In New Zealand, The Cancer Society of New Zealand and the Genesis Oncology Trust.

Result:
Between 12/09 and 6/15, 101 patients were enrolled. There were 56 males and 45 females with a median age of 74 years (range 55-89), ECOG performance status – 28 were 0, 71 were 1 and 1 was 2. TNM stage was T1N0M0 in 71 and T2aN0M0 in 30. Sixty six patients were randomized to SABR and 35 patients to CRT. Patients randomized to SABR had superior freedom from local failure (HR = 0.29, 95% CI 0.130, 0.662, P=0.002) and longer overall survival (HR = 0.51, 95% CI 0.51, 0.911, P=0.020). Worst toxicities by arm were: CRT grade 3, 2 patients; SABR grade 4, 1 patient and grade 3, 9 patients.

Conclusion:
In patients with inoperable stage I NSCLC, compared with CRT, SABR resulted in superior freedom from local failure and was associated with an improvement in overall survival.

Background:
Stereotactic radiotherapy (SBRT) is an efficient treatment for early stages of inoperable NSCLC. SBRT may, however, also be used as salvage treatment for recurrent disease. This retrospective study reports and compares the outcome of patients initially treated with surgery and patients initially treated with curative radiotherapy (RT).

Method:
All cases of NSCLC treated with RT with curative intent at our institution are prospectively recorded. We here report the results of 114 cases treated at our institution July 2009 to June 2016 with SBRT as salvage therapy. The doses used for peripheral located tumors have been 45-66 Gy (central doses) in 3 fractions (F) while centrally located tumors have been treated with 50-78.4 Gy/ 5-8 F. The patients have been treated with IMRT or VMAT. A group of 80 patients had surgery initially (Surg-Grp): Resection 19 (24%), lobectomy 56 (70%), bi-lobectomy 1 (1%), and pneumonectomy 4 (5%). Another group of 34 patients was initially treated with RT (RT-Grp): SBRT 30 (88%) and conformal chemo-RT 4 (12%). All patients had more than 1 year of potential follow-up.

Result:

The patient characteristics

Surg-Grp RT-Grp p-value Age (yr.) 72.6 (55.1; 89.3) 71.7 (53.5; 87.1) 0.56 Female /Male 45 / 35 18 /16 0.91 PS 0-1 55 (69%) 15 (44%) PS 2 21 (26%) 15 (44%) PS 3 4 (5%) 4 (12%) Median FEV1 (L/sec) 1.54 (.39-2.72) 1.37 (.42-2.75) 0.59 Time from initial treatment to salvage treatment (mo) 22.4 (0.6; 272) 20.7 (4.4; 100) Salvage RT 45 Gy/3 F 10 (13%) 9 (26%) 66 Gy/3 F 54 (68%) 18 (53%) 50 Gy /5 F 3 (4%) 0 78.4 Gy /8 F 13 (16%) 7 (21%)

The median, 1, 2, 3, and 4 year overall survival was 50.5 mo, 85%, 72%, 59%, and 59 % in the Surg-Grp and 31.3 mo., 71%, 55%, 46%, and 46% in the RT-Grp, (p=.13).

Conclusion:
SBRT gives excellent survival used as salvage therapy after surgery and curative intended radiotherapy.

Background:
Five-year local control rates in early-stage NSCLC following stereotactic ablative radiotherapy (SABR) are approximately 90%. However, the resulting focal fibrosis can be difficult to distinguish from tumor recurrences. We investigated the incidence, and patterns of change in previously reported high-risk radiological features (HRF’s), in patients who were known to have no local recurrence.

Method:
Patients treated using volumetric modulated arc therapy SABR were eligible if follow-up CT-scans were available for at least 2 years. Five clinicians who were unaware of clinical outcomes scored the following HRF’s on CT-scans: enlarging opacity(EO), sequential enlarging opacity(SE), enlarging opacity after 12 months(EO12), bulging margin(BM), loss of linear margins(LOM), cranio-caudal growth(CCG) and loss of air bronchogram(LOB). CT-scans were reviewed at a workstation using in-house plugin customized for ClearCanvas (Synaptive Medical, Toronto, Canada). After each review, clinicians recommended follow-up procedures based on previously published recommendations.

