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Abstract:
A cancer diagnosis is one of the most feared events rarely diagnosed before the late 20th century now competes with the Cardio-vascular disease, stroke, respiratory failure. The last half century has produced substantial advances in the treatment and early detection of few types of cancer and atleast modest gain in many other. Yet the reality is that half of the patients diagnosed with cancer will die within the first couple of years. With people living longer, the continued use of tobacco products, infectious disease that transmit cancer causing virus, and epidemic of obesity and arm-chair lifestyle, the cancer burden is projected to increase substantially over the decade. The delivery of high quality cancer care across the care continuum from diagnosis and treatment to maintaining the health of survivors and providing end-of-life care consistent with patients’ needs, values, and preferences. The provision of patient-centered care planning, palliative care, and psychosocial care; the prevention and management of long-term and late effects of cancer treatment; and family caregiver support should span the cancer care continuum from diagnosis through end-of-life care. The full cancer care continuum also includes the domains of prevention and risk reduction and screening. Cancer care for older adults, as noted throughout this report, is especially complex. Age is one of the strongest risk factors for cancer. The majority of cancer diagnoses and cancer deaths occur in individuals 65 years and older, and the majority of cancer survivors are in this age range. There are many important considerations to understanding the prognoses of older adults with cancer and formulating their care plans, such as altered physiology, functional and cognitive impairment, multiple coexisting morbidities, increased side effects of treatment, distinct goals of care, and the increased need for of social support. Their ability to participate in clinical trials has been limited, and thus the evidence base for informing treatment decisions in this population is lacking. The current health care delivery system is poorly prepared to address these concerns comprehensively. Thus, meeting the needs of the aging population will be an integral part of improving the quality of cancer care. Lung cancer is one of the commonest cancer causing death and it presents late. It is an extremely symptomatic disease and majority of the patients succumb to this disease. It is innately human to comfort and provide care to those suffering from cancer particularly who are close to death. Yet what seems evident as an individual’s personal level has by and large no guided policy all over the world. There is no argument that palliative care should be integrated into cancer care from diagnosis to death. Palliative care provides a specialized holistic approach to providing medical care with serious illness and the focus of Palliative Care is on providing relief from symptom and improving the quality of life of patients. Palliative Care is not End-of-Life or hospice but encompasses both. There is a dichotomy in the principle of medical care in cancer which single mindedly focuses on attempts to cure every patient at every stage. Recognition of the importance of symptom control and other aspects of Palliative care from diagnosis through dying process has been growing. Patients should not have to choose between treatment with curative intent or comfort care. There is need for both in varying degrees throughout the course of cancer whether the eventual outcome is survival or death. The goal is to maintain the best possible quality of life allowing the patients to choose whatever treatment they so wish while also meeting the needs of advanced disease through adequate symptom control. This goal is most often not met. For atleast half of those patients dying from cancer - most of whom are elderly and many vulnerable - death entails a spectrum of symptoms including pain, labored breathing, distress, nausea, confusion, and other physical and psychological conditions that go untreated and vastly diminishes the quality of remaining days. The patient is not the only one who suffers; family, care givers undergo unreleaved emotion and financial burden. This cannot be ignored within the context of the patients' who are terminally ill. A major problem in Palliative care is the under recognization, under diagnosis and thus undertreatment of the patients with significant stress ranging from existentional anguish, axiety and depression. Living with and eventually dying from a chronic illness runs substantial cost for patients, family, society and cost of those dying from cancer are 20% higher than average costs. Inadequacy of Palliative and End-of-Life care springs not from a single cause of a sector of society the separation of palliative and hospice care from potentially life prolonging treatment within the health care system, which is both influenced by and affects reimbursement policy; inadequate training of health care personnel in symptom management and other palliative care skills; inadequate standards of care and lack of accountability in caring for dying patients; disparities in care, even when available, for ethnic and socioeconomic segments of the population; lack of information resources for the public dealing with palliative and end-of-life care; lack of reliable data on the quality of life and the quality of care of patients dying from cancer (as well as other chronic diseases); and low level of public sector investment in palliative and end-of-life care research and training. This is not to suggest that there is no relevant ongoing research or relevant question or training program - there are - but the efforts are not coordinated and there is no focus for these activities in the Government agencies. What has resulted is under funding, lack of training and lack of research, leadership, with no sustained program for developing and disseminating Palliative treatment. Care for those approaching death is an integral and important part of health care. Everyone dies, and those at this stage of life deserve attention that is as thorough, active, and conscientious as that granted to those for whom cure or longer life is a realistic goal. Care for those approaching death should involve and respect both patients and those close to them. Particularly for patients with a grim prognosis, clinicians need to consider patients in the context of their families and close relationships and to be sensitive to their culture, values, resources, and other characteristics. Good care at the end of life depends on strong interpersonal skills, clinical knowledge, and technical proficiency , and it is informed by scientific evidence, values, and personal and professional experience. Clinical excellence is important because the frail condition of dying patients leaves little margin to rectify errors. Changing individual behavior is difficult, but changing an organization or a culture is potentially a greater challenge—and often is a precondition for individual change. Deficiencies in care often reflect flaws in how the health care system functions, which means that correcting problems will require change at the system level. The health care community has special responsibility for educating itself and others about the identification, management, and discussion of the last phase of fatal medical problems. Although health care professionals may not have a central presence in the lives of some people who are dying, many others draw heavily on physicians, nurses, social workers, and others for care—and caring. Thus, health care professionals are inescapably responsible for educating themselves and helping to educate the broader community about good care for dying patients and their families. More and better research is needed to increase our understanding of the clinical, cultural, organizational, and other practices or perspectives that can improve care for those approaching death. The knowledge base for good end-of-life care has enormous gaps and is neglected in the design and funding of biomedical, clinical, psychosocial, and health services research. Time is now to integrate Palliative care with mainstream care in cancer.

Abstract:
Southeast Asia comprises of 10 main countries including Malaysia, Indonesia, Thailand, Philippines, Singapore, Brunei, Cambodia, Laos, Myanmar and Vietnam. The concept of palliative care first developed around the mid-1980s in Singapore and the Philippines and later in the 1990s in Malaysia, Thailand and Indonesia. In other countries such as Brunei, Cambodia, Myanmar, Vietnam and Laos palliative care has only been developing more rapidly over the past 10 years. Levels of development of palliative care in Southeast Asia are highly variable depending very much upon factors such as availability of medical resources, funding, geography, demographics and the priorities of the country’s leadership. In 2011, the Worldwide Palliative Care Alliance(WPCA) mapped out the global development of palliative care dividing countries into 4 categories. Category 1 where there is no known development of palliative care, category 2 where development is at the level of capacity building, category 3 where there is isolated provision of palliative care services and category 4 where services are approximating integration into mainstream medicine. Among these countries, only Singapore and Malaysia have achieved category 4 status while majority are in category 3 (Indonesia, Thailand, Philippines, Myanmar, Cambodia, Brunei and Vietnam). Regardless of the level of development, challenges faced in developing palliative care in Southeast Asia are common throughout and include first and foremost barriers of drug availability and fear of using opioids amongst public as well medical practitioners. Apart from this is the challenge of public perceptions towards death and dying which have made development of this discipline difficult. Even till today there are many misconceptions regarding the role and concept of palliative care amongst healthcare professionals. For countries that are more advanced in their development, the key challenge now is how to continue development in a sustainable manner and how to improve and maintain standards of care. In Malaysia, palliative care began in the early 1990s with the development of voluntary organisations providing homecare services for patients with terminal cancer. In 1995 the concept was introduced into government hospitals and soon received nationwide support by the Ministry of Health in Malaysia. In 2005, the subspecialty of palliative medicine was established and a formalised training programme for medical specialists was developed. At present there are a total of 18 trained palliative medicine specialists in Malaysia with 2 more in training. In 2014, an advanced diploma programme for nurses, physiotherapists and occupational therapists was developed in the Ministry of Health which has now trained 38 nurses and paramedics who have now become permanent stakeholders in palliative care service provision and development. Apart from this, non-governmental organisations also serve as a backbone to community palliative care services in Malaysia and there are currently 25 services throughout the country providing homecare. It is with such initiatives that Malaysia hopes to create a sustainable and credible workforce to continue the development and growth of palliative care throughout the nation and possibly the region.

Abstract:
It is well known that palliative care is a necessity in cancer patients, as early on as the time of diagnosis. In adult oncology, there is evidence to suggest early specialist palliative care improves HRQOL, mood, treatment decision-making, health-care utilization, advanced care planning, patient satisfaction, and end-of-life care (1). Early admission to community-based palliative care also reduces the use of Emergency departments by cancer patients in the 90 days before death (2). Palliative care for cancer patients is rather new in Iran and has a history of less than 7 years. Here we give an overview on the status of palliative care in Iran. We also present the demographics of our patients in the first and largest palliative care ward in Iran over the last two years. Iran has a population of around 80 million people. In Iran, cancer is known as the third cause of death. Adult morbidity rate of cancer in different regions of Iran is estimated 48-112 cases per million people among the females and 51-144 cases per million people among the males (3). Also, mortality rate related to cancer was about 53500 people in 2014 (4). The majority of cancer patients expire in the intensive care units (ICU), whereas bed occupancy of ICUs is in crises, being about 100% in Iran. For each ICU bed, 4 people are applicants (5). We currently have around 8 active palliative care units for cancer patients and one palliative care ward in Iran, all run by charities. In these palliative care units, we have oncologists, palliative care specialists, pain specialists, psychologists, spiritual care specialists, social workers and dieticians. A total number of 3677 patients, ages between 16 and 94 (Median 61), of whom 3277 (89%) with a similar age distribution had a cancer diagnosis were referred to our palliative care unit in Firoozgar Hospital, which is run by the Ala Charity, in Tehran in the last three years. 1770 female (54%) and 1457 male (46%) advanced cancer patients were referred. A number of 388 (12%) patients had breast cancer, 339 (10%) had hematologic malignancies, 312 (10%) had esophageal or gastric cancer, 311 (10%) had colorectal cancer, 105 (3%) had a cancer of the CNS, 101 (3%) had lymphoma, 93 (3%) had renal cancer, 87 patients (3%) had ovarian cancer, 81 (2%) had lung cancer, 54 patients (2%) had prostate cancer and 50 (2%) had pancreatic cancer. The other 40% of the cancer patients had either less frequent cancers or their exact cancer site was not recorded. In most countries, the gap between death and specific therapies is considered as an indicator of the quality of physician services and more length of time will be a better indicator for physician services, while cancer patients in health system of Iran receive specific treatment and chemotherapy even to moment of death. To consider countless benefits of home care and the patients’ desire to receive services at home, if we can provide the conditions that at least 20% of end stage cancer patients receive home based palliative care, 1000 deaths will occur at home yearly, and 1000 ICU beds will be released for use for other patients with better prognosis for survival (5). For this reason, the Ala charity has also started free of charge home care services in Isfahan and Tehran. Iran, like many other countries, needs many more palliative care units as well as an expansion of home based palliative care services to advanced and very advanced cancer patients. As palliative medicine is not financially lucrative, charities play a major role in setting up, maintaining and expanding these units. References: Salins N, Ramanjulu R, Patra L, Deodhar J, Muckaden MA. Integration of Early Specialist Palliative Care in Cancer Care and Patient Related Outcomes: A Critical Review of Evidence. Indian J Palliat Care. (2016) 22:252-7 McNamara BA, Rosenwax LK, Murray K, Currow DC. Early admission to community-based palliative care reduces use of emergency departments in the ninety days before death. J Palliat Med. (2013) ;16:774-9 Mousavi SM, Gouya MM, Ramazani R, et al. Cancer incidence and mortality in Iran. Annals of Oncology. (2009) ;20:556–63. World Health Organization. Cancer country profiles in Iran 2014. Geneva: WHO; 2014. [cited 29 August 2015]. Avilable from: http://www.who.int/cancer/country-profiles/en/ Heydari H. Home-based Palliative Care: A Strategy for Keeping Intensive Care Unit Beds Vacant. Int J Community Based Nurs Midwifery. (2016);4:186-7.

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Background:
Conventionally, the classification of lung cancer and many other malignancies is determined by the histology of a tumor. Large cell neuroendocrine carcinoma (LCNEC) is traditionally classified as a histological variant of large cell carcinoma (LCC), which is a subtype of non-small cell lung cancer (NSCLC). However, LCNEC exhibits differential cytological, morphological, clinical and biological features than those of classic LCC, thus rendering controversies regarding its classification. In 2015, with the integration of immunohistochemical analyses, the World Health Organization (WHO) has re-classified LCNEC under neuroendocrine tumors. Due to the rareness of LCNEC, few studies have been conducted on the molecular genetic profiling of LCNEC. In this study, we characterized molecular signature associated with a cohort of LCNEC, SCLC and LCC using capture-based targeted sequencing.

Methods:
We performed capture-based targeted sequencing on 30 surgically resected samples from patients with lung cancer using BurningRock Biotech’s OncoScreen Panel. This panel, consisting of all exons and critical introns of 295 genes, covering multiple classes of somatic mutations, including single nucleotide variation (SNVs), rearrangements, copy number variations (CNVs) and insertions and deletions (INDELs), can be used to detect genetic alterations both qualitatively and quantitatively. Among the 30 patients, 15 of them were diagnosed with LCNEC, 5 with LCC and 10 with small cell lung cancer (SCLC).

Results:
While no statistically significant difference was observed in total number of mutations among the three subtypes, LCC carries the most number of somatic mutations followed by LCNEC then SCLC. Overall, we identified 331 mutations with TP53 being the most frequently mutated gene in all three subtypes. Genes with recurrent somatic mutations detected in LCNEC, but not in LCC or SCLC include RUNX1, ERBB4, BRCA1, and EPHA3. Copy number analysis revealed a higher prevalence of CNV in LCNEC, with 60% of cases harboring such alteration. There is no common CNVs shared among all three subtypes. NFкBIA amplification is the only common CNV found in both LCNEC and LCC; and AKT2 amplification is shared by LCNEC and SCLC. Most CNVs are subtype-specific. Interestingly, one RET-fusion was discovered in one LCC sample and one EGFR exon 19 deletion accompanied by EGFR copy number amplification was discovered in one LCNEC sample.

Conclusion:
Targeted deep sequencing reveals distinct genetic profile for LCNEC compared to LCC and SCLC. LCNEC harbors more CNV and contains a panel of genes, including RUNX1, ERBB4, BRCA1 and EPHA3 that are more frequently mutated comparing to LCC and SCLC.