Result:
In 88 patients (747 CT-scans) evaluated, the HRF’s most frequently recorded by ≥3 observers on at least one follow-up CT-scan were EO (64.8%), EO12 (50.0%) and SE (13.6%). Cumulative mean incidence rates of each HRF per category are displayed (figure). Fifty-six patients developed EO in the first year, and 46 of these patients developed subsequent EO12. In 76 patients who developed EO12, 30 had no EO previously. The presence of ≥3 HRF’s have been associated with recurrences, and this was observed in 20 patients. When HRF’s were identified, clinicians indicated that they were either very certain (mean: 37.2%, range: 11.9-70.4%) or moderately certain (mean: 51.2%, range: 26.5-87.1%) about the presence of this feature. In routine care, only 6 patients underwent PET-scans because of a suspected local recurrence, and 4 underwent an attempt at biopsy. Figure 1



Conclusion:
Although HRF’s on CT-scan develop in more than 50% of patients without local recurrence after SABR, only 23% had ≥3 HRF’s.

Abstract not provided

Background:
The CONVERT Trial is a multicentre phase III study which recruited 547 patients with limited-stage SCLC from April 2008 to November 2013. Patients were randomised to receive once daily (66Gy in 33 fractions) or twice daily (45Gy in 30 fractions) radiotherapy concurrently with chemotherapy. The primary endpoint was overall survival. This study investigates the effect of non-compliance to radiotherapy protocol on survival for the CONVERT Trial.

Method:
489/557 received chemo-radiotherapy according to protocol. As part of the CONVERT trial quality assurance (QA) programme, 94 patient datasets (19.2%) treated with concurrent chemoradiotherapy (n=489) were reviewed and deviations from protocol were categorised as acceptable, acceptable variation and unacceptable variation using the Global Harmonisation Group (GHG) variation definitions. Organ at risk outlining (heart, spinal canal and lung minus planning target volume (PTV)), target delineation and margins applied, PTV coverage, treatment planning technique and radiotherapy treatment time were reviewed and classified according to the GHG definitions. A multiplicative factor (F) was calculated for each treatment plan, based on the GHG definitions. A low factor indicates a low number of protocol deviations. Protocol deviations were correlated with survival and number of patients recruited per centre.

Result:
94/489 patients were included in this analysis (19.2% of the randomised patients). The median number of patients recruited per centre was 6 (range 1-109). Protocol deviations were categorised as acceptable (57.6%), acceptable variation (23.3%) or unacceptable variation (19.1%). Amongst the unacceptable variations the PTV coverage was the most common deviation to protocol. In these 71 patients (75.5%) the dose distribution within the PTV was greater than 7% of the prescribed dose. Patients with increasing number of organ at risk outlining protocol deviations and with an increase in the multiplicative factor (F) had a lower survival. Further details will be presented at the meeting including survival in the 3 GHG categories. Centres recruiting >25 patients were found to have a lower number of protocol deviations (median 2, range 2-3) compared with centres recruiting fewer than 25 patients (median 3, range 0-4.5), and were most likely to delineate organs at risk correctly.

Conclusion:
High recruiting centres are most likely to comply with a trial protocol. Overall survival was affected by the number and type of protocol deviations, highlighting the importance of a robust trial QA programme in prospective radiotherapy trials.

Background:
Radiation (RT) dose to the heart was a predictor of inferior overall survival (OS) in the non-small cell lung cancer trial RTOG 0617, but little data quantifies cardiac morbidity for small cell lung cancer (SCLC) patients treated with RT.

Method:
The Surveillance, Epidemiology, and End Results (SEER) Program database and Medicare claims data were queried to establish rates of cardiac events (CE) among SCLC patients treated with chemotherapy (CTX) +/- RT. CE were defined as any new cardiac diagnosis including ischemic disease, cardiomyopathy, dysrhythmia, heart failure, and pericarditis. Chronic/pre-existing diagnoses were not counted as events. CTX-only patients were matched to CTX + RT patients to account for start date of RT. Second phase of propensity score matching (PSM) balanced demographical and clinical differences. Multivariate analysis (MVA) determined effect of tumor and RT covariates on CE and OS. Kaplan-Meier and cumulative incidence (CI) function curves were generated.

Result:
From 2000 – 2011, 7,060 patients were available: 2,892 (40.9%) limited-stage and 4,168 (59.0%) extensive-stage. As expected, CTX + RT patients had better OS (p < 0.001). OS for the CTX + RT and CTX-only groups: 35.0 vs. 21.4% at 12 months, and 6.6 vs 2.3% at 60 months, respectively. RT was associated with CE (p = 0.008), with CI as follows for the CTX + RT and CTX-only groups: 36.4 vs. 35.4% at 12 months, and 44.1 vs 39.0% at 60 months, respectively. MVA demonstrated higher hazard ratio of CE for extensive-stage patients (p < 0.001), black race (p < 0.001), and increased Charlson-Deyo score (p = 0.001). After PSM, 5,286 patients were included. Again, CTX + RT patients had better OS (p < 0.0001). OS for the CTX + RT and CTX-only groups: 30.6 vs. 22.5% at 12 months, and 5.3 vs 2.7% at 60 months, respectively. RT was still associated with CE (p = 0.033) after PSM, with CI of CE for the CTX + RT and CTX-only groups: 36.3 vs. 34.8% at 12 months, and 43.0 vs 38.6% at 60 months, respectively. Tumor laterality (p = 0.84) and RT modality (p = 0.62) were not associated with CE, though low numbers were treated with intensity-modulated versus 3D conformal RT (1:15 ratio).

Conclusion:
In this large database study we demonstrated RT is associated with an absolute increase in the rate of CE at 5-years of approximately 5%. Further evaluation of cardiac sparing radiation techniques should be evaluated for patients with SCLC.

Background:
During standard concurrent chemoradiotherapy (CRT), patients with NSCLC often report severe symptoms that should be routinely assessed and managed. According to the United States FDA specified standards, patient-reported outcome (PRO) instruments used in clinical trials should have good measurement properties of reliability, validity, and the ability to detect change. This quantitative study used a validated PRO symptom-assessment tool, the MD Anderson Symptom Inventory-Lung Cancer (MDASI-LC), to compare a cluster of CRT-related symptoms in NSCLC patients receiving CRT, and to investigate the sensitivity of a composite score of these symptoms.

Method:
We enrolled patients with locally advanced NSCLC (n=118) who underwent intensity-modulated radiation therapy (IMRT, n=33), 3-dimensional conformal radiation therapy (3DCRT, n=22), or proton-beam therapy (PBT, n=63). Patients completed the MDASI-LC weekly for up to 12 weeks. Two criteria used for item selection to form a subscale for CRT-related symptoms: MDASI-LC items rated 4-10 in >25% of observations, and that increased significantly during therapy (by mixed-effect models). A CRT-symptom score (MDASI-LC-CRT) was generated by averaging scores from those symptoms. The MDASI-LC-CRT’s responsiveness to treatment was examined by within-person change over time and effect size (ES) statistics.

Result:
Six symptoms—pain, fatigue, drowsiness, lack of appetite, sore throat, coughing—were identified as the most-severe CRT-related symptoms during and after therapy. Before CRT, MDASI-LC-CRT scores did not differ by treatment (3DCRT 2.2±1.8, IMRT 1.6±1.5, PBT 1.8±1.7, p=0.329). At the end of CRT, MDASI-LC-CRT was highest for 3DCRT (4.85±2.40), followed by IMRT (3.18±1.85) and PBT (2.29±1.65). A large ES (1.24) was found for 3DCRT vs. PBT; medium ES were found for 3DCRT vs. IMRT (0.78) and IMRT vs. PBT (0.51). The ES for pre-CRT vs. post-CRT difference (1.8±1.7 vs. 3.0±2.1) was medium (0.63) for all patients, large for 3DCRT (1.25) and IMRT (0.93), and small for PBT (0.28). The MDASI-LC-CRT score increased significantly over treatment (estimated weekly increase=0.21, p<0.0001), peaking at week 7 (95%CL=6.2-7.8, p<.0001) and then decreasing to week 12 (est=0.18, p=0.001). Significantly larger weekly increase was reported by 3DCRT and IMRT patients, compared with PBT patients (all p<0.0001).