Background:
Tumor mutational load (TML) by whole-exome sequencing (WES) is a potential determinant of response to immune checkpoint blockers. The use of PD-L1 as a predictive biomarker for use of PD-1/PD-L1 inhibitors is limited. To date, there are few data concerning TML in puNETs.

Methods:
WES was performed in fresh-frozen tumor-normal pairs from 35 typical carcinoid (TC), 4 atypical carcinoid (AC) and 9 large-cell neuroendocrine carcinoma (LCNEC) consecutively collected. Exome enriched libraries were sequenced on an Illumina HiSeq 2000 with a paired-end 2 x 100 bp protocol. Reads were aligned to the reference hg19 using an implementation of the Burrows-Wheeler Aligner, and a BAM file was produced for each tumor and normal sample using the Picard pipeline. The MuTect algorithm was used to identify SSNVs in WES data. We used a minimal allelic fraction cutoff of 0.1. Patients' characteristics and TML were described (median and interquartile for quantitative variables and frequencies for qualitative variables). To evaluate the effect of some factors on the TML, an analysis of variance was used. A log transformation was performed according to the distribution of the TML. The median follow-up was estimated using the Schemper's method. The number of relapses and deaths was reported.

Results:
Cohort included 24 male and 24 female. Median age at diagnosis was 57 [Q1= 46; Q3= 70] years, 38% of carcinoids (TC+AC) and 89% of LCNEC were smokers, 26 (54%) stage I, 16 (34%) stage II, 3 (6%) stage III and 3 (6%) stage IV. All patients underwent surgery and 5 (10%) received neoadjuvant treatment. Median follow-up was 32.6 (min= 4.4; max= 179.9) months; there were 8 (17%) relapses (6/9 LCNEC, 2/39 carcinoids) and 10 deaths. On average, 11.6 Gb of sequence were produced per sample, aiming a mean coverage of 72X. Overall median TML was 0.31/Mb [Q1= 0.22; Q3= 0.67], significantly lower in carcinoids tumors than LCNEC (0.28 [Q1= 0.20; Q3= 0.38]/Mb vs. 2.98 [Q1= 1.20; Q3= 4.84]/Mb, respectively, p<0.0001). Similar findings were observed among smoker vs. non-smoker patients (0.28 [Q1= 0.18; Q3= 0.38]/Mb vs. 0.60 [Q1= 0.28; Q3= 2.98]/Mb, respectively, p=0.04). Both variables were found to be independently correlated with TML within the ANOVA test (p=0.0016).

Conclusion:
Our findings provide a unique portrait of puNETs, revealing different histotype mutational burden. Continued work in harnessing immunological data in puNETs are needed for better understanding immunotherapy-treatment option in this orphan disease.

Background:
Insulinoma-associated protein 1 (INSM1) is expressed predominantly in embryonic developing neuroendocrine (NE) tissues, and the expression is significantly reduced/restricted in adult tissues. We previously revealed that INSM1 is expressed exclusively in small cell lung cancer (SCLC) compared to non-small cell lung cancer (NSCLC). The significance of the expression of INSM1 in lung cancer has been largely unknown. We investigated the utility of INSM1 as a novel immunohistochemical marker and researched the biological significance in lung cancer cell lines.

Methods:
We compared INSM1 as an immunohistochemical marker for NE tumours of the lung to conventional markers (chromogranin A (CGA), synaptophysin (SYP), and CD56). To elucidate the biological function of INSM1 in the NE differentiation pathway, we conducted INSM1 gene knockdown/overexpression experiments using human lung cancer cell lines.

Results:
INSM1 was expressed in 100% of SCLCs (44/44), Large cell neuroendocrine cell carcinomas (7/7), and Carcinoids (11/11), but was not expressed in NSCLCs (90 adenocarcinomas and 47 squamous cell carcinomas). This novel immnohistochemical marker showed high sensitivity and specificity when compared to conventional NE markers. We demonstrated that knockdown of INSM1 expression resulted in significant reduction of NE molecules in SCLC cell lines, and overexpression of INSM1 induced NE differentiation in NSCLC cell lines.

Conclusion:
INSM1 was a superior NE immunohistochemical marker when compared to conventional markers. Furthermore, our biological molecular experiments revealed that INSM1 is a critical upstream regulator of the NE differentiation pathway in SCLC cell lines. The elucidation of the significance of INSM1 expression in lung cancer strongly supports the diagnosis of NE tumours of the lung and promotes the understanding of the molecular biology of these tumours.

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Background:
Circulating-tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays universal inactivation of TP53 (Peifer and Fernandez-Cuesta et al., Nat Genet 2012; George et al., Nature 2015).

Methods:
We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. The results were further validated in an independent series of 102 non-cancer controls. We identified mutations using Needlestack (Delhomme et al., in preparation; https://github.com/IARCbioinfo/needlestack), a pipeline specifically designed to accurately detect variants at very low allelic fractions (AF).

Results:
We detected TP53 mutations in the cfDNA of 49% of the SCLC patients (35.7% of the stage I-II). While statistically significant in cases versus controls (p-value=6x10[-9]), TP53 mutations were also detected in the cfDNA of 11.4% of the non-cancer controls, and these results were confirmed in the replication series (10.8%). The presence of TP53 mutations in controls was not correlated with age, smoking, or alcohol-intake status. There was a statistically significant difference between the mutational patterns found in cases versus controls (p-value=0.008): within controls the fraction of nonsense, indel, or splicing mutations was lower than in cases. The median AF of the TP53 mutations detected in the five stage I-II SCLC (0.9%) was not significantly different from that found in controls (1.2%; p-value=0.64), while it differed from the median AF of stage III-IV SCLC tumors (8.2%; p-value=2x10[-6]). Finally, we sequenced the DNA extracted from the white-blood cells (WBC) of 39 cfDNA TP53-positive patients, from which material was available (19 cases and 20 controls). Four cfDNA TP53 mutations (1 case and 3 controls) were detected in the WBC DNA, with similar AFs to those found in the cfDNA. These AFs, below 11%, are consistent with a somatic origin in both cfDNA and WBC DNA.

Conclusion:
The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests for the early diagnosis of cancer (Fernandez-Cuesta, Perdomo, and Avogbe et al., EBioMedicine 2016). We will discuss these results as well as follow-up analyses in retrospective and prospective series.

Background:
Patients with extensive stage small cell lung cancer (ES-SCLC) who progress after frontline platinum-based chemotherapy are often considered “platinum-sensitive” (progression ≥ 90 days from last platinum dose) or “platinum-refractory” (progression < 90 days), as each group reportedly has differential overall survival (OS) outcomes. In a pooled analysis of recent SWOG trials of second and/or third-line targeted therapy, we showed that platinum-sensitivity status may no longer be as strongly associated with OS (Lara et al, JTO 2015). We assessed post-progression survival (PPS) following frontline platinum-based therapy in the context of platinum sensitivity status in ES-SCLC patients treated on SWOG 0124, a phase III trial of Irinotecan/Cisplatin vs Etoposide/Cisplatin.

Methods:
Data from 657 patients enrolled in S0124 were pooled. PPS was calculated as OS from the reported progression date. Crude PPS was evaluated according to platinum-sensitivity status. Hazard ratios (HRs) for PPS accounting for platinum-sensitivity and baseline clinical covariates (i.e., measured at the time of first line therapy) were calculated using single and multivariable Cox Proportional Hazard models. Baseline covariates were included in a logistic regression model to identify predictors of platinum-sensitivity. Recursive partitioning analysis (RPA) was performed to define prognostic risk groups.

Results:
Of 657 patients, 534 had a progression date and thus included in the analysis: 162 (25%) were platinum-sensitive and 372 (75%) refractory. Fewer patients with PS 0 (32% vs. 41%) and more patients with weight loss > 5% (40% vs. 31%) were seen in the refractory group. Crude unadjusted PPS was higher in platinum-sensitive vs refractory patients (median PPS 7.5 vs. 4.3 months; HR=1.64, p <0.001, 95%CI 1.356, 1.981). A multivariable Cox model showed that baseline elevated serum lactate dehydrogenase (LDH; HR=0.66, p<0.001) and platinum-sensitivity status (HR=1.54, p<0.001) were independently associated with PPS. None of the baseline covariates predicted for platinum-sensitivity. Prognostic groups with differential PPS based on platinum-sensitivity status, gender, and LDH were identified by RPA.

Conclusion:
PPS was significantly higher for S0124 patients categorized as platinum-sensitive vs. refractory. Limitations of this work include lack of relevant clinical data at the time of progression and number and type of post-progression therapies. These data have implications for the development of ES-SCLC trials in the salvage setting. [Supported by NIH/NCI/NCTN grants to SWOG: CA180888, CA180819, and in part by Pharmacia & Upjohn, a subsidiary of Pfizer. ClinicalTrials.gov Identifier: NCT00045162]

Background:
PARP1 is overexpressed in small cell lung cancer (SCLC) and represents a novel therapeutic target for this disease. Preclinical data indicates that combining veliparib (an oral PARP-1/2 inhibitor) and temozolomide (TMZ) results in synergistic tumor growth delay or regression. In this study, we investigated whether adding veliparib to TMZ would improve outcomes in patients with relapsed sensitive and refractory SCLCs. Candidate predictive biomarkers, including SLFN11, were then explored.

Methods:
SCLC patients previously treated with 1 or 2 prior regimens were enrolled in the trial and randomized 1:1 to receive oral TMZ 150-200mg/m[2]/day (D1-5) with either veliparib or placebo 40mg twice daily, orally (D1-7) (NCT01638546). Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in patients with platinum sensitive (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Archived tissue was available for 53 patients for biomarker analysis.

Results:
104 patients were enrolled and 100 patients were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. Progression free survival at 4-months was similar between the two arms, 36% vs. 27% (p=0.39). However, in 93 evaluable pts, response rate was significantly higher in pts treated with veliparib/TMZ compared to TMZ alone (39% vs 14%, p =0.016). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Levels of SLFN11, a marker of SCLC response to PARP inhibition in preclinical models, were assessed by immunohistochemistry. High SLFN11 in patient tumors (obtained at original diagnosis) was associated with a trend towards better overall survival in the veliparib/TMZ arm, but no difference in outcome in the TMZ alone arm. Additional correlative studies are ongoing, including assessment of MGMT promoter methylation, and will be available at the time of presentation.

Conclusion:
The combination of veliparib/TMZ increased response rates significantly, compared to TMZ alone. Hematologic toxicities of the combination may have impacted PFS (which was not significantly different between the arms) by limiting dosing. Biomarkers such as SLFN11, ATM, or MGMT promoter methylation could potentially help guide patient selection in the SCLC population.

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Background:
For patients with SCLC, response to chemotherapy is monitored by computed tomography (CT) scans, which can be costly and inconvenient. A previous study showed that baseline levels (>100 pg/ml) of the tumor marker, ProGRP, were positively correlated with advanced SCLC, and a decline in ProGRP levels during treatment was associated with response.[1] However, the best approach to fully exploit ProGRP for monitoring treatment response is still unknown. The objective of this study was to determine if progression could be ruled out solely by combining the changes in ProGRP levels over two chemotherapy cycles.

Methods:
Patients with SCLC receiving first-line platinum-based doublet chemotherapy or a single-agent cytotoxic in any subsequent treatment line were included from six centers in Europe and China. Samples were collected prospectively and ProGRP levels were measured in serum or plasma samples using a fully automated ProGRP assay at baseline and after chemotherapy cycles 1 and 2. Only patients with blood samples taken at these time points and with elevated baseline ProGRP >100 pg/ml were eligible for this analysis. A logistic regression model was calculated to incorporate changes after the first cycle (i.e. from baseline to the end of cycle 1) and in between cycles (i.e. end of cycle 1 to the end of cycle 2). Progression was ascertained with CT scans. A non-progressor was defined as a patient with complete response, partial response, or stable disease, according to the RECIST v1.1 or WHO criteria. Progressors were patients with progressive disease only.

Results:
Overall, 123 patients (n=108 non-progressors, n=15 progressors) satisfied the eligibility criteria. Median age was 62.0 years (range 36.0–83.0), 56% were male, and 78% reported to be current or past smokers. In this population, a decline in ProGRP from both baseline to cycle 1 and from cycle 1 to cycle 2 was associated with non-progression (AUC 91.5%; 95% CI: 85.3−97.8; sensitivity 100%; specificity 71%). All patients who experienced a >25% relative decline in ProGRP levels after the first chemotherapy cycle, followed by any further decrease (>0%) after the second cycle, were found to be non-progressors.

Conclusion:
By measuring the change in ProGRP levels at baseline and after each of the two subsequent chemotherapy cycles, we were able to identify patients with non-progressive disease. This might reduce the need for interim CT scans. References 1. Muley, et al. Journal of Thoracic Oncology 2015; 10(9) Supplement 2:MINI27.13

Background:
Small cell lung cancer (SCLC) that has progressed after 1[st] line therapy has few effective treatments and no new class of approved therapies in over 20 years. Paired tumor-normal exome and transcriptome sequencing efficiency, coverage, cost, and analytics has improved over the last decade and has begun to be applied in the clinic. In this prospective study, we used genome-wide strexome (exome+structural variation) plus whole transcriptome sequencing (NGS) to identify genomic events and associated expression changes in advanced SCLC and attempt to prescribe systemic therapy based on the results (NCT02297087, study was funded by SU2C).

Methods:
After informed consent a prospective fresh frozen tumor biopsy was obtained. Germline DNA was extracted from PBMC and reference normal tissue RNA was obtained commercially. Strexome and RNA-seq libraries were prepped and NGS, data analysis, and reporting were performed in a CLIA-certified CAP accredited environment.

Results:
The study completed its accrual goal of 12 evaluable patients. There was one screen failure due to anticipated inadequate sample yield because of tumor location. The cohort included 10 women, median age was 56.5 years and had 3 never smokers. All patients received prior platinum-based chemotherapy and were receiving >1[st] line systemic treatment while awaiting NGS results. The minimum tumor content for successful NGS was 20%. The median turnaround time from sample collection to report was 27 days (range 21-38). Average strexome coverage was 420X (tumor), 200X (germline), with an average of 277 million RNA reads generated for tumors. All patients had ³2 clinically actionable targets identified (associated with a commercially available, FDA-approved drug by predefined rules), median 4 targets (range 2-8). Three patients received treatment identified by NGS. One has continuing partial response by RECIST 1.1 >8 months on a clinical trial involving PD-1 inhibitor+irinotecan (MLH1 mutation); treatment linked to NGS was already initiated prior to the report becoming available. One is too early to evaluate on olaparib (PARP1 mutation), and one had disease progression on dasatinib (KIT overexpression) as best overall response. One patient has not yet received NGS recommended therapy, and the remaining 8 evaluable patients had clinical deterioration or died before NGS recommended therapy was initiated.