Conclusion:
The MDASI-LC-CRT is a sensitive indicator of dynamic change in major symptom burden during CRT. This subscale could be routinely used for symptom monitoring while patients are going through CRT and appropriate supportive measures could be instituted early. PBT was the best tolerated of the radiation modalities when given concurrently with chemotherapy with the least worsening of symptoms over the CRT period.

Abstract not provided

Background:
AURA3 (NCT02151981) showed osimertinib, a third-generation EGFR-TKI, significantly prolongs progression‑free survival and improves response rate vs platinum‑pemetrexed in patients with T790M-positive advanced NSCLC, whose tumors had progressed on first-line EGFR-TKI therapy. Using patient baseline samples, we report concordance between plasma circulating tumor DNA (ctDNA) and tissue for the detection of EGFR mutations (T790M, exon 19 deletions [Ex19Del], L858R) using three distinct plasma detection technologies.

Method:
Tumor tissue biopsy samples were taken following progression on first-line EGFR‑TKI treatment. Baseline central confirmation of EGFR mutation status was by cobas[®] EGFR Mutation Test (Roche Molecular Systems). Where possible, baseline blood samples for plasma ctDNA screening were collected from patients in the osimertinib treatment group and analyzed using allele specific (AS)‑PCR (cobas[®] EGFR Mutation Test v2), ddPCR (Biodesix) and next generation sequencing (NGS, Guardant Health).

Result:
Figure 1 ctDNA was undetectable (negative for all three EGFR mutations [T790M, Ex19Del, L858R]) in 51/228 (22%) patients by AS-PCR, 58/211 (27%) by ddPCR, and 54/230 (23%) by NGS. Robust correlations (Spearman’s Rank) were observed for EGFR mutant allelic fractions (AFs) between ddPCR and NGS assays: T790M R[2] 0.9129 (n=201), Ex19Del R[2] 0.9384 (n=201), L858R R[2] 0.8090 (n=200). Discordant results between ddPCR and NGS were observed in 24/201 (12%) samples for T790M, 17/201 (8%) Ex19Del and 11/200 (6%) L858R. All discordant samples had AFs ≤1% by both assays.



Conclusion:
Using cobas tissue test as a reference, sensitivity for the detection of plasma T790M appeared higher for ddPCR and NGS assays compared with AS-PCR. Robust correlations were observed between quantitative ddPCR and NGS assays for determination of AFs across all three mutations. About 25% of AURA3 patients did not appear to shed ctDNA, as evidenced by absence of all three EGFR mutations across the three platforms.

Background:
Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) with EGFR mutations. Resistance mechanisms of LM remained unclear due to limited access to leptomeningeal lesions.

Method:
Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing with 168 genes panel. Thirty patients diagnosed as LM and harboring EGFR mutation were enrolled in this cohort, and CSF cfDNA and plasma of two patients and CSF precipitates of another two patients were not available

Result:
Driver genes were detected in 100% (28/28) , 85.7% (24/28) and 75% (21/28) patients of CSF cfDNA, CSF precipitates and plasma, respectively; and 92.9% (26/28) patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA when compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were privately detected in CSF cfDNA, and CNVs in patients after TKI failure were more complicated when compared to those TKI naïve before LM. MET copy number gain identified in 44.0% (11/25) patients was the most frequent one, other CNVs included ERBB2, KRAS, ALK, MYC and FGFR1. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 67.9% (19/28) CSF cfDNA, which was much higher than that in plasma (2/28, 7.1%; p<0.001), and there was a trend towards higher rate of concomitant resistance mutations in patients with TP53 LOH than those without one (70.6% vs. 25%; p=0.036 ). EGFR T790M was identified in 28% (7/25) patients with progression to TKIs in CSF cfDNA.

Conclusion:
CSF cfDNA could reveal the unique genetic profiles of LM, and it should be the most representative medium of liquid biopsy for LM in NSCLC harboring EGFR mutations.

Background:
Liquid biopsy for plasma circulating tumor DNA (ctDNA) next generation sequencing (NGS) is now commercially available and increasingly adopted in clinical practice with a paucity of evidence based guidance. We set out to prospectively determine the utility of plasma ctDNA NGS in the lung cancer clinic.

Method:
Patients (pts) with advanced NSCLC who were driver unknown or resistance mechanism unknown were eligible. Pts were enrolled prospectively at Memorial Sloan Kettering (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood was collected in Streck tubes (10-20mL) and sent to Resolution Bioscience (Bellevue, WA) for targeted NGS of extracted DNA using a bias corrected hybrid capture 21 gene assay in a CLIA laboratory with unique reads at 3000x and sensitive detection at variant allele frequency above 0.1%. Clinical endpoints included detection of oncogenic drivers, turnaround time, comparison to tissue NGS when available, and ability to match pts to targeted therapy along with their treatment outcomes.

Result:
Seventy-six pts were prospectively accrued. Plasma NGS detected an oncogenic driver in 36% (27/76) of pts, of whom 14% (11/76) were matched to targeted therapy; including pts matched to clinical trials for HER2 exon 20 insYVMA, BRAF L597Q and MET exon14. Of the 10 evaluable pts, 10 partial responses were observed. Mean turnaround time for plasma was 6 days (3-12) vs 21 days (16-30) for tissue (P <0.0001). Plasma ctDNA was detected in 60% (46/76) of pts; detection rate was 46% (16/35) if blood was drawn on active therapy and 73% (30/41) if drawn off therapy, either at diagnosis or progression (Odds ratio 0.31, 95% CI 0.12 – 0.81; P=0.02). Of the 25 concurrent tissue NGS performed to date, there was a 96% plasma concordance with tissue and a 60% tissue concordance with plasma for driver mutations.

Conclusion:
In pts who were driver or resistance mechanism unknown, plasma NGS identified a variety of oncogenic drivers with significantly shorter turnaround time compared to tissue NGS, and matched patients onto targeted therapy with clinical benefit. Plasma ctDNA is best detected at diagnosis of metastatic disease or at progression. A positive finding of an oncogenic driver in plasma is highly specific and can immediately guide treatment, but a negative finding may still require tissue biopsy. Our findings provide evidence to support the incorporation of plasma NGS into practice guidelines.

Abstract not provided

Background:
Molecular characterization of tumor can guide the choice of therapy for NSCLC patients. However, tumors are complicated by spatial heterogeneity and sometimes may not be of sufficient quality and quantity for analysis. NGS using plasma cell-free DNA (cfDNA) input may capture temporal and spatial heterogeneity, and enable genomic profiling in patients without adequate available tumor tissue. Targeted gene panels allow for robust detection of known oncogenic drivers, but may not be comprehensive enough to screen for novel biomarkers or mechanisms of acquired resistance. Whole exome sequencing (WES) allows for hypothesis-free biomarker discovery, but may be technically challenging in the setting of limited tumor-derived DNA content in plasma cfDNA. In this study, we aim to develop a workflow to guide the selection of samples for targeted and whole exome sequencing for noninvasive molecular profiling.

Method:
Plasma samples were collected from 20 NSCLC patients receiving a variety of treatment (chemotherapy, targeted therapy, or immunotherapy). Most patients (>70%) had stage III or IV disease at the time of plasma collection. CfDNA was extracted from 3 mL of plasma, and analyzed using low-pass shallow whole genome sequencing (sWGS) and MSK-IMPACT, a hybridization capture-based assay targeting over 400 cancer-related genes. Analysis of matched normal was performed for somatic variant calling.

Result:
Median cfDNA yield per plasma sample was 28ng (range 7 - 236ng). We applied z-score statistics to estimate the levels of tumor-derived mutant allele fractions in cfDNA based on sWGS data. We trained the algorithm using a separate cohort of cfDNA data from >100 patients with metastatic solid tumors to classify samples by mutant allele fraction (MAF) as either low (<5% MAF) or high (>5% MAF) tumor-derived DNA. In the subset of 10 patients with unknown drivers, two were estimated to have MAF >5% in cfDNA, and WES recapture was performed. MSK-IMPACT targeted sequencing identified actionable alterations in a subset of patients who did not have sufficient materials for tissue profiling. WES in cases with high tumor-derived DNA content by sWGS identified alterations in genes outside of the MSK-IMPACT panel.

Conclusion:
Molecular profiling using cfDNA is feasible in lung cancer and may identify actionable alterations to inform treatment decisions in patients without sufficient tissue for molecular characterization. The application of sWGS to estimate the levels of tumor-derived mutant allele fractions in plasma cfDNA samples may help guide selection of the optimal downstream sequencing strategy.