Conclusion:
SCLC after 1[st] line therapy tends to have more rapid progression and deterioration making NGS application for systemic therapy challenging. Either applying NGS earlier in the earlier stages of disease course or further improvements in turnaround time may better address these challenges.

Background:
Hippocampal avoidance (HA) during whole brain radiotherapy (WBRT) is performed to prevent neural stem-cell injury causing decreased neurocognitive function. Nevertheless, the estimated risk for metastases in HA area in small cell lung cancer (SCLC) patients is unknown. The current study aimed to characterize the metastatic distribution within the brain relative to the hippocampus and estimate the incidence of hippocampal metastasis in SCLC patients and also identify clinical and radiographic variables that may be associated with the presence of metastases within the HA area.

Methods:
SCLC patients treated with WBRT between January 2010 and December 2015 were reviewed. T1-wighted, post-contrast axial MRI (1.5 or 3 Tesla) images obtained just before therapeutic cranial irradiation were retrieved and reviewed for each patient. The HA area was generated by expanding the hippocampal contour by 5 mm volumetrically to account for necessary dose fall-off between the hippocampus (HP) and the whole brain planning target volume. Metastatic lesions within HP or HA area were defined as HP metastasis. HP metastasis rate was evaluated and characteristics of patients with HP metastasis were analyzed and compared to patients without HP metastasis.

Results:
54 patients evaluated with cranial MRI were enrolled. HP metastasis rate was 32% (17 patients). 4.4% of all metastases involved the HP and HA area (2.2% of metastases each) Figure 1. The most common location of metastasis was frontal lobe followed by cerebellum and temporal lobe. Having diabetes mellitus (OR: 12.1, 95% CI: 1.1-137.4, p=0.045) and being younger than 65 years of age (OR: 4.8, 95% CI: 1-23.2, p=0.049) were found to be independent risk factors for HP metastasis.



Conclusion:
HP metastasis might be more common in SCLC patients. Reducing the dose to the HP by HA-WBRT plan in SCLC may be risky for the development of HP metastasis compared with other malignant solid tumors.

Abstract not provided

Abstract:
Recent Advances in Radiation Treatment Technique for Lung Cancer Lung cancer is the leading cause of cancer-related death in the United States and throughout the world. Advancement of Radiation Treatment have been parallel to imaging capability to target cancer and avoid surrounding normal tissue structure which associated with volume and dose. We can cure most of early lung cancer if it is well staged early cancer and targeted correctly by stereotactic body radiation therapy (SBRT). Because of high dose per fraction, technical aspects and quality assurance to deliver the radiation to the tumor precisely and avoid high dose of radiation to the critical surrounding normal tissue are critical issues organs in addition to controlling tumor motion. Technologic advancements of imaging and radiotherapy to conform the gross target volume(GTV) with tighter margins but adequate clinical targeted volume (CTV) and planning tumor volume (PTV) considering daily set up variations which are supposed to minimize the dose to nearby normal tissues. We have tried to answer higher radiation dose improve survival by the RTOG 0617 which compared overall survival after standard-dose versus high-dose intensity-modulated radiation therapy (IMRT) or three-dimensional conformal radiation therapy (3DCRT) with concurrent chemotherapy +/- cetuximab for patients with inoperable stage III non-small-cell lung cancer. In this open-label randomized, phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0–1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All received concurrent chemotherapy with 45 mg/m2 paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m2) and carboplatin (AUC 6). Radiation dose was prescribed to the PTV and was given in 2 Gy daily fractions with either IMRT or 3DCRT. For patients assigned to receive cetuximab, 400 mg/m2 cetuximab was given on day 1 followed by weekly doses of 250 mg/m2, and was continued through consolidation therapy. 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5–33.3). Median overall survival was 28.7 months (95% CI 24.1–3.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7–25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09–1.76; p=0.004). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2–30.5) compared with 24.0 months (19.8–28.6)in those who did not (HR 1.07, 95% CI 0.84–1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). Severe esophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001). This study did not mandate 4D simulation and possibly GTV was not well covered by the dose prescribed. There was higher local failure in the 74 Gy arm because of tighter margin in this group. We assumed from this study that 74 Gy radiation given in 2 Gy fractions with further improvements are expected from the use of charged particle therapy with protons or other particles; randomized comparisons of proton therapy vs. intensity-modulated photon radiation therapy for lung cancer are underway in the United States .A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617. The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P =.005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distance metastasis were not different between IMRT and 3D-CRT. IMRT was associated with fewer grade 3 or greater pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses (P <0 .05), and volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis (P<0.05). Lung V5 was not associated with any toxicity equal or greater than grade 3, whereas lung V20 was associated with increased grade 3 or greater pneumonitis risk on multivariable analysis (P = .026). IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC. We have evidence that severe pneumonitis and esophagitis have been reduced by proton compared to IMRT with concurrent chemotherapy for stage III NSCLC. However it is difficult to do a randomized trials. In conclusion, screening by low dose spiral CT scan for among previous or current smokers to detect early lung cancer. Early lung cancer can be curable by SBRT Lung cancer treatment planning requires 4D simulation. The technical advancement such as IMRT or Proton Treatment compared to 2 or 3 dimensional radiotherapy with concurrent chemotherapy reduced normal tissue toxicity among patients with locally advanced lung cancer which will improve their outcome in future. We are testing this hypothesis by a randomized prospective study.

Abstract:
Dose escalation with conventional fractionation and concurrent platin-based chemotherapy within the RTOG 0617 trial has failed to show a survival benefit. Proton therapy has failed to show a reduction in radiation pneumonitis in comparison to intensity modulated photon radiotherapy at the same total dose according to the NCT 00915005 trial. Randomized trials for comparison of IMRT and 3D conformal radiotherapy are lacking. While randomized trials conducted so far failed to show an increment in survival by newer radiotherapy concepts on one hand, the old standard of giving 60 Gy with conventional fractionation and concurrent chemotherapy consolidated on the other. So where does the hope come from that technological advances in radiotherapy lead to an improved survival in locally advanced lung cancer, if not from randomized trials? It comes from many small precious components that can lead to an increase of loco-regional control by radiotherapy in locally advanced NSCLC, the primary goal of radiotherapy. First of all, the determination of tumor spread has been substantially improved by the introduction of FDG-PET/CT, by systematic mediastinal evaluation with EBUS-TBNA, and by brain MRI. The determination of tumor position during irradiation has been improved by stereoscopic KV imaging during irradiation or real-time magnetic resonance imaging and therefore tumor targeting can be optimized. Volumetric modulated arc therapy can deliver conformal dose distributions within a breath hold of 20 s. With hyperfractionated acceleration and concurrent chemotherapy, high biologically effective doses can be given for patients with locally advanced NSCLC resulting in similar survival and local control rates than with trimodality treatment. Integrated boost radiotherapy controlling dose gradients form gross tumor volume towards organs at risk as the contra-lateral bronchial wall or the esophagus has become feasible and is tested within prospective trials. Immunotherapy and molecular targeted therapies are upcoming as combination partners with radiotherapy in selected tumors. Proper patient selection criteria resulted long term survival as high as 30-45% in multicenter prospective trials in locally advanced NSCLC. These advantages have to be bundled into new radiotherapeutic concepts and tested against the standard of conventional fractionated radiotherapy up to 60 Gy and simultaneous chemotherapy in future well designed randomized trials.

Abstract:
Several trials have evaluated the appropriate initial duration of platinum based chemotherapy: 3 versus 6 cycles, 4 versus continuous cycles, or 2 versus 4 cycles after non-progression to the initial 2 treatments. In all situations there was no benefit to longer duration of chemotherapy and both ASCO and NCCN recommend no more than 6 cycles of initial treatment. Continuation of lower intensity therapy (typically with a single agent from the initial doublet) was also tested. Studies of weekly paclitaxel after carboplatin-paclitaxel (Belani et al) or gemcitabine after cisplatin-gemcitabine (Brodowicz et al) showed no OS difference, but a possible benefit in PFS. Studies evaluated the introduction of a non-cross resistant agent (early second line) in patients without progression after initial chemotherapy. Westeel et al. randomized patients after MIC x 3 to either observation versus vinorelbine; Fidias et al. evaluated immediate versus delayed docetaxel after carboplatin-gemcitabine x 4 and JMEN study looked into pemetrexed versus placebo after four cycles of platinum doublet. For the latter two studies, about 50% of patients completed 6 maintenance cycles and 50-60% of patients in the observation arm received second line therapy; this is consistent with rates of second line therapy in multiple studies of NSCLC. Results showed a 2-3 month difference in PFS favoring immediate therapy. In terms of overall survival, there was no difference with vinorelbine, and a 2.6-2.8 month difference with either docetaxel or pemetrexed (significant only with pemetrexed). QoL was not affected by continuous chemotherapy and tumor related symptoms improved with pemetrexed. Erlotinib has been evaluated in 3 randomized trials against placebo (SATURN), observation (IFCT-GFPC 0502) or in combination with bevacizumab against placebo-bevacizumab (ATLAS). In all studies there was a PFS benefit (HR 0.71-0.82), but OS was only significant in the SATURN trial (HR 0.81). PFS benefit was limited to non-squamous histology for pemetrexed, as opposed to the docetaxel and erlotinib trials. Despite the initial negative trials, continuation pemetrexed following platinum-pemetrexed doublet has emerged as a standard option for non-squamous NSCLC. PARAMOUNT randomized between pemetrexed and placebo following four cycles of cisplatin pemetrexed. It showed a PFS benefit (HR 0.64) and also an OS benefit (2.9 month difference, HR 0.78) in favor of continuation maintenance. AVAPERL used a similar design, however with the addition of bevacizumab throughout therapy, i.e. initial cisplatin-pemetrexed-bevacizumab followed by pemetrexed-bevacizumab versus bevacizumab. PFS significantly favored pemetrexed (10.2 versus 6.6 months), and although OS was also superior (19.8 versus 15.9 months) it was not statistically significant. The IFCT-GFPC 0502 trial also evaluated continuation gemcitabine and demonstrated a PFS advantage, but no OS benefit in an underpowered study. Bevacizumab continuation is an accepted approach based on the design of E4599, although its contribution has never been established in a randomized trial. However, a direct comparison between E4599 (carboplatin-paclitaxel-bevacizumab followed by bevacizumab) and carboplatin-pemetrexed-bevacizumab followed by pemetrexed-bevacizumab was undertaken in the POINTBREAK study. It showed no OS differences (numerically favored E4599: 13.4 versus 12.6 months), although in pre-specified analysis of patients going through maintenance (as opposed to ITT) there was a 2-month difference favoring the combination of pemetrexed-bevacizumab. E5508 [ClinicalTrials.gov identifier:NCT01107626] is attempting to answer this question by directly randomizing patients to either bevacizumab, pemetrexed or the combination after carboplatin-paclitaxel-bevacizumab. Subset data from the SATURN trial strongly supports switch maintenance with erlotinib for EGFR mutant patients, who had an impressive three fold higher median PFS (44 vs 14 weeks; HR: 0.10; 95% CI: 0.04–0.25). INFORM included 296 asian patients, who were randomized between gefitinib and placebo. PFS favoured gefitinib maintenance (4.8 vs 2.6 months, HR=0.42; 95% CI: 0.33–0.55; p <0.0001). No overall survival benefit has been found for squamous cell patients. However, a PFS benefit was seen in IFCT-GFPC 0502 for continuation maintenance with gemcitabine and in SATURN for sequential erlotinib. The ABOUND study with carboplatin/ nab-paclitaxel is exploring the nab-paclitaxel maintenance in squamous-cell and results are awaited. The SQUIRE trial evaluated the anti-EGFR monoclonal antibody necitumumab in combination with cisplatin-gemcitabine followed by maintenance necitumumab. It modestly improved overall survival and PFS over chemotherapy alone (median OS 11.5 vs 9.9 months, HR 0.84, p=0.012; PFS HR 0.85, p=0.02). The contribution of bevacizumab maintenance phase was not prospectively been established. However, a retrospective landmark analysis of E4599 evaluated the patients who were alive without progression for at least 3 weeks after completion of 6 cycles of chemotherapy. The PFS favored bevacizumab maintenance (4.4 vs 2.8 months; HR 0.64). OS was also longer (median 12.8 vs 11.4 months). ECOG 5508 is an important ongoing study, as mentioned previously Another ongoing study (MO 22097) is evaluating the role of continuing bevacizumab in combination with a second line chemotherapy, beyond progression to maintenance bevacizumab. In a phase III placebo-controlled study, carboplatin and paclitaxel were given with or without concurrent and maintenance sorafenib, but no improvement in overall survival was shown and the results were detrimental in patients with squamous cell histology. CALGB 30607 of maintenance sunitinib versus placebo met its primary endpoint of improving PFS (4.3 versus 2.8 mos), including squamous histology. There was no effect on OS. EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis. A phase III trial of carboplatin, paclitaxel with or without concomitant and maintenance ipilimumab (an anti-CTLA4 agent) is ongoing, and was initiated taking into account the positive results obtained adding maintenance ipilimumab to the platinum doublet in a previous phase II study. Vaccine therapy has also been studied as maintenance treatment in NSCLC. Belagenpumatucel-L (Lucanix) is an allogeneic cancer vaccine, obtained from TGF-beta2 antisense gene modified whole NSCLC cell lines. There was no difference in overall survival between arms (median survival 20.3 versus 17.8 months with belagenpumatucel-L versus placebo, respectively. Tecemotide (L-BLP-25) is a vaccine against MUC1 antigen. START trial randomized patients with stage III NSCLC who completed chemoradiotherapy between tecemotide injections or placebo. No significant difference in overall survival with the administration of tecemotide after chemoradiotherapy was found - median OS was 25.6 months with tecemotide versus 22,3 months with placebo. References 1. Cost-utility analysis of maintenance therapy with gemcitabine or erlotinib vs observation with predefined second-line treatment after cisplatin–gemcitabine induction chemotherapy for advanced NSCLC: IFCT-GFPC 0502-Eco phase III study. I Borget, M Pérol, D Pérol, A Lavolé, L Greillier, P Dô, V Westeel, J Crequit, H Léna, I Monnet, H Le Caer, P Fournel, L Falchero, M Poudenx, F Vaylet, S Chabaud, A Vergnenegre, G Zalcman, C Chouaïd. BMC Cancer2014,14:953 DOI: 10.1186/1471-2407-14-953) 2. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Tudor Ciuleanu, Thomas Brodowicz, Christoph Zielinski, Joo Hang Kim, Maciej Krzakowski, Eckart Laack, Yi-Long Wu, Isabel Bover, Stephen Begbie, Valentina Tzekova, Branka Cucevic, Jose Rodrigues Pereira, Sung Hyun Yang, Jayaprakash Madhavan, Katherine P Sugarman, Patrick Peterson, William J John, Kurt Krejcy, Chandra P Belani. Lancet Vol 374: 1432, 2009 3. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT):a double-blind, phase 3, randomised controlled trial. Luis Paz-Ares, Filippo de Marinis, Mircea Dediu, Michael Thomas, Jean-Louis Pujol, Paolo Bidoli, Olivier Molinier, Tarini Prasad Sahoo, Eckart Laack, Martin Reck, Jesús Corral, Symantha Melemed, William John, Nadia Chouaki, Annamaria H Zimmermann, Carla Visseren-Grul, Cesare Gridelli. Lancet Vol 13: 247, 2012 4. PointBreak: A Randomized Phase III Study of Pemetrexed Plus Carboplatin and Bevacizumab Followed by Maintenance Pemetrexed and Bevacizumab Versus Paclitaxel Plus Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB or IV Nonsquamous Non–Small-Cell Lung Cancer. Jyoti D. Patel, Mark A. Socinski, Edward B. Garon, Craig H. Reynolds, David R. Spigel, Mark R. Olsen, Robert C. Hermann, Robert M. Jotte, Thaddeus Beck, Donald A. Richards, Susan C. Guba, Jingyi Liu, Bente Frimodt-Moller, William J. John, Coleman K. Obasaju, Eduardo J. Pennella, Philip Bonomi, and Ramaswamy Govindan. JCO 31:4349, 2013

Abstract not provided

Background:
The eighth edition of lung TNM does not change any N descriptors, but it suggests some potential changes that might be used in the next edition. In fact, N2 would be divided into three groups: pN2a1 (skip lymph-node involvement), pN2a2 (single mediastinal station with hilar involvement) and pN2b (multiple mediastinal involvement). The aim of this study was to verify the value of this classification proposal analyzing our recent surgical experience.

Methods:
We retrospectively selected all patients treated with lobectomy, bilobectomy or pneumonectomy for T1/T2 N2 NSCLC (VII TNM edition) in the period between 2006 and 2010. We excluded all patients who underwent any kind of extended resection and who had another active tumor at the time of operation. A systematic lymph-node dissection was always carried out according to the IASLC guidelines. All patients were then restaged according to the new IASLC proposal. Overall Survival (OS), Disease Free Interval (DFI) and most important variables were analyzed.

Results:
Among 248 surgically treated pN2 patients, 108 entered our inclusion criteria. Pathology report showed a majority of T2 tumors (67,6%) and in almost half of cases an adenocarcinoma (50,9%); a mean number of 16,4 (DS 7,8) lymph-nodes were resected (5,8 (DS 2,9) from the hilum and 10,6 (DS 5,9) from the mediastinum). After restaging all cases with the new IASLC proposal we observed: 30 (27,8%) pN2a1; 57 (52,8%) pN2a2 and 21 (19,4%) pN2b. With a median follow up of 93 months, the median overall survival of the entire cohort was 27 months. pN2a1 had a significant better overall survival compared with the other two groups (p=0,020); conversely no statistically significant difference was found in OS between pN2a2 and pN2b. 1, 3 and 5-year survival for pN2a1, pN2a2 and pN2b were 90%, 81% and 71%; 53%, 37% and 24%; 45%, 26% and 19% respectively. Concurrently DFI was significantly better for pN2a1 (p=0,025). At univariate survival analysis age>65 years, more than 4 positive lymph nodes and postoperative complications were statistically significant variables. At the multivariate analysis only age and the number of positive lymphnodes were independent prognostic factors of a worse survival.

Conclusion:
Our experience partially validate the new proposal of IASLC of N2 staging. Patients with skip lymph-node metastasis (pN2a1) have a statistically significant better prognosis. Concurrently we observed and confirmed the important prognostic value of the number of the involved lymph-node, which should be considered as well in the next editions of the lung cancer staging system.

Background:
Stage IIIB non-small cell lung cancer (NSCLC) is a heterogeneous patient group, including T4N2 and T1-4N3 NSCLC. Traditionally, treatment for stage IIIB consists in definitive chemoradiation. Surgical treatment for stage IIIB NSCLC is used anecdotally in highly selected patients. Here, we studied patient outcome who underwent surgical resection as part of multimodality treatment for stage IIIB NSCLC.

Methods:
All patients from a single institution who underwent surgery for stage IIIB between 2000 and 2015 were included. Surgical candidates were selected on a case-by-case basis during multidisciplinary tumorboard conference. In general, N2-N3 diseases are not considered an absolute contraindication to surgery if lymph node involvement is limited to a non-bulky single site, the tumor is deemed completely resectable without major morbidity and the patient will tolerate multimodality treatment. Mediastinal staging comprised cervical mediastinoscopy, positron emission tomography coupled with CT from 2005 and endobronchial ultrasound guided fine-needle aspiration from 2011. Charts were retrospectively reviewed and data analyzed. Survival was calculated from the date of surgery until last follow-up. Univariate and multivariate analysis were performed to identify prognostic factors.

Results:
From 2000 to 2015, 5416 patients underwent lung resection for NSCLC in our center. Sixty patients (1%) underwent surgery for stage IIIB NSCLC. Forty-three were males (72%). Median age was 58 years (from 22 to 79). Thirty-two patients had T4N2 NSCLC involving the carina (n=16, 50%), superior vena cava (n=4, 12%), carina and superior vena cava (n=5, 16%), left atrium (n=5, 16%), pulmonary artery (n=1, 3%) and spine (n=1, 3%). Twenty-eight patients had N3-disease, involving supraclavicular (n=14, 50%) or contralateral mediastinal lymph nodes (n=14, 50%). Pneumonectomy was performed in 27 patients (45%). Twenty-nine patients (48%) had induction therapy, consisting in chemotherapy alone for all patients. Adjuvant therapy was administered to 52 patients (87%) and consisted mostly of chemoradiation (n=35, 67%). Complete resection (R0) was performed in 55 patients (92%). Post-operative mortality was 3% (n=2). Three- and 5-year overall survivals were 51% and 39%, respectively. Median survival was 40 months. Median follow-up was 17 months. Results of the multivariate analysis identified incomplete resection (p=0.008) and absence of adjuvant treatment (p=0.032) as prognostic factors for poor survival.

Conclusion:
An excellent 5-year survival of 39% was achieved in highly selected patients with stage IIIB NSCLC and treated with multimodality including surgery. Patients with stage IIIB NSCLC should therefore be discussed in a multidisciplinary setting, including thoracic surgeons.

Background:
Adjuvant chemotherapy is the standard of care for completely resected stage II-IIIa non-small cell lung cancer (NSCLC). A few trials suggest that neoadjuvant chemotherapy is a promising strategy for resectable NSCLC. Indirect comparison meta-analysis of adjuvant versus neoadjuvant therapy showed no difference in survival. This study was conducted to determine the difference of disease-free survival(DFS) between adjuvant chemotherapy and neoadjuvant chemotherapy among patients with resectable NSCLC.

Methods:
Patients with clinical stage IB-IIIA NSCLC were eligible. Patients were randomly assigned to 3 cycles adjuvant DC (Docetaxel: 75mg/m2, Carboplatin:AUC=5 on day 1, every 3wk) after completely resection (lobectomy or pneomonectomy with mediastinal lymphnode dissection, or 3 cycles neoadjuvant DC at the same schedule followed by surgery 3-6 wk after chemotherapy. The primary end point was 3 years DFS; secondary end points were 3ys and 5ys Overall Survival(OS) and Safety. Planned sample size is 410. The trail was early closed because slowly accrued.

Results:
Between March 2006 and May 2011,198 patients from 8 Institute were randomized to neoadjuvant arm (97 cases) or adjuvant arm (101 cases). The median age was 58, male accounted for 80.3%, Adenocarcinoma 48.5%, stage Ib, II a, II b and IIIa were 32.5%, 12.2%, 28.4% and 26.9% respectively. Two arms were balanced. 100% cases received neoadjuvant chemotherapy and 87.4% finished the planned adjuvant chemotherapy. No unexpected toxicities were seen and 41.2% of patients experienced grade 3-4 neutropenia. In neoadjuvant arm, the ORR was 34% and 12.4% patients developed PD. No difference in postoperative complication was found between two arms. Survival analysis show in Table 1.Figure 1



Conclusion:
Adjuvant or neo-adjuvant chemotherapy with docetaxel plus carboplatin in resectable clinical stage IB-IIIA NSCLC are feasible and safe. The final results showed no difference in 3ys DFS and OS between two arms. Long term survival in Adjuvant arm show the tendency of superior to neoadjuvant arm.

Abstract not provided

Background:
Tumor hypoxia is an adverse prognostic factor in many cancers. Hypoxia tracer [18]F-FAZA provides a non-invasive method of hypoxia imaging. This study aims to evaluate the feasibility and potential benefits of using FAZA-PET scans to assess NSCLC tumor hypoxia.

Methods:
The initial 17 patients of an ongoing study with stage II–III NSCLC have been analyzed prospectively by imaging with FAZA-PET before initiation of a radical course of radiotherapy. The hypoxic volume (HV) was defined as all voxels within the tumor with standard uptake value (SUV) more than 1.2 times the aorta SUVmean. The Tmax/Bmean ratio (T/B) was defined as maximum tumor SUV divided by aorta SUVmean. The hypoxic fraction (HF) was determined by dividing the HV by the entire gross tumor volume. Spearman correlation and Fisher’s test were used to explore potential correlations among several variables.

Results:
Median primary and nodal FAZA SUVmax were 1.7 (range: 1.0-3.8) and 1.7 (range: 1.0–3.3). Median primary and nodal T/B ratios were 1.4 (range: 1.0–2.5) and 1.3 (range: 1.0–2.2). Median primary and nodal HF were 3.9% (range: 0.0-38.2%) and 0.6% (range: 0.0-50.7%). The median time from diagnostic FDG PET to study FAZA PET scans was 28 days (range: 1–63). Median primary and nodal FDG SUVmax were 13.5 (range: 5.1–32.2) and 8.3 (range: 2.3–15.7). Larger primary tumor volume is correlated with higher FAZA-T/B (p=0.01) and higher HF (p=0.01). Primary tumors with higher T/B also had higher HF (p<0.0001). The same correlations also apply to nodal disease. Nodal FAZA SUVmax is correlated with primary FAZA SUVmax (p<0.0001). When comparing FAZA-PET with FDG-PET, nodal FDG SUVmax is correlated with nodal FAZA T/B (p=0.01) and nodal FAZA HF (p=0.01), which was not observed for primary disease. For each patient, the nodal station with the highest FAZA SUVmax correlates with the highest FDG SUVmax (p=0.02).

Conclusion:
Imaging intra-lesional hypoxia in NSCLC primary and nodal tumors is feasible and can be achieved with FAZA-PET. Larger tumor volume is correlated with higher T/B and HF in both primary and nodal masses. In the nodal volume only, higher FDG activity is correlated with higher FAZA T/B and higher HF. Ongoing trial accrual and follow-up of our patient cohort will provide more information with regards to the imaging and clinical value of FAZA-PET. This study may eventually lead to using FAZA-PET as a guiding tool to escalate dose to the hypoxic region of the tumor.

Background:
An increasing body of (pre)clinical evidence has suggested that metformin has an anticancer effect. The aim of this study was to investigate whether the use of metformin during concurrent chemoradiotherapy (cCRT) for locally advanced non-small cell lung cancer (NSCLC) improved treatment outcome.

Methods:
A total of 682 patients were included in this retrospective cohort study (59 metformin users, 623 control patients). All received cCRT in one of three participating radiation oncology departments in the Netherlands between January 2008 and January 2013. Primary endpoint was locoregional recurrence free survival (LRFS), secondary endpoints were overall survival (OS), progression-free survival (PFS) and distant metastasis free survival (DMFS)

Results:
No significant differences in LRFS or OS were found. Metformin use was associated with an improved DMFS (74% versus 53% at 2 years; p = 0.01) and PFS (58% versus 37% at 2 years and a median PFS of 41 months versus 15 months; p = 0.01). In a multivariate cox-regression analysis, the use of metformin was a statistically significant independent variable for DMFS and PFS (p = 0.02 and 0.03).

Conclusion:
Metformin use during cCRT is associated with an improved DMFS and PFS for locally advanced NSCLC patients, suggesting that metformin may be a valuable treatment addition in these patients. Evidently, our results merit to be verified in a prospective trial.

Background:
RTOG 0617 recommended 60Gy as the standard dose for unresectable stage Ⅲ non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT) Is the conclusion true? The phase I/II trial to determine the feasibility and effects of individual isotoxic radiation dose escalation in unresectable stage Ⅲ NSCLC treated with CCRT based on bilateral lung V20 and advanced technologies was studied.

Methods:
Consecutive patients with unresectable stage III NSCLC were entered in cohorts of eight from March 2006 to May 2009. Patients were assigned to receive concurrent administration of late course accelerated hyperfrationation (LCAHF) intensity modulated radiotherapy (IMRT) and chemotherapy. Isotoxic dose escalation was based on V20 and advanced  technologies including PET-CT, single-photon emission computed tomography (SPECT) and LCAHF IMRT. PET-CT was used to delineate the gross tumor volume. SPECT lung perfusion was applied to define different functional lung regions, which was used to optimize the IMRT plans. Patients with a V20 of 27% as a base level were enrolled into the first cohort. From the second cohort, the V20 further increased to 30%, 33%, 35%, 37%, and so on. The criteria for cessation of dose escalation was defined as more than 25% of patients in the cohort experienced dose limiting toxicity (DLT). To test the power of escalation dose, patients with total radiation dose over 66Gy would be assigned to the higher dose group (HD), while the other patients would be assigned to the standard dose one (SD).

Results:
Forty patients were enrolled. The maximum tolerated value of V20 was 37% in this study. Nineteen patients entered SD group, while twenty-one in HD. The overall response rate was as high as 80%. Follow-up for all patients ranged from 1 to 112 months with survival patients from 101 to 112 months. The median overall and progression free survivals were 25.0 and 13.0 months, respectively. 1-, 3-, 5- and 8-year overall survival (OS) rates were 72.5%, 22.5%, 17.5%, and 10.0%, respectively. Patients with stage Ⅲa achieved a longer median OS than those of stage Ⅲb (31 vs. 21 months, P=0.029). Especially, patients received HD radiotherapy got a significant better OS and local recurrence free survival than those in SD (27, 23 vs. 16, 19 months, P = 0.053, 0.037) without increasing severe toxicity.

Conclusion:
The protocol is feasible and effective. In the future, the radiation dose escalation for unresectable stage Ⅲ NSCLC treated with CCRT should be focused on toxicity control and advanced technology application.

Abstract not provided

Background:
Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, based on low intensity alternating electric fields delivered non-invasively using a portable, home use, medical device. In-vitro, human mesothelioma cells were found to be highly susceptible to TTFields. TTFields have been shown to extend survival of patients with glioblastoma when added to standard of care chemotherapy.

Methods:
The trial will accrue a total of 80 patients with unresectable, previously untreated mesothelioma. Patients are treated with TTFields in combination with pemetrexed and cisplatin or carboplatin. Continuous TTFields at 150 kHz for a minimum of 18 hours/day are applied to the thorax together with standard dosing of chemotherapy. Inclusion criteria include ECOG 0-1, pathological evidence mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients are followed q3 weeks (CT scan q6 weeks) until disease progression. The primary endpoint is overall survival (OS) and secondary endpoints are response rate, progression free survival (PFS) and treatment-emergent toxicity. This prospective, single arm study assumes that historical control has an exponential survival distribution and a median survival of 12.1 Months (Vogelzang et al.). The sample size provides 80% power with a two sided alpha of 0.05 to detect a Hazard Ratio of 0.67 for OS, compared to the historical data.

Results:
To date, 42 patients have been enrolled in the trial with an average follow up time of 11.5 months. Median age is 67±9 (range 43-78), 79% are male and 48% smokers. 14% (6 patients) have metastatic disease and 33% (14 patients) have an ECOG score of 1. Median survival has not been reached at this time. The 12-month survival rate is 79.7% (95% CI 57.2-91.2) and median PFS is 7.3 months (95% CI 5.6-NA). No device-related serious adverse events (AEs) have been reported to date. Expected TTFields-related dermatitis was reported in 55% (23 patients). Only 2 patients had grade 3 dermatitis. The following severe (grade 3-4) systemic AEs were reported: hematological (26%), hepatobiliary (2%), respiratory (2%).

Conclusion:
These interim results of the ongoing STELLAR study demonstrated no safety concerns for the combination of TTFields to the thorax together with standard chemotherapy for previously untreated mesothelioma patients. The 12-month survival rate was significantly higher, and PFS longer, than that of historical controls reported by Vogelzang et al. Final analysis of the study will be performed after enrollment and follow up of all 80 patients in the study are completed.

Background:
Standard first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin, yielding a median overall survival (OS) of only ~1 year, thus new approaches are required. As demonstrated by the bevacizumab MAPS study, inhibition of the VEGF pathway is of interest as a treatment approach for MPM. Nintedanib is an oral, triple angiokinase inhibitor of VEGFR, PDGFR and FGFR. This study will evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with advanced MPM.

Methods:
Patients with unresectable MPM (chemo-naïve, ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomised (1:1) to receive up to 6 cycles of pemetrexed (500 mg/m[2])/cisplatin (75 mg/m[2]) on Day 1 plus nintedanib (200 mg bid)/placebo on Days 2–21. Patients without disease progression received maintenance treatment with nintedanib/placebo. The primary endpoint was progression-free survival (PFS).

Results:
87 patients were randomised to receive pemetrexed/cisplatin, plus nintedanib/placebo. Patient characteristics were comparable between the groups. PFS was longer in the nintedanib vs the placebo arm, in both the overall study population and in epithelioid patients (Table 1). Preliminary OS data also favour nintedanib. All patients experienced at least one adverse event (AE, any grade), with 7% of patients in the nintedanib arm discontinuing due to AEs, vs 15% with placebo. Serious AEs occurred in 36% vs 42% of patients in the nintedanib and placebo arms, respectively. The most common ≥grade 3 AEs occurring in nintedanib vs placebo patients were neutropenia (34% vs 10%), ALT increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%).

Conclusion:
Nintedanib plus pemetrexed/cisplatin demonstrated clinical efficacy with improved PFS and a tolerable safety profile in patients with unresectable MPM. Based on these promising findings, this Phase II study was extended to a confirmatory Phase III trial, which is currently enrolling patients. Clinical trial identifier: NCT01907100.

Background:
Millions of people have been potentially exposed to asbestos, the primary cause of malignant mesothelioma (MM). Presently, no reliable biomarkers are available to identify among potentially exposed people, those individuals who have actually been exposed and who are at high risk of MM. High Mobility Group Box Protein-1 (HMGB1) is a key mediator of asbestos-induced inflammation and MM pathogenesis. Recently, HMGB1 hyper-acetylation has been functionally associated to its active release by inflammatory cells. Here, we compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls.

Methods:
We compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls. Previously proposed MM biomarkers fibulin-3, osteopontin, and mesothelin were also blindly measured in blood collected from participants to the study.

Results:
HMGB1 serum levels reliably distinguished asbestos-exposed individuals and MM patients from unexposed controls. Moreover, the levels of total and hyper-acetylated HMGB1 were significantly higher in MM patients compared to asbestos-exposed individuals, and did not vary with tumor stage, suggesting that early lesions are also associated to increased HMGB1 levels. At a cutoff value of 2.00 ng/mL, the sensitivity and specificity of hyper-acetylated serum HMGB1 in differentiating MM patients from asbestos-exposed individuals was 100%, outperforming, in parallel experiments, other previously proposed biomarkers: osteopontin, fibulin-3, and mesothelin. When comparing MM patients to patients with other non-MM cytologically benign or malignant pleural effusion, the combination of two biomarkers, HMGB1 and fibulin-3, provided the highest sensitivity and specificity in differentiating these two groups. Moreover, we found that HMGB1 drives MM development and sustains MM progression, and we demonstrated that targeting HMGB1 inhibits MM cell growth and motility in vitro, reduced tumor growth in vivo and prolonged survival.

Conclusion:
Despite the relatively small size of our cohorts, our results are of exceptional significance and clinical relevance as they provide the first biomarker of asbestos exposure and indicate that hyper-acetylated HMGB1 is a very sensitive and specific biomarker to differentiate MM patients from individuals occupationally exposed to asbestos and unexposed controls. Moreover, our results on HMGB1 inhibitors indicate that HMGB1 targeting hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.

Abstract not provided

Background:
A 6-microRNA signature (miR-Score, Kirschner et al 2015) was previously demonstrated to show high prognostic accuracy in a series of surgical specimens (with and without induction chemotherapy). In the present study we investigated these microRNAs in an independent cohort of MPM patients all treated with induction chemotherapy followed by extrapleural pneumonectomy (EPP). The main focus of the study was to evaluate the possible effects of induction chemotherapy on microRNA expression and to refine and validate the miR-Score for use in chemo-naïve diagnostic specimens.

Methods:
We identified a cohort of 120 MPM patients who received chemotherapy followed by EPP between 1999 and 2014 at University Hospital Zurich. At present microRNA analysis (RT-qPCR) has been carried out in 34 pairs of chemo-naïve (diagnostic biopsy) and chemo-treated (EPP) specimens. Paired-samples t-test was employed to determine differences in microRNA expression pre- and post-chemotherapy. Accuracy of the miR-Score in predicting a good prognosis (>20 months survival post-surgery) was evaluated by ROC curve analysis. In addition, binary logistic regression modelling was used to build a refined miR-Score.

Results:
Applying the miR-Score to chemo-naïve diagnostic specimens revealed an area under the ROC curve (AUC) of 0.65 (95% CI: 0.46-0.84), and the same analysis on the EPP specimens gave an AUC of 0.57 (95% CI: 0.37-0.77). Therefore, the accuracy of the miR-Score was lower than observed in the previous study. However, pairwise comparison of microRNA expression before and after chemotherapy showed that although not reaching statistical significance, the levels of several microRNAs were lower following induction chemotherapy. We next employed binary logistic regression modelling on microRNA levels in chemo-naïve tissue to determine whether a refined microRNA signature less susceptible to chemotherapy-induced changes could be created. A refined miR-Score consisting of miR-221 and miR-30e, the two microRNAs least affected by chemotherapy, achieved AUCs of 0.77 (95% CI: 0.61-0.94) and 0.80 (95% CI: 0.64-0.96) in diagnostic and EPP specimens, respectively. When applied to samples from the previous study, the refined score resulted in an AUC of 0.72 (95% CI: 0.54-0.90).

Conclusion:
This validation and refinement study has shown that the expression of several miR-Score microRNAs appears to be affected by standard chemotherapy. A refined miR-Score was generated which is less susceptible to the effect of chemotherapy and may have prognostic value when applied to diagnostic specimens. Further validation in additional paired samples and investigation of the effect of cisplatin, pemetrexed and gemcitabine on microRNA expression are ongoing.

Background:
Tumor volume has been reported to be a valuable prognosticator for malignant pleural mesothelioma (MPM) survival. We wanted to assess the precision of CT scan based preoperatively measured tumor volume when correlated to the actual resected tumor weight and tumor volume after pleurectomy/decortication.

Methods:
From 10/2012 – 06/2016 the tumor weight of surgery specimens was measured in 32 patients undergoing macroscopic complete resection by (extended) pleurectomy/decortication ((e)P/D). The median tumor weight of all patients was (n=32) 443g (95-783g). In all patients tumor volume was measured in the CT or PET-CT scans performed before surgery as described previously (Frauenfelder 2011). Tumor volume of the resected specimen was additionally measured in 21 patients. Relations between tumor weight, tumor volume at surgery, CT-volume, cT stage and pT stage were analyzed using Spearman rank correlation.

Results:
Median time between CT scan and surgery was 18 days (range 1-48). The analysis revealed a moderate correlation between CT tumor volume and weight (p=0.001, correlation coefficient 0.58, CT volume and tumor volume at surgery showed strong correlation (p=0.001, correlation coefficient 0.65). No significant correlation was observed between cT stage and tumor weight (p=0.1, correlation coefficient 0.31), but a moderate correlation between cT stage and CT volume (p=0.001, correlation coefficient 0.58) as well as specimen volume (p=0.008, correlation coefficient 0.58). There was a moderate correlation of tumor weight with pT stage (p=0.02, correlation coefficient 0.42), but no correlation of CT volume (p=0.1, correlation coefficient 0.31) as well as specimen volume with the pT stage (p=0.2, correlation coefficient 0.32). Figure 1



Conclusion:
The correlation between preoperatively assessed CT tumor volume and volume of the resected specimen showed a strong correlation. To assess the prognostic role of CT measured tumor volume a correlation to prognosis has to be performed before implementation as a new T-factor.

Abstract not provided

Background:
Malignant pleural mesothelioma (MPM) is an asbestos-related tumour with poor prognosis. Since MPM is diagnosed at advanced stage due to non-specific symptoms and investigations, it is thought that only an early diagnosis will improve patient’s outcome. Breathomics allows to detect volatile organic compounds (VOCs) in breath which can be used as non-invasive biomarkers. Although we were able to discriminate MPM patients from controls using ion mobility spectrometry breathomics, we were not able to identify specific VOCs. Therefore, we aimed to identify VOCs in the breath of MPM persons and persons at risk with gas chromatography-mass spectrometry (GC-MS).

Methods:
Fourteen MPM patients, eighteen asymptomatic asbestos-exposed individuals, 16 individuals with benign asbestos-related diseases and fourteen healthy non-exposed persons were included. After 2 hours of fasting, participants breathed tidally for 5 minutes through a mouthpiece connected to a VOC filter. Subsequently, a full vital capacity was captured in a Tedlar bag of which 500 ml was immediately transferred on a Tenax[GR]-column. Samples were thermally desorbed followed by GC-MS analysis (Agilent 6890A–Thermo Focus DSQII). VOCs were manually selected in the chromatogram and standardised to an internal standard (toluene-d8). Only VOCs with a S/N-ratio>10 were used. Using SPSSv23, significant differences were searched and ROC-curves for discriminating MPM from all control groups were constructed. VOCs which had an AUC~ROC~>0.80 are reported.

Results:
114 VOCs were selected of which 17 were significantly different between MPM patients and controls. Of these, 7 had AUC~ROC~>0.80 and are possible markers for MPM diagnosis.Figure 1



Conclusion:
The large discriminative power and good sensitivity and specificity imply the possibility to use breath analysis for MPM screening. Therefore, persons exposed to asbestos with a positive test should be considered for follow-up in a cost-effective way, decreasing the need for CT-scans and radiation exposure in low-risk persons. Further work includes combining models for discrimination and validating these findings.

Abstract not provided

Abstract not provided

Abstract:
Intraoperative Therapies in Malignant Pleural Mesothelioma The rational of localized / intracavitary treatment is to eliminate microscopic residual disease (MRD) after macroscopic complete resection (MCR) for mesothelioma patients. The advantage of the treatment is that local effects can be enhanced whereas systemic side effects of the therapeutic agents applied might be reduced. Several approaches have been investigated over the past decades in preclinical and clinical trials, such as intracavitary chemotherapy (iCTX), immunotherapy (iIT), photodynamic therapy (PDT) and gene therapy (iGT). Intracavitary chemotherapy (iCTX) iCTX has been studied after mesothelioma resection, not only after extrapleural pneumonectomy (EPP) but also after (extended) pleurectomy/decortication ((e)P/D). The main therapeutic agent used is cisplatin. In some trials hyperthermia was additionally added with the aims to enhance the penetration of cisplatin into tissues and maximize its cytotoxicity in tumor cells [1]. Hyperthermic intrapleural perfusion had a maximum tolerated dose of 225-250 mg Cisplatin/m[2] BSA [2]. The morbidity ranges from 13 to 85% and the mortality from 0 to 29% [2, 3]. Some complications are related to renal toxicity which was the dose limiting adverse event [2]. Median survival time reaches up to 35.3 months in low-risk MPM patients receiving hyperthermic intraplueral cisplatin chemotherapy following MCR [4]. This treatment is only considered for well-designed clinical trials. In vivo preclinical model using intrapleural administration of cisplatin-mixed loaded to a fibrin carrier improved the local drug concentration and prolonged the exposure of tissue to high cisplatin concentration [5]. Our phase I dose escalation trial (INFLuenCe – Meso; see figure) has proven the safety of this treatment approach (manuscript in preparation). This treatment regimen is now being tested in a phase II trial (NCT01644994). Figure 1 In addition to chemotherapy, other substances have also been tested for intracavitary treatment. Recently, Tada, et. al. reported study plan for a phase I trial for intrapleural treatment with zoledronic acid, a third generation of bisphosphonates, in inoperable MPM, after having successfully proven the efficacy of zoledronic in a pre-clinical model [6]. Intracavitary immunotherapy (iIT) MPM is not a classical “immunogenic” tumor. Intrapleural instillation of cytokines such as interleukin (IL)-2, interferon (IFN)-α and IFN-γ provided a good control of malignant pleural effusion (MPE) and MPM with minimal toxicity [7, 8]. To prolong and increase local exposure of IFNs, recent studies implemented immuno-gene therapy approach using adenoviral vector expressing human IFNs. Four out of 10 patients with MPM and metastatic pleural effusions showed stable disease following a single dose of intrapleural adenoviral vector expressing IFN-β [9]. Nevertheless due to rapid production of neutralizing antibody against adenovirus, no improvement of gene transfer efficacy was achieved after the second dose [10]. The same research group conducted a clinical trial assessing the safety of adenoviral-mediated IFN-α2b in combination with chemotherapy. Recent data from this trial showed that the treatment is well tolerated and 25% of patients had partial response [11]. An intrapleural treament with re-directed T cells genetically engineered to express chimeric antigen receptor (CAR) that specifically recognizes tumor antigens is an attractive therapeutic option. A clinical phase I trial for intrapleural administration of fibroblast activation protein (FAP)-specific re-directed T cells is currently being conducted (NCT01722149). Photodynamic therapy (PDT) PDT is a light based cancer therapy. Most modern PDT applications involve three key components: a photosensitizer, a light source and tissue oxygen. The photosensitizing agent accumulates in tumor cells and is activated by light of a specific wavelength to produce reactive singlet oxygen that mediates cellular toxicity. The tumor cells are killed through both apoptosis and necrosis and by damaging tumor vasculature. It may also induce inflammatory reaction capable of stimulating a tumor directed host immune response. The advantages of this treatment are that its efficacy is not influenced by chemo- or radio-resistance of tumor cells, that it can be repeated at the same site without compromising its efficacy and that it does not compromise the ability to administer other treatment modalities in patients with recurrent or residual disease. PDT should be combined with macroscopic complete resection due to limited depth of penetration. Localized inflammation and fluid accumulation after treatment can modestly extend hospital stay. PDT appears promising and may improve local control and potentially prolong survival in properly selected patients who are able to undergo MCR, with clinical outcomes appearing best when PDT is combined with lung-sparing definitive surgery [12]. Friedberg reported a median survival of 31.7 months (41.2 months in patients with epithelioid histological subtype), but the progression free survival was only 9.6 months [13]. Intracavitary gene therapy (iGT) Gene therapy is based upon transfer of genetic material, including complementary DNA, full-lengths genes, small interfering RNA or oligonucleotids into cells for therapeutic purposes. For sufficient gene delivery, adenovirus is the most widely used in clinical trials among a variety of viral and non-viral vectors. In addition to delivering cytokine expressing vectors or re-directed T cells (see iIT part), several different cancer gene therapy approaches are currently used including the so called suicide gene therapy wherein a neoplasm is transduced with a cDNA encoding for an enzyme rendering tumor cells sensitive to a benign agent by converting the product to a toxic metabolite. The Herpes Simplex Virus 1- thymidine kinase (HSVtk) gene encodes for an enzyme that converts ganciclovir, an antiviral drug, to its cytotoxic metabolite. Intrapleural adenovirus HSVtk/ganciclovir administration was safe in MPM and two patients survived >6.5 years. Nevertheless, due to the fact that transgenes HSVtk were only detected at the surface of tumor tissues, the authors suggested that the treatment efficacy may be a result of antitumor immune response stimulation [14]. MPM tumor genome is characterized by frequent mutations in tumor suppressor genes such NF2, BAP1 or p53, thus the delivery of tumor suppressor gene expressing vectors into tumor cells can serve as an attractive treatment approach. The delivery of adenovirus expressing p53 has been tested in clinical trials for lung cancer but did not show better clinical benefit over chemotherapy [15]. This may be due to limited transfection efficiency of the vector and the stimulation of neutralizing antibody, therefore an improvement of transfection is still needed for the further development of gene therapy. References: 1. Sugarbaker, P.H., et al., Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy. Oncologist, 2005. 10(2): p. 112-22. 2. Richards, W.G., et al., Phase I to II Study of Pleurectomy/Decortication and Intraoperative Intracavitary Hyperthermic Cisplatin Lavage for Mesothelioma. J Clin Oncol, 2006. 24(10): p. 1561-1567. 3. de Bree, E., et al., Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thymoma. Chest, 2002. 121(2): p. 480-7. 4. Sugarbaker, D.J., 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, 2013. 145(4): p. 955-63. 5. Lardinois, D., et al., Intrapleural topical application of cisplatin with the surgical carrier Vivostat increases the local drug concentration in an immune-competent rat model with malignant pleuromesothelioma. J Thorac Cardiovasc Surg, 2006. 131(3): p. 697-703. 6. Tada, Y., et al., An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol. Springerplus, 2016. 5: p. 195. 7. Astoul, P., et al., Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion. Chest, 1993. 103(1): p. 209-13. 8. Antoniou, K.M., E. Ferdoutsis, and D. Bouros, Interferons and their application in the diseases of the lung. Chest, 2003. 123(1): p. 209-16. 9. Sterman, D.H., et al., A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses. Clin Cancer Res, 2007. 13(15 Pt 1): p. 4456-66. 10. Sterman, D.H., et al., A phase I trial of repeated intrapleural adenoviral-mediated interferon-beta gene transfer for mesothelioma and metastatic pleural effusions. Mol Ther, 2010. 18(4): p. 852-60. 11. Sterman, D.H., et al., Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNalpha Combined with Chemotherapy. Clin Cancer Res, 2016. 22(15): p. 3791-800. 12. Simone, C.B., 2nd and K.A. Cengel, Photodynamic therapy for lung cancer and malignant pleural mesothelioma. Semin Oncol, 2014. 41(6): p. 820-30. 13. Friedberg, J.S., et al., Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma. Ann Thorac Surg, 2012. 93(5): p. 1658-65; discussion 1665-7. 14. Sterman, D.H., et al., Long-term Follow-up of Patients with Malignant Pleural Mesothelioma Receiving High-Dose Adenovirus Herpes Simplex Thymidine Kinase/Ganciclovir Suicide Gene Therapy. Clin Cancer Res, 2005. 11(20): p. 7444-7453. 15. Schuler, M., et al., Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study. J Clin Oncol, 2001. 19(6): p. 1750-8.

Abstract:
The significant improvement in outcome observed with immune checkpoint inhibitors in advanced melanoma and NSCLC have triggered their use in mesothelioma and thymic tumours. Both tumours are characterized by an unmet need to improve their prognosis and an immunosuppressive environment induced by (i) the (over-)expression of checkpoint receptors, responsible for controlling and inactivating the immune system in order to avoid autoimmunity and prevent collateral tissue damage- and (ii) by a silencing of the antigen presenting function of dendritic cells by tumor-derived soluble factors, leading to a defective induction of cytotoxic T–lymphocytes response [1]. The new paradigm consists of reactivating these silenced immune responses by either monoclonal antibodies or cell-based therapies. CTLA-4 is responsible for modulating central T-cell activation in the lymph nodes. Under physiological conditions, the immune inhibitory effect of CTLA-4 is involved in provoking an effective immune response without causing excessive damage to the normal surrounding tissue. However, tumor cells can stimulate abnormal expression of CTLA-4 by secreting TGF-beta, that induces CTLA-4 overexpression, resulting in a state of T-cell dysfunction whereby T-cells fail to proliferate and are no longer able to exert their effector functions. Tremelimumab and ipilimumab are selective monoclonal antibodies against CTL-A4 and block its binding to CD80 and CD 86, thereby enhancing T cell activity and anti tumor immunity. There are no known predictive factors for anti-CTL-A4 therapy in mesothelioma. After 2 phase 2 trials at different dose levels –which were negative for their primary endpoint, but nevertheless considered promising- DETERMINE compared tremelimumab to placebo as second line treatment in MPM [2]. No difference in outcome was reported, but an increased class specific toxicity in the patients treated with tremelimumab. The PD-1-PD-L1 axis is responsible for controlling peripheral T-cell activation at the tumor site. Overexpression of PD-L1 is thought to induce immune tolerance. In MPM, PD-L1 expression by immunohistochemistry was reported in 20-70% of formalin-fixed paraffin embedded mesothelioma, in 70% of thymic carcinomas and in 23% of thymomas [1,3]. In mesothelioma, PD-L1 expression overexpression is more common in non-epitheloid histology, is associated with a significantly worse survival. PD-L1 expression is furthermore considered a –weak- predictive factor for the activity of immune checkpoint inhibitors in NSCLC, besides mutagenic load and the formation of neo-epitopes. Several anti PD-(L)1 antibodies are registered and/or in development for use in other tumour types. Promising phase 2 trial results in mostly pretreated mesothelioma patients are summarized in the table [4-6]. Expression level of PD-L1 did not correlate with response in either trial.

Checkpoint inhibitors in mesothelioma

Trial	Drug	Phase	Line	N	Subtype	ORR/DCR (%)	PFS
DETERMINE (2)	Tremelimumab	3	2/3	382	Ep: 83%	4.5/31.7	2.8 m
KEYNOTE 28 (4)	Pembrolizumab	2	2	25	all PDL1+	28/76	49.4% @ 6m
NIVOMES (5)	Nivolumab	2	NR	18	NR	27/49	NR
JAVELIN (6)	Avelumab	1b	2-5	53	Ep: 83%	9.4/56.6	17.1 w

Dendritic cells (DC), obtained by leukapheresis, can be loaded with synthetic peptides coding for parts of tumor-associated antigens, a lysate of tumor material of the patient itself (autologous dendritic cell-therapy) or with other sources of tumor-specific antigens (allogeneic dendritic cell-therapy). Wilms' tumor 1 (WT1) is an ideal candidate for a tumor selective cancer vaccine in cancers expressing WT1, such as MPM. Two vaccines have investigated this approach. Vaccination with autologous DC’s, electroporated with mRNA encoding the WT1 antigen was evaluated in 10 patients with mesothelioma not progressing after platinum/ pemetrexed-based chemotherapy [7]. Biweekly intradermal vaccinations were administered for an intended period of 6 months, followed by monthly or bimonthly injections. DC vaccination was well-tolerated: no systemic toxicity was recorded; local reactions at the injections sites occurred in all patients, but were mild and self-limiting. At a median follow-up of 22.7 months, 6 patients are alive, 4 have died and 1 year survival rate is 90% from start of treatment, suggesting that adjuvant DC-based immunotherapy provides a clinical benefit. In a pilot trial in pretreated MPM, the multivalent native and synthetic WT1 peptide vaccine Galinpepimut-S was well-tolerated and CD4/8 immune responses were generated. After completing multimodality therapy, 40 mesothelioma patients were randomized to receive maintenance Montanide and GM-CSF with or without Galinpepimut-S [8]. There were no serious treatment related adverse events. Based on a pre-specified futility analysis, accrual was stopped. Median PFS from randomization was 11.4 months in the experimental arm vs. 5.7 months in the control arm (HR 0.69). Similarly, median overall survival (OS) from randomization was 21.4 months in the Galinpepimut-S arm vs. 16.6 months in the control arm (HR 0.52). In the subgroup with R0 resection, median OS was 39.3 months in the Galinpepimut-S and 24.8 in the control arm (p = 0.04). A confirmatory adequately powered randomized adjuvant study is awaited. In the European DENIM trial, patients not progressing after 1[st] line platinum-pemetrexed chemotherapy will be randomized between standard follow up and a maintenance treatment consisting of 5 injections of DC’s, pulsed with an allogeneic lysate obtained from 5 well-characterized clinical grade human malignant mesothelioma cell lines. Cell-based immunotherapy carries high expectations but remains cumbersome and labour-intensive. Anti-CTL-A4 antibody-based immunotherapy in mesothelioma has so far failed to deliver the expected improvement in outcome. Whether this also applies to anti-PD-(L)1 monoclonal antibodies remains to be seen from ongoing and future trials. A low mutational burden and the limited formation of neo-epitopes under chemotherapy, -both considered important predictive factors for immune checkpoint therapy- are the challenges for this approach. As in other tumour types, studying a combination of different checkpoint inhibitors either with or without chemotherapy or with anti-angiogenic agents is of interest [9]. In thymic tumours, the presence or risk of developing immune-mediated paraneoplastic syndromes is of particular concern. This could be an argument to prioritize checkpoint inhibitors in thymic carcinomas[10]. References 1: Marcq E et al. Targeting immune checkpoints: new opportunity for mesothelioma treatment? Cancer Treatm Rev 2015; 41(10):914 2:Kindler HL et al.. Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma (MM): Results from the global, double-blind, placebo-controlled DETERMINE study. J Clin Oncol 2016; 34 (suppl): abstr 8502 3: Katsuya Y et al. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer. 2015;88(2):154 4: Alley EW et al. Single-Agent Pembrolizumab for Patients with Malignant Pleural Mesothelioma. J Thorac Oncol 2015; 10(9) supplement 2: abstr O11.03 5: Quispel-Janssen J et al. NIVOLUMAB IN MALIGNANT PLEURAL MESOTHELIOMA (NIVOMES): AN INTERIM ANALYSIS. Proc IMiG 13, Birmingham 2016; abstr MS 04.07 6: Hassan R et al. Avelumab in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: safety, clinical activity and PD-L1 expression. J Clin Oncol 2016; 34(suppl): abstr 8503 7: Berneman ZN et al. Dendritic cell vaccination in malignant pleural mesothelioma: A phase I/II study. J Clin Oncol 2014; 32:5s: abstr 7583 8: Zauderer MG et al. Randomized phase II study of adjuvant WT1 vaccine (SLS-001) for malignant pleural mesothelioma after multimodality therapy. J Clin Oncol 2016; 34 (suppl): abstr 8519 9: Anonymous. Nivolumab Monotherapy or Nivolumab Plus Ipilimumab, for Unresectable Malignant Pleural Mesothelioma (MPM) Patients (MAPS2). Available at: https://clinicaltrials.gov/ct2/show/NCT02716272 10: Anonymous. MK-3475 in Patients With Thymic Carcinoma. Available at: https://clinicaltrials.gov/ct2/show/NCT02364076

Abstract not provided

Abstract:
Patients with advanced squamous NSCLC receive first-line chemotherapy with a platin-based doublet. Combining first-line chemotherapy with EGFR-directed monoclonal antibodies has been studied as a strategy to improve outcome of these patients. Anti-EGFR monoclonal antibodies inhibit EGFR-mediated signal transduction and may also act via immunological mechanisms. Several monoclonal antibodies have been studied within clinical trials and data from phase III trials are available for cetuximab and necitumumab (for review see ref. 1). Two randomized phase III trials compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced NSCLC (2, 3). The FLEX trial demonstrated improved overall survival for cetuximab added to chemotherapy in patients with advanced NSCLC and enriched for EGFR expression in their tumors (2). The hazard ratio was 0.87 (p=0.044), median survival times were 11.3 months and 10.1 months, and 1-year survival rates were 47% and 42%, respectively. For patients with squamous cell carcinomas (n=347), the hazard ratio was 0.80 and median survival times were 10.2 months and 8.9 months, respectively. The BMS 099 trial failed to show an improvement in progression-free survival for cetuximab added to carboplatin plus paclitaxel in unselected patients with advanced NSCLC (3). A meta-analysis based on individual patient data from four randomized trials demonstrated a survival benefit for chemotherapy plus cetuximab compared to chemotherapy alone (4). The hazard ratio was 0.88 (95% CI 0.79-0.97; p=0.009). The benefit was greater in patients with squamous NSCLC in whom a hazard ratio of 0.77 (95% CI 0.64-0.93) was seen. Necitumumab has also been studied in combination with first-line chemotherapy in two phase III trials (5, 6). The SQUIRE trial assessed cisplatin plus gemcitabine with or without necitumumab in 1,093 patients with advanced squamous NSCLC (5). Necitumumab was intravenously administered at a dose of 800 mg on days 1 and 8 of every 21 days and was planned to be continued after the end of chemotherapy until disease progression or intolerable toxicity. Necitumumab improved the outcome of chemotherapy. The hazard ratio was 0.84 (95% CI 0.74-0.96; p=0.012). Median survival times were 11.5 months and 9.9 months, and 1-year survival rates were 47.7% and 42.8% for the chemotherapy-plus-necitumab arm and chemotherapy arm, respectively. Progression-free survival and response rates were also improved with the combined treatment. Grade ≥3 adverse events more frequently seen with chemotherapy plus necitumumab compared to chemotherapy were skin rash and hypomagnesemia. Based on these results, necitumumab has been approved as first-line therapy of squamous NSCLC in combination with gemcitabine and cisplatin. In contrast to the SQUIRE trial, the INSPIRE trial was prematurely stopped after enrolment of 634 patients because an interim analysis showed increased thrombo-embolic events and a lack of survival benefit for the combined treatment (6). Research has also focussed on the characterization of predictive biomarkers. Immunohistochemical EGFR protein expression and EGFR FISH positivity were of particular interest. In the FLEX trial, immunohistochemical EGFR expression of tumor cells was prospectively assessed by means of the DAKO pharmDx[TM] kit (7). Membrane staining intensity was divided into no staining, weak staining (1+), intermediate staining (2+), and strong staining (3+). The fractions of cells at the various staining intensities were determined. An immunohistochemistry score (IHC) based on both intensity and frequency of staining was then used for further analysis on the association between EGFR expression levels and clinical outcome. Patients were divided into those with high (IHC score ≥200) and those with low (IHC score <200) EGFR expression. High EGFR expression was seen in 31% of the patients. Among patients with high EGFR expression, patients treated with chemotherapy plus cetuximab had prolonged survival compared to those treated with chemotherapy alone. The hazard ratio was 0.73 (95% CI 0.58–0.93; p=0.011), median survival times were 12.0 and 9.6 months, and 1-year survival rates were 50% versus 37%. Among patients with low EGFR expression, survival times were not different between the two treatment arms. The treatment interaction between EGFR expression levels and treatment effect was statistically significant (p=0.04). The survival benefit achieved by the addition of cetuximab to chemotherapy in patients with high EGFR expression was seen across most subgroups including all major histological subgroups. Among patients with squamous NSCLC and high EGFR expression, the hazard ratio was 0.62 (0.43-0.88) in favour of cetuximab plus chemotherapy compared to chemotherapy alone. The survival benefit by the addition of cetuximab to chemotherapy in patients with high EGFR expression was achieved without an increase in toxicity. In summary, patient selection based on EGFR expression levels resulted in a clinically meaningful improvement in the risk benefit assessment of platinum-based first-line chemotherapy plus cetuximab in patients with advanced NSCLC (7). The SWOG S0819 biomarker validation study indicated that EGFR FISH positivity predicted benefit from cetuximab, particularly in patients with squamous NSCLC (8). Similarly, the benefits from necitumumab appeared to be greater in patients with EGFR FISH positivity or high EGFR expression (5, 9-10). References 1. Pirker R et al. Curr Opin Oncol 2015, 27, 87-93 2. Pirker R et al. Lancet 2009, 373, 1525-31 3. Lynch TJ et al. J Clin Oncol 2010, 28, 911-7 4. Pujol JL et al. Lung Cancer 2014, 83, 211-8 5. Thatcher N et al. Lancet Oncol 2015, 16, 763-74 6. Paz-Ares L et al. Lancet Oncol 2015, 16, 328-37 7. Pirker R et al. Lancet Oncol 2012, 13, 33-42 8. Herbst R et al. J Thorac Oncol 2015, 10, S795 9. Hirsch F et al. J Thorac Oncol 2015, 10, S797 10. Paz-Ares L et al. Ann Oncol 2016, 27, 1573-9

Abstract:
Lung cancer is the leading cause of cancer-related mortality worldwide with 1.59 million deaths in 2012 and, with an estimated 1.8 million new lung cancer cases, it accounts for about 13% of total cancer diagnoses[1]. Non-small cell lung cancer (NSCLC) represents around 85% of all lung cancers with the majority of patients in advanced stages of the disease when diagnosed. Squamous cell carcinoma (SqCC) is the second most common histology in NSCLC accounting for 20-30% of cases[2]. Compared to the most frequent advanced lung adenocarcinoma, for which targeted therapies are available in case of presence of actionable mutations, treatment options for advanced lung SqCC have not changed with the same vividness in the last decade. But, to date, we can definitely say that also for these patients, the research has made progresses and new therapeutic scenarios are now open. Docetaxel and erlotinib were the only standard second-line treatment options for lung SqCC until, in December, 2014, the US Food and Drug Administration (FDA) approved ramucirumab (an anti-VEGFR-2 antibody) in combination with docetaxel, for the treatment of metastatic NSCLC patients who progressed during or after a platinum-based chemotherapy. In March 2015 nivolumab (an immune-checkpoint-inhibitor) was approved, for treatment of patients with metastatic SqCC, who progressed during or after a platinum-based chemotherapy and pembrolizumab (another immune-checkpoint-inhibitor) was approved in October, in the same setting of patients but whose tumors expressed PD-L1 (evaluated with the approved specific companion diagnostic, the PD-L1 IHC-22C3 pharmDx test). Finally, in April 2016, afatinib (an EGFR tyrosine-kinase inhibitor) was approved for treatment of patients with metastatic SqCC progressing after a platinum-based chemotherapy[3][,[4],[5],[6]]. It has been suggested that SqCC patients treated with docetaxel had a poorer survival compared to non-SqCC patients hypothesizing that docetaxel may be less effective in squamous compared with non-squamous lung cancer[7]. This was also evidenced in the phase III study (REVEL), in which squamous and non-squamous NSCLC patients were treated with docetaxel with or without ramucirumab: an OS benefit was seen with ramucirumab-docetaxel in the whole population (10.5 vs 9.1 months, HR 0.86, 95% CI 0.75–0.98, p = 0.023). In those patients who presented squamous cell histology (25%) the OS benefit, when treated with ramucirumab-docetaxel, was 9.5 months (4.4–17.6) vs 8.2 months (3.6–14.9, HR: 0.88, 95% CI 0.69–1.13) in placebo-docetaxel subgroup, while in those with non-squamous disease a better OS was described (11.1 months, Interquartile Range, IQR 5.3–24.3) in the ramucirumab-docetaxel group, vs 9.7 months (4.4–19.6) in the control group (HR 0.83, 95% CI 0.71–0.97), however it needs to be noted that subgroup analyses in this study were not pre-planned[4]. In LUX-Lung 8, a phase III study of second-line afatinib vs erlotinib, which enrolled squamous patients only, OS was 7.9 vs 6.8 months (HR 0.81, 95% CI 0.69–0.95, p = 0.007), in the afatinib subgroup vs erlotinib one[7]. Survival benefits highlighted in these studies when compared to older studies with docetaxel, while statistically significant, evidenced modest developments in the treatment of advanced-stage SqCC, as a consequence, novel therapeutic approaches have been considered and well accepted in the oncology community as well as largely awaited. Research on tumor immunosurveillance led to the development of PD-1 immune-checkpoint-inhibitors, such as nivolumab and pembrolizumab, and the PD-L1 inhibitors atezolizumab (MPDL3280A), durvalumab (MEDI4736) and avelumab (MSB0010718C)[8]. Nivolumab produced response rates equal to 15 to 17% with a median OS of 8.2 to 9.2 months, in phase I and II trials, among previously treated patients with advanced SqCC[5]. Then in the phase III CheckMate 017, Nivolumab induced a median OS of 9.2 months (95% CI, 7.3-13.3) vs 6 months (95% CI, 5.1-7.3) with docetaxel. The results in the docetaxel group were worst than expected. The risk of death was 41% lower with nivolumab than with docetaxel (HR, 0.59; 95% CI, 0.44-0.79; p < 0.001)[5]. PD-L1 expression is largely debated and its specific influence in the squamous population still needs further elucidations, since a total of 83% of the patients who underwent randomization (225 of 272 patients) in this trial had quantifiable PD-L1 expression and PD-L1 was assessed on archival tumor tissue, which may not have reflected its real status at the time of treatment[5]. SqCC is considered the tumor with the second highest amount of molecular aberrations, (eg, FGFR1 amplification, PIK3K3 abnormalities, DDR2 mutations), providing a plausible explanation about heterogeneity of treatment responses and efficacy results in the second-line setting[9]. However, despite the identification of those specific molecular alterations, progress in targeting oncogenic drivers in SqCC still runs behind adenocarcinoma. There is a need to develop predictive and specific molecular biomarkers, that might identify subgroups of patients with lung SqCC that are most likely to benefit from targeted treatments or immunotherapic approaches. In this context Pilotto et al. elaborated a project with the aim to evaluate the molecular profile of resected SqCC in order to identify those immunologic pathways and molecular aberrations potentially able to estimate the probability of disease recurrence (prognostic factors) and to characterize novel biomarkers, whose targeting with specific drugs could potentially limit the oncogenic potential and change the natural history of this disease (predictive factors). Preliminary results of this study were consistent with literature data: several molecular alterations might be identified [PIK3CA, MET, FGFR3, DDR2, FRS2, CDKN2A, SMAD4, PD-L1] and some of them might impact on the biological behavior of SqCC contributing in the determination of patients prognosis[10]. These data will be further presented at WCLC this year. In conclusion, as more treatment options turn out to be available for patients, it will become essential to tailor those choices on patient’s unique molecular characteristics and his own needs, identifying the best sequence of treatments, especially in the era of rising healthcare costs and longer lifespan of advanced lung cancer patients. References [1] WHO Statistics. http://www.who.int/mediacentre/factsheets/fs297/en/ [Accessed on 21 August , 2016]. [2] Travis WD. Pathology of lung cancer. Clin Chest Med 2011; 32: 669–92. [3] Garon EB et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665–73. [4] Brahmer J et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373(2):123-35. [5] FDA approves Keytruda for advanced non-small cell lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htm [Accessed on 21 August , 2016]. [6] Soria JC et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial Lancet Oncol 2015; 16: 897–907. [7] LE Ang Y et al. Profile of nivolumab in the treatment of metastatic squamous non-small-cell lung cancer. OncoTargets and Therapy 2016:9 3187–3195. [8] Melosky B et al. Pointed Progress in Second-Line Advanced Non–Small-Cell Lung Cancer: The Rapidly Evolving Field of Checkpoint Inhibition. J Clin Oncol 2016;34:1676-1688. [9] The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489(7417): 519–525. [10] S. Pilotto et al. Analyzing prognostic outliers to unravel biologically and clinically relevant molecular and immunologic pathways: a model from resected squamous cell lung carcinoma (R-SQCLC). Poster presented at 58 Annual Meeting of the Italian Cancer Society helded in Verona on 5-8 September 2016.

Abstract not provided

Abstract:
More than 100 million people in Latin America will be > 60 years of age by 2020. Age, smoke exposure and infectious causes of cancer (HPV, Hepatitis B, and H. pylori) will continue to drive the burden of cancer in the region. Cancer mortality rates in Latin America are approximately twice those of the United States (1). Until not so long ago, drug development and cancer clinical research were conducted almost exclusively in wealthy developed regions of the world. However, over the last 2 or 3 decades, clinical trials have been progressively incorporated in a challenging globalization process. As such, the conduct of trials in a global scale represents a major aspect to be taken into account when analyzing the future development of the area. The globalization of clinical trials, as well as multinational and multi-institutional research collaboration, represents a scenario that requires permanent and concentrated efforts by all involved if we are to achieve the fundamental objective of generating the appropriate answers to the health problems we face around the world (2). Up to the 1980s, North American and European cooperative groups mostly sponsored by the National Cancer Institute (NCI) conducted most of the pivotal practice changing trials. At that time, a progressive shift in the funding of research toward pharmaceutical companies was seen. In parallel, an increasing participation of research sites from countries outside North America and Western Europe was identifıed and has since transformed the development of new medications to what is now an increasingly globalized process (2). The number of registered clinical trials has increased in all geographic regions during this time period, with the average annual growth greatest in the Asian (30%) and Latin American/ Caribbean (12%) regions (3). Early trials seem to be conducted more frequently in North America (62%), whereas confırmatory trials are more frequent in Eastern Europe, Latin America, and Asia (4). Data from ClinicalTrials.gov shows that over 70% of the registered cancer phase I trials are conducted in the United States, whereas less than 1% are conducted in Latin America. In larger registered phase III studies, 40% are conducted in the United States, 43% in Western Europe, and 17% in Latin America (5). Involvement of investigators from developing countries in the planning phases of the trial is essential as they may provide valuable contribution while being exposed to an experience that will have long lasting effects in the future development of regional studies. Other than addressing a question that interests a pharmaceutical company, developing a reliable research infrastructure and local expertise allow researchers to expect the development of locally coordinated research addressing pertinent regional health questions benefıting the local community. As quality is a fundamental principle in the conduct of clinical research, we need to address monitoring, auditing, and inspections as a basic element in the process of globalization. In recent years, a number of independent research groups have been created in Latin America: The Chilean Cooperative Group for Oncological Research (Grupo Oncológico Cooperative Chileno de Investigación, or GOCCHI) is a nonprofit corporation registered in Chile since 1998. GOCCHI is conducting academic clinical trials in oncology based on the highest scientific, methodologic, and ethical standards (http://www.gocchi.org). The Peruvian Oncology Clinical Studies Group (Grupo de Estudios Clínicos Oncológicos Peruano, or GECOPERU) was founded in March 2005 as a nonprofit academic and research organization. It has a central operating office and partnerships with several international groups (CIBOMA, IBCSG, BIG, and others) (http://www.gecoperu.pe). Founded in 2007, the Argentine Group for Clinical Research in Oncology (Grupo Argentino de Investigación Clínica en Oncología, or GAICO [is composed of 15 cooperating groups and includes various health professionals from public and private institutions (www.gaico.org.ar). The Latin American Cooperative Oncology Group (LACOG) was founded in 2008 by medical oncologists from several Latin American countries that has developed a network of investigators in oncology for epidemiologic and clinical studies in cancer. LACOG has 47 members in 39 sites from 10 countries in the region. Currently, the group has several ongoing studies. The Brazilian Group of Thoracic Oncology (GBOT) is currently hosted at LACOG and is involved in some research initiatives (www.lacog.org.br) (www.gbot.med.br). CLICaP (Latin American Consortium for Lung Cancer Research) This consortium was created in 2010 to develop collaborative studies on the biology, diagnosis and treatment of lung cancer. CLICaP has published over 20 studies involving participants from Mexico, Costa Rica, Panama, Venezuela, Colombia, Ecuador, Peru, Chile, Argentina and Uruguay. Some of this work has established genomic differences between populations for mutations in EGFR, KRAS and ALK ROS1 following analysis of over 8500 samples (7). There are several challenges of research in South America including costs (6), regulatory issues and difficulty in recruitment but there also several advantages of performing trials in developing countries such as availability of patients, lower costs and faster accrual. As an added and very important characteristic, patients enrolled in developing countries are more frequently treatment-naive and have less, or many times, no competing trials as alternative (8) As more trials are conducted in resource-limited settings, good clinical practices and ethical assurances must be secured. Human participation in clinical research is essential to advance medicine and public health, and expanding clinical trials mandates constant oversight to ensure research quality and protection of study subjects. Some decades ago, the development of global clinical research could have been considered a dream; it is now a pressing need that should be considered unavoidable in the future (2). References: 1 Goss, P; Lee, BL; Badovinac-Crnjevic, T et al. Planning Cancer Control in Latin America and the Caribbean. Lancet Oncol 2013; 14: 391–436 2 Barrios, C; Werutsky, G and Martinez-Mesa, J. The Global Conduct of Cancer Clinical Trials: Challenges and Opportunities. ASCO Educational Book, e132- e139, 2015 3 Drain PK, Robine M, Holmes KK, et al. Trail watch: global migration of clinical trials. Nat Rev Drug Discov. 2014;13:166-167 
 4 Thiers FA, Sinskey AJ, Ernst R. Trends in the globalization of clinical trials. Nature Reviews Drug Discovery. 2008;7:13-14. 
 5 www.clinicaltrials.gov 6 Kaitin KI. The Landscape for pharmaceutical innovation: drivers of 
cost- effective clinical research. Pharm Outsourcing. 2010;2010: 
3605. 
 7 Rolfo C, Caglevic C, Bretel B et al. Cancer clinical research in Latin America: current situation and opportunities. Expert opinion from the first ESMO workshop on clinical trials, Lima, 2015. ESMO Open 2016;1 8 Smith WT. FDA requires foreign clinical studies be in accordance with 
good clinical practices to better protect human subjects. ABA Health 
eSource. 2008; 5:1-3. 


Abstract not provided

Abstract:
Lung cancer has the second highest absolute incidence globally as well as in developing countries and ranks fourth in developed countries. It is the most common cause of cancer death by absolute cases globally as well as in developing and developed regions. The economic burden of lung cancer care is highest relative to other cancers in the European Union. Research is at the core of achieving improved outcomes from cancer, be it in defining country-specific epidemiology of the disease, understanding the pathogenesis of disease, identifying new targets for therapeutic agents, or directing policy to achieve affordable and equitable outcomes. Cancer researchs are one of the most globally active domains of science, with more than $14 billion per annum. A critical part of the health research portfolio is the testing of interventions through randomized controlled trials. Trials can range from highly controlled explanatory trials through to pragmatic trials of new health technologies and models of service delivery. Recruitment problems also have practical and financial impacts, as they can delay completion of research or reduce its timely impact on patient health and wellbeing. Achieving appropriate levels of patient and professional participation has been a significant obstacle to evidence-based practice. Published data show that the minority of trials recruit successfully, either in terms of reaching their planned sample size, or delivering the planned sample in the expected recruitment window Despite all the diffuculties, clinical trials have become increasingly globalized due to the inclusion of more non-traditional locations, especially those in central and eastern Europe, Latin America, and Asia. The increased globalization of clinical research has arisen for several reasons, but primarily due to the need for faster and more economically efficient studies. Moves towards standardizing and harmonizing clinical research practices have facilitated the rise of globalized clinical research. However, the expansion of multinational clinical research peaked in 2009, which could reflect that the large-scale expansion of multinational clinical research effort has reached its global capacity. When the distribution of multinational clinical trials is examined after being stratified according to the condition or disease, lung cancer is not among the five most frequently studied conditions apart from Asia. The results of a bibliometric analysis of global research on lung cancer between 2004-2013 in the 24 leading countries in cancer research showed that despite a doubling of the volume of lung cancer research worldwide between 2004 and 2013, it still only accounts for a small proportion of the overall oncology research publication output (5.6%). In fact, the relative commitment (RC) to lung cancer research compared with that to total oncology research output has fallen in most countries during this period, including in the 23 countries with exception of the China. Turkey, Poland, Canada, Greece, and the United States, despite having the highest country-specific burden of lung cancer, have all seen a decrease in their RC to lung cancer research. Research from Norway, Austria, Switzerland, Belgium, and Sweden had the highest proportion of international contributors . By comparison, relative to their research output, the East Asian countries (Taiwan, India, the Republic of Korea, and Japan) and Turkey had the least amount of international collaboration. With regard to multinational studies, only 1.2% of articles had collaborators from five or more countries and 0.3% from 10 or more countries. The aim of co-operative groups in oncology is to perform multi-center clinical trials for cancer research. Research results are often conveyed to the worldwide medical community through scientific publications. In order to complete the trials within the period specified, it is obvious the need of the qualified and high-volume cancer centers. The barriers to participation of high-volume hospitals in the cooperative group trials should be determined and eliminated. Since the 1970s, centers for thoracic diseases that emerged from former tuberculosis hospitals, particularly in Europe, have focused on the diagnosis and treatment of patients with lung cancer. Traditionally, these centers were staffed by pulmonologists and thoracic surgeons, but now include an extended range of health care workers including the disciplines of radiation oncology, medical oncology, palliative care and rehabilitation medicine. These high-volume centers treat all aspects of problems affecting patients with lung cancer. In 2010, the hospitals with a median 400 new patients per year were in Albania, Belarus, Bulgaria, the Czech Republic, Poland, Romania and Slovenia. The hospitals with more than 1000 new patients with lung cancer per year were in Poland, Bulgaria, Croatia, Turkey. We have to foster the cooperative study groups in lung cancer to provide collaboration between study group and these hospitals. High-volume hospitals should be identified and hospital-based representatives should be determined. Supreme organisations as European Thoracic Oncology Platform providing collaboration among study groups and hospitals, should be able to invite the high-volume hospitals with site evaluation. These high-volume centers have to review whether adequately equipped and set up or not for participation in research projects and clinical trials. References 1- Gaga M. An Official American Thoracic Society/European Respiratory Society Statement: The role of the pulmonologist in the diagnosis and management of lung cancer. Am J Respir Crit Care Med 2013; 188(4): 503-7. 2- Blum T. G. The European initiative for quality management in lung cancer care. Eur Respir J. 2014; 43: 1254-77 3- Loddenkemper R, 100 years DGP-100 years of pneumology in Germany. Pneumologie 2010; 64:7-17. 4- Richter TA. Clinical research: A globalized network. PLoS ONE 2014; 9(12): 1-12 5- Aggarwal A. The state of lung cancer research: A global analysis. J Thorac Oncol 2016; 11(7): 1040-50

Abstract:
In order to keep up with the rapid development of world cancer treatment exploring, Chinese clinical oncology professionals, relevant enterprises and public institutions voluntarily constituted a non-profit professional academic group which is known as The Chinese Society of Clinical Oncology (CSCO) in April 1997. The CSCO organization not only pay attention to international collaboration such as establishing reciprocal memberships with American Society of Clinical Oncology (ASCO) , European Society for Medical Oncology (ESMO), Clinical Oncological Society of Australia (COSA) and participating rotation of presidency organization of Asia Clinical Oncology Society (ACOS), but also committed to Chinese Oncology development. The CSCO annual meeting delivered the latest advancements and research fruit from home and abroad which offered a great academic exchange platform for vast amount of Chinese oncologists. CSCO also organize experts to make tumor diagnosis and treatment standardized guideline. Up to date, CSCO has launched dozens of guidelines regarding many major cancers in china, including non-small cell lung cancer, colorectal cancer and hepatocellular carcinoma. The newly made guideline about non-small cell lung cancer has fully considered Chinese special situation, not only disease characteristics, but also social economic factors, which made a good example of better suiting Chinese oncologists and patients. Other than this, CSCO developed multi-center clinical researches which offered solid evidence for Chinese cancer patients and made contribution to world cancer diagnosis and treatment. Most of clinical researches were carried out by Study Group majored in different cancers, such as Chinese Thoracic Oncology Group (CTONG), Chinese Breast Cancer Study Group (CBCSG) and Chinese Gastrointestinal Oncology Group (CGOG). The CSCO also keeps an open mind and follows the trend of hot spot, such as building expert committee on cancer biomarkers and precise medicine, even making consensus on standard of driver gene mutation test, standard of operation procedure and so on. Of all the Study Groups in CSCO, CTONG is the most active and fruitful committee. CTONG is also the most active organization in lung cancer field in China. Through the great effort of four top experts majored in lung cancer (Yi-Long Wu, Li Zhang, Shun Lu and Cai-Cun Zhou), CTONG was successfully established in 2007. With the goal of designing and developing multi-center clinical trials in the field of chest tumor, especially for lung cancer, providing high level of evidence for clinical practice of thoracic tumor, promoting standardization, modernization and internationalization of clinical and research work in thoracic tumor area and finally improving the level of diagnosis and treatment of chest tumor in China, as well as international status, CTONG has actually made massive efforts and achieved great success. Up to date, CTONG has 31 members from 15 provinces and municipality cities and has successfully performed 47 clinical trials in China. Half of these clinical trials established China lung cancer treatment modalities. Take CTONG 0802 study (OPTIMAL) for example, the multicenter open-label randomized phase II study compared erlotinib with combination of gemcitabine and cisplatin in first-line treatment of patients with EGFR mutation-positive NSCLC[1], Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 [95% CI 10.58-16.53] vs 4.6 [4.21-5.42] months; hazard ratio 0.16, 95% CI 0.10-0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib), which suggested that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC. The results of CTONG0802 was orally presented on ESMO2010, WCLC 2011, discussed on ASCO 2011 and published on Lancet Oncology. CTONG 0901 study compared erlotinib with gefitinib in patients with EGFR mutation positive stage IIIb/IV NSCLC and found no PFS or OS difference between these two regimens which offered solid evidence for clinical choice[2]. CTONG also paid attention to first-line maintenance therapy, second-line treatment, Another well-known study of CTONG is FASTACT-II (CTONG0902) proved that erlotinib maintenance therapy after first-line gemcitabine combined with cisplatin improves overall survival of stage IIIB/IV NSCLC patients[3]. CTONG 0806 study suggested improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced non-squamous NSCLC[4]. There were also many studies focused on palliative treatment, brain metastasis and peri-operative treatments and achieved meaningful results in these fields. Additionally, CTONG has initiated the very first real-world study in China targeting 1st line treatment pattern of advanced non-squamous NSCLC patients, the study concern difference between scientific achievements and clinical practice in China and set a great beginning of caring for patients’ actual profits. The currently ongoing reform for new drug approval of CFDA provides great chances for the development of clinical trials in China and domestic drug innovation such as icotinib and apatinib. CTONG and other study groups also face more opportunities. CTONG, as the successful example of CSCO study groups, is expected to make more contributions to china lung cancer treatment. Hopefully, CSCO achievements will finally benefit more Chinese cancer patients and make more contribution to world cancer control. Reference: 1. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. 2. Yang JJ, Zhou Q, Yan HH, et al. A Randomized Controlled Trial of Erlotinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations (CTONG0901). J Thorac Oncol 2015;10(2), S321(ABSTRACT MINI 16.03) 3. Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. 4. Zhou Q, Cheng Y, Yang JJ, et al. Pemetrexed versus gefitinib as a second-line treatment in advanced nonsquamous nonsmall-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial. Ann Oncol. 2014 ;25(12):2385-2391.

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Abstract not provided