Background:
Circulating tumor DNA (ctDNA) sequencing and analysis has the potential to transform clinical management of patients with advanced NSCLC. Non-invasive sampling of blood draws at different time points during treatment could potentially be used for routine monitoring of disease progression and detection of therapy resistant mutations by using next generation sequencing (NGS).

Method:
448 longitudinal plasma samples (mean 6.3 per subject) collected from 71 subjects with advanced NSCLC during 1[st] line treatment were analyzed by NGS. Of these 71 subjects, 47 also had matched baseline tumor tissue samples. The AVENIO ctDNA Surveillance kit and AVENIO FFPET Analysis kit (RUO, Roche, Pleasanton, CA, USA) were used for sequencing analysis. The Surveillance kit contains 17 cancer driver genes and additional 180 frequently mutated genes mainly selected for NSCLC and colorectal cancer. This kit is capable of detecting four mutation classes: SNVs, fusions, CNVs and InDels. CT images were reviewed centrally using RECIST v1.1.

Result:
Somatic, disease-associated mutations were detected with allele frequency (AF) of >5% in 94% of baseline tumor samples (44/47), and in 100% of plasma samples with AF in ctDNA ranging from ≥0.5% to ≤30%. The most commonly mutated genes in tumors were TP53 (22/47 subjects), KRAS (14/47), BRAF (7/47), STK11 (5/47), and ERBB2 (5/47). Tracking the AF’s of key tumor mutations by the Surveillance panel in the paired longitudinal plasma samples allowed the monitoring of treatment response at the molecular level. We identified a number of subjects in which the AF of cfDNA mutations increased three to four months before clinical evidence of progression of disease detected by CT scans that were centrally reviewed according to RECIST v1.1. Cases were also observed where the AF’s of key mutations decreased in 1[st] line chemotherapy to nearly zero which correlated with clinical partial response and stable disease. . Additionally, first post treatment plasma samples collected during first line treatment showed a difference of 96 days in median survival times of ctDNA- vs ctDNA+ groups (logrank p value =0.0371).

Conclusion:
ctDNA testing with molecular bar coded duplex sequencing and digital background error suppression of a large 197 gene panel offers high sensitivity for tumor variant detection. The study demonstrated that the presence of tumor variants detected in blood at the beginning and end of 1[st] line treatment is a risk factor for early disease progression. Longitudinal mutation monitoring has the potential to predict disease progression earlier than regular CT imaging.

Background:
The detection of driver gene mutation based on tumor tissue can instruct target therapy and conduct molecular monitoring after drug-resistance in advanced NSCLC, but many patients have no access to this kind of test because of inadequate tumor tissue or inability to tolerate the invasive test. Some studies have explored the value of EGFR mutation test in body fluids such as plasma，urine and sputum from NSCLC patients. But the sensitivity based on individual liquid specimen is poor compared with gold standard---tissue. We detect multi-genes in multi-liquid samples in parallel to investigate the Consistency and complementarity of genetic profile in different liquid samples and it’s correlation with efficacy of the real world therapy in advanced NSCLC.

Method:
The patients newly diagnosed with NSCLC and first-generation EGFR-TKI acquired drug-resistance were enrolled into our research (NCT:02778854) prospectively, the pre-treatment samples including tumor tissue, plasma, urine and sputum were collected. We conducted capture-based NGS (next generation sequencing) on all of these samples from 50 patients with a ctDNA panel covering significant exons and introns from 400 human genes including EGFR, KRAS, ALK, ROS1, c-MET and other important genes in the tumor related singling pathways such as PI3K-AKT-mTOR, JAK-STAT, Notch, Wnt and so on. Patients recruited in our experiment have been given unique treatment such as targeted treatment or chemotherapy according to the clinical examination. The final molecular diagnostic results of all clinical liquid or tissue specimen are supposed to be correlated with clinical response data.

Result:
（Applied for Late-Breaking Abstract） This section is not applicable now because the sequencing and complex data analysis is in progress. Therefore, we will submit the final results as late-breaking abstract.

Conclusion:
Section not applicable. We expect to figure out the molecular diagnostic value of different body fluid compared with tumor tissue. we are able to analyze for correlation of the genomic profile derived from liquid samples and respective tissue results and clinical response of each patient.

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided