Virtual Library

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Abstract:
Oncogene-driven lung cancer remains the embodiment of personalized medicine. Since the first description of EGFR activating mutations found in patients with what was then called bronchiolalveolar carcinoma of the lung (BAC) in 2004, the topic of oncogene-driven lung cancer has grown rapidly and expanded to now encompass a number of additional mutation- and fusion-related entities. Recent updates to molecular testing guidelines, such as those of IASLC, have added several new oncogenes to the initial EGFR and ALK recommendations, including ROS1 and RET fusions, MET amplification or mutation, and HER2 mutations (1,2,3). Although the efficacy of tyrosine kinase inhibitors (TKI) in the treatment of some of these disease subsets is well established, the treatment decision-making process at the time of each relapse is becoming more complex as our knowledge of resistance pathways grows and more treatment options become available, with 2[nd] and 3[rd] generation drugs now in play. Subtping of progressive disease (PD) in oncogene-driven lung cancer into systemic PD versus oligo-PD or CNS-santuary PD can assist in determining the most appropriate therapeutic approach, as shown in Figure 1 below(4).Further, the methods by which we assess tumor at the time of initial or re-biopsy are also rapidly evolving, from single gene or multiplexed gene panels to highly sensitive and specific next generation sequencing (NGS). Lastly, we and others (4,5) have proposed algorithms for possible substitution of plasma cell free DNA by NGS platforms for tissue re-biopsy or for serial monitoring in plasma, as demonstrated in Figure 2.In this presentation we will present a step-wise approach to molecular testing and personalizing treatment for patients with oncogene-driven NSCLC, focusing on EGFR-mutated and ALK-rearranged subsets, since the treatment paradigms are most well established. We will emphasize some of the real world challenges faced by treating physicians. Decision criteria for selecting the best first-line therapy will be reviewed, the importance of re-biopsy upon disease progression to determine the most appropriate next-line therapy highlighted, and third line therapy and beyond discussed. The emerging role of liquid biopsy for assessment of plasma cell free DNA will be discussed, as well as a rationale for substituting liquid biopsy for initial or repeat tumor biopsy in some clinical settings. Algorithms designed to facilitate treatment decision-making will be presented. Two examples in EGFR-mutated lung cancer are shown below.Figure 1: Algorithm for management by Progressive Disease SubtypingEGFR-mutated NSCLCFigure 1Figure 2: Algorithm for Re-Biopsy and/or Plasma cf DNA AnalysisIn EGFR-mutated NSCLCFigure 2 References 1. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2013, 8(7):823-859. 2. Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ramalingam SS, West H, Whitlock S, Somerfield MR: Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists Guideline. Journal of Clinical Oncology 2014. 3. Ettinger, D. S., Akerley, W., Borghaei, H., Chang, A. C., Cheney, R. T., Chirieac, L. R., ... & Grant, S. C. Non–small cell lung cancer, version 2.2013. Journal of the National Comprehensive Cancer Network, 2013, 11(6), 645-653. 4. Gandara DR, Li T, Lara PN, Kelly K, Riess JW, Redman MW, Mack PC: Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clinical lung cancer 2014, 15(1):1-6. 5. Oxnard, G. R., Thress, K. S., Alden, R. S., Lawrance, R., Paweletz, C. P., Cantarini, M., ... & Jänne, P. A. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non–small-cell lung cancer. Journal of Clinical Oncology, 2014, JCO667162.

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Background:
Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved efficacy and tolerability vs docetaxel in patients with advanced NSCLC that progressed on or after platinum-based chemotherapy and is approved in >50 countries in this patient population. We report efficacy and safety data from a phase 1 study (CheckMate 012; NCT01454102) evaluating first-line nivolumab in patients with advanced NSCLC.

Methods:
Patients (N=52) with advanced, chemotherapy-naive NSCLC (any histology) were treated with nivolumab monotherapy at 3 mg/kg IV Q2W until disease progression or unacceptable toxicity. Safety and tolerability was the primary study objective. Efficacy, as measured by objective response rate (ORR) and 24-week progression-free survival (PFS) rate per RECIST v1.1, was the secondary objective. Overall survival (OS) was an exploratory endpoint.

Results:
Treatment-related adverse events (TRAEs) were reported in 71% (any grade) and 19% (grade 3‒4) of patients. The most frequent select TRAEs (those with potential immunologic causes) by category were skin, endocrine, and gastrointestinal (Table). With a median follow-up of 14.3 months (range, 0.2 to 30.1), the confirmed ORR was 23% (12/52) and 8% (4/52) of patients had complete responses. Of the 12 responses, 8 (67%) were ongoing at the time of database lock; median duration of response was not reached. Median OS was 19.4 months (range, 0.2‒35.8+). The 24-week PFS rate was 41% (95% CI: 27‒54); 18-month OS rate was 57% (95% CI: 42‒70). Updated long-term data will be presented, including 2-year OS and will represent the longest follow-up to date for a PD-1/PD-L1 inhibitor for first-line advanced NSCLC. Updated data from patients treated with nivolumab plus ipilimumab (N = 77) will also be presented.

Background:
Atezolizumab, a humanized anti-PDL1 mAb, inhibits the PD-L1/PD-1 pathway to restore tumor-specific T-cell immunity, resulting in durable anti-tumor effects. BIRCH (NCT02031458) is a single-arm Phase II study of atezolizumab monotherapy in PD-L1–selected advanced NSCLC patients, across multiple therapy lines. Primary analyses (median follow-up, 8.5 months) demonstrated a meaningful ORR with durable response in chemotherapy-naive 1L and 2L+ PD-L1–selected patients. Here we report updated efficacy data in 1L patients.

Methods:
1L eligibility criteria included PD-L1–selected, advanced-stage NSCLC with no CNS metastases or prior chemotherapy. PD-L1 was centrally evaluated (VENTANA SP142 IHC assay). Patients expressing PD-L1 on ≥5% of tumor cells (TC) or tumor-infiltrating immune cells (IC), ie, TC2/3 or IC2/3, were enrolled. Patients with EGFR mutation or ALK rearrangement must have had prior TKI treatment. Atezolizumab 1200mg was administered IV q3w until radiographic disease progression or unacceptable toxicity. The primary endpoint was independent review facility(IRF)-assessed ORR. Secondary endpoints included investigator(INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.

Results:
With a median follow-up of 14.6 months, median OS was not reached in TC3 or IC3 patients and was 20.1 months in TC2/3 or IC2/3 (ITT) patients; INV-assessed ORR was 32% and 24%, respectively (Table). Furthermore, ORR was 31% for mutant EGFR (n=13) vs 20% for wild-type EGFR patients (n=104), and 27% for mutant KRAS (n=33) vs 21% for wild-type KRAS patients (n=67). No new safety signals were observed. Updated efficacy (including IRF ORR), safety and exploratory biomarker analyses will be presented.

Conclusion:
With longer follow-up, atezolizumab continued to demonstrate promising efficacy in 1L NSCLC. These results indicate that atezolizumab has durable efficacy in the 1L setting, in EGFR and KRAS mutant and wild-type tumors, and support ongoing Phase III trials evaluating atezolizumab vs chemotherapy in 1L NSCLC.

Background:
Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody that has shown antitumour activity in various malignancies. We report safety and clinical activity of avelumab as first-line therapy in a cohort of patients with non-small–cell lung cancer (NSCLC) from a phase 1b trial (NCT01772004).

Methods:
Patients with advanced NSCLC not previously treated systemically for metastatic or recurrent disease, without an activating EGFR mutation or ALK rearrangement, and not preselected for PD-L1 expression, received avelumab 10 mg/kg IV over 1 hour Q2W until progression, unacceptable toxicity, or study withdrawal. Objective response rate (ORR) and progression-free survival (PFS) were evaluated by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0.

Results:
As of 23 Oct 2015, 145 patients had received avelumab (median 10 weeks of treatment; range 2-30) and were followed for a median of 13 weeks (range 0-31). Median age was 70 years (range 41-90), ECOG PS was 0 (31.0%) or 1 (69.0%), and tumour histology was adenocarcinoma (63.4%) or squamous (26.9%) in most patients. Eighty-two patients (56.6%) had a treatment-related (TR) AE; those occurring in ≥10% were infusion-related reaction (IRR; n=24, 16.6%) and fatigue (n=21, 14.5%). Thirteen patients (9.0%) had a grade ≥3 TRAE; only IRR and fatigue occurred in >1 patient (each n=3, 2.1%). Four patients (2.8%) had a potential immune-mediated TRAE, all grade 1-2 (pneumonitis n=3, 2.1%; hypothyroidism n=1, 0.7%). There were no treatment-related deaths. Among 75 patients with ≥3 months’ follow-up, unconfirmed ORR was 18.7% (95% CI: 10.6, 29.3) based on 1 complete response and 13 partial responses; 12 were ongoing. Thirty-four additional patients (45.3%) had stable disease as best response (disease control rate 64.0%). Updated analysis will be presented, including efficacy data with ≥3 months’ follow-up in all patients and PD-L1 analysis.

Conclusion:
First-line avelumab monotherapy showed clinical activity and was well-tolerated in patients with EGFR-wildtype/ALK-negative NSCLC unselected for PD-L1 expression. A phase 3 trial of avelumab vs platinum-doublet in first-line NSCLC is in progress. *Proposed nonproprietary name.

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Background:
Nivolumab significantly improved OS versus docetaxel in patients with previously treated advanced non-squamous NSCLC (CheckMate 057; NCT01673867). Kaplan−Meier OS curves for nivolumab and docetaxel crossed at ~7 months, suggesting non-proportional hazards between arms.

Methods:
Post-hoc analyses were conducted to explore relationships between baseline patient/disease characteristics, including PD-L1 expression, and death within the first 3 months of treatment (3motx). Additionally, the association between PD-L1 expression level and magnitude of clinical benefit was explored.

Results:
During the first 3motx, risk of death (rDt) was numerically higher with nivolumab versus docetaxel (59 versus 44 deaths among 292 and 290 patients, respectively). Early deaths were most commonly attributed to disease progression (no treatment-related deaths occurred). At 3motx, 80% of nivolumab-treated patients (233/292) and 85% of docetaxel-treated patients (246/290) were alive. After 3motx, the rDt was consistently higher in the docetaxel arm. In univariate analyses, no single baseline factor, including PD-L1 expression, EGFR mutation, ECOG PS, or smoking status, reliably characterized the rDt within the first 3motx with nivolumab. Among patients alive >3 months, the OS HR (95% CI) favored nivolumab in the overall population (0.59 [0.47−0.74]) and PD-L1 non-expressors (PD-L1 expression <1%; 0.66 [0.45−0.97]). In a multivariate analysis, factors associated with higher rDt within the first 3motx on nivolumab versus docetaxel were ECOG PS=1, time since last treatment <3 months, and/or progressive disease as best response to prior treatment combined with lower or no PD-L1 expression. However, the majority of nivolumab-treated patients with these attributes (including PD-L1 non-expressors), did not die within the first 3motx and experienced subsequent benefit. PD-L1 expression was a continuum, ranging from 1 to 100%, with increasing expression associated with enhanced ORR/OS benefit from nivolumab.

Conclusion:
In CheckMate 057, the benefit−risk profile of nivolumab versus docetaxel was favorable across the overall patient population. During the first 3motx, a small difference in the number of deaths (n=15) was observed; thereafter the OS rate consistently favored nivolumab (2-year OS was >2-fold higher with nivolumab versus docetaxel). Patients with poorer prognostic factors and/or more aggressive disease combined with lower or no PD-L1 expression appeared to be at higher rDt within the first 3motx on nivolumab versus docetaxel. With the exception of PD-L1 status, these are recognized prognostic factors. While PD-L1 expression may help inform individual treatment decisions, PD-L1 status alone is not considered an appropriate biomarker for nivolumab treatment selection in pre-treated advanced NSCLC, but rather should be considered in the context of other patient/disease characteristics.

Background:
Monoclonal antibodies against Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1) have emerged as effective therapies in NSCLC. We updated our initial systematic review of trials investigating differences in the toxicities of PD-1 and PD-L1 inhibitors.

Methods:
An electronic literature search was performed of public databases (MEDLINE, EMBASE) and conference proceedings for trials utilizing PD-1 inhibitors (nivolumab, pembrolizumab) and PD-L1 inhibitors (atezolizumab, durvalumab, avelumab) in NSCLC patients. Studies that did not report toxicities were excluded. A formal meta-analysis was conducted with Comprehensive Meta-Analysis software (Version 2.2). Clinical and demographic characteristics, response, and toxicity data were compared between the two groups.

Results:
Twenty-two studies reported between 2013-2016 were eligible for this analysis. The total number of patients evaluated for toxicities were 2,863 patients in the PD-1 group and 2,006 patients in the PD-L1 group. Patient characteristics % (PD-1/PD-L1): median age 64/65, male 58/56, smokers 82/83, squamous histology 25/32, performance status 0-1 98/100. There was no difference in response rate between PD-1 (17%) and PD-L1 (18%) inhibitors, p=0.3. The incidence of overall adverse events (AEs), immune related AEs, and pneumonitis trended in favor of the PD-L1 group but did not reach statistical significance (see table). Figure 1



Conclusion:
In this updated systematic review involving 4,869 patients, the toxicity profiles of PD-1 and PD-L1 inhibitors in NSCLC patients are not significantly different.

Background:
Checkpoint inhibitors such as the anti–PD-1 monoclonal antibody pembrolizumab have demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Although checkpoint inhibitors are rapidly becoming a standard-of-care therapy in multiple tumor types, the optimal treatment duration has not been established. We assessed outcomes in patients who completed the maximum 24 months of pembrolizumab in the phase 3 KEYNOTE-010 study (NCT01905657), in which pembrolizumab provided superior OS over docetaxel in patients with previously treated, PD-L1–expressing advanced NSCLC.

Methods:
1034 patients with advanced NSCLC that progressed after ≥2 cycles of platinum-based chemotherapy (and an appropriate therapy for targetable EGFR and ALK aberrations if present) and had a PD-L1 tumor proportion score ≥1% were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg Q3W or to docetaxel 75 mg/m[2] until disease progression, intolerable toxicity, or physician or patient decision; the maximum duration of pembrolizumab was 24 months of uninterrupted treatment or 35 cycles, whichever was later. Response was assessed per RECIST v1.1 by independent central review every 9 weeks. After completion of 24 months/35 cycles, patients continued to undergo imaging every 9 weeks; patients with subsequent disease progression were eligible for a second treatment course if they did not receive other anticancer therapy after stopping pembrolizumab.

Results:
In the overall population, median OS was longer (10.5 months for pembrolizumab Q2W, 13.4 months for pembrolizumab Q3W, and 8.6 months for docetaxel) and 24-month OS rates were higher (30.1%, 37.5%, and 14.5%, respectively) with pembrolizumab compared with docetaxel. Of the 691 patients allocated to pembrolizumab, 47 patients received 35 cycles of pembrolizumab and were included in this analysis. As of the September 30, 2016 data cutoff date, all patients had completed all 35 cycles of treatment, but one withdrew from the study treatment after completing 35 cycles. Best overall response (ORR) among these 47 patients was complete response (CR) in 3 (6%) patients and partial response (PR) in 39 (83%) patients, for an ORR of 89%; 5 (11%) patients experienced stable disease (SD). Two of these patients experienced disease progression since stopping pembrolizumab and two of these patients resumed pembrolizumab therapy. As of the cutoff date, none of the 47 patients had died.

Conclusion:
With long-term follow-up, the OS benefit has been maintained and pembrolizumab continues to demonstrate superiority over docetaxel. Pembrolizumab provides durable clinical benefit with few patients progressing after completing two years of therapy.

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Abstract:
In 2030, 60% of all new cancer diagnoses (15/25 million cases) and 80% of cancer related deaths (10/13 million deaths) will occur in low and middle income countries (LMICs) [1]. This explosion in cancer incidence is attributed to prolonged life expectancy in steadily growing populations with high levels of modifiable risk factors such as tobacco/alcohol and unhealthy diets. Despite the significant health burden, LMICs spend less than 10% of the global cancer budget. Cancer therapies are exponentially sprouting in rich countries but LMICs are not proportionally benefitting from this growth. Corruption, lack of infrastructure, poverty, and absence of national cancer policies/goals have hindered the development of quality cancer care programs. Radiotherapy has particularly suffered because of the perceived assumption that establishing quality radiotherapy centers in LMICs is unaffordable, non-sustainable and therefore unattainable and should not be pursued. Currently, up to 90% of LMIC inhabitants lack sufficient radiotherapy access and about 30 countries in Africa do not have a single treatment machine. It is estimated that by 2020, >9000 treatment machines, >10,000 radiation oncologists, and thousands of physicists and therapists are needed to treat patients in LMICs per evidence-based radiotherapy recommendations [2]. Recently, a group of experts with the Lancet Oncology Commission [3] reviewed the current radiotherapy capacity in LMICs and estimated the 20-year burden of cancer requiring radiotherapy and the needed investments to bring radiotherapy capacity in these countries to the needed levels. The published report provides compelling evidence that investment in radiotherapy not only will save millions of lives but will also bring significant economic benefits. The initial capital costs of scaling up radiotherapy may appear prohibitive, but these figures are based on estimations and projections that promise to deliver radiotherapy that is safe, timely, effective, efficient, equitable and patient centered. By aiming at quality care delivery, we can guarantee the highest returns on investments not only in oncologic outcomes but also in curbing loss in health-related productivity and life years. We hereby discuss few strategies to directly or indirectly reduce the capital or operating costs of such an expansion: - Trans-national, public and private partnerships: International organizations (such as the WHO, IAEA, etc) in collaboration with interested academic consultants and national governments should plan the required radiotherapy centers based on individualized national cancer priorities in the setting of a wide cancer care policy. This will require however a significant buy-in from national governments which are expected to establish effective social security systems with universal health coverage, create reliable cancer registries, implement effective cancer preventative and early diagnosis programs and finally promote outreach health literacy programs in real-world settings. Once international investments are coupled to national needs/efforts, minimal wasting of resources and maximal return on investment will be attained. - Centralization and pooling of resources regionally and internationally: This is a crucial step to at least jump start radiotherapy programs especially in the very low income countries where efforts are generally starting from nothing or close to nothing at best. High quality radiotherapy/simulation units donated by and refurbished in developed countries can provide a starting point around which other resources can be pooled. Regional centers can create circles of remote dosimetry/physics support and chart rounds via video conferencing to promote continued education and high quality treatment plans. These regional networks can be also connected to international cancer centers of excellence for further support and collaboration. Tax breaks could be offered to academic institutions or manufacturers in rich countries to participate in this process. - Investing in technology/science adapted to local needs in developing countries: Even if the capital is available, current manufacturing capabilities will not be able to build the required number of machines by 2020 as required. There is thus an immense need for innovative low cost, high quality radiotherapy units. Research and development departments should be offered incentives to create these tools. Optimizing the use of radiation techniques and per-unit activity to adapt to the treatment demands in developing countries will also improve benefit to cost ratio. - Hypofractionation: The number of “radiation fractions per year” is used as a surrogate for radiotherapy demand. Hypofractionation, thus, is a major strategy to optimize radiotherapy utilization and decrease operating costs without compromising outcomes in many cancer sites. For example, in the case of 1000 early breast [4] and 1000 early prostate cancer [5] patients requiring radiotherapy per year, using evidence-based hypofractionated treatments, not necessarily the extremely hypofractionated high-tech stereotactic radiation, would decrease the number of needed treatment machines from 10 to 6 and the number of therapists from 25 to 14. It will also decrease the duration of treatment per patient and thus allow more patients to be treated daily. Despite these benefits, hypofractionation remains widely underutilized even in developed countries [6]. Figure 1 - Investing in building local skills: Skilled radiation oncologists, therapists and physicists are very expensive commodities. While initial external support is crucial, new radiation centers need to eventually become self-sufficient and sustainable. Establishing local training programs should be a national priority in developing countries to decrease the cost of external training and limit brain drain. There is no magic wand to decrease the initial cost of investing in building radiotherapy capabilities but through careful planning and strong collaborations, millions of lives can be saved. Cost is crucial but we should not lose compass of our goal: delivering quality radiotherapy treatments to cure, improve the quality of life and alleviate pain in of millions of patients with cancer who are desperately in need.

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Abstract:
Cancer incidence and mortality have been increasing in mainland China, making cancer the leading cause of death since 2010 and a major public health problem in the country. Much of the rising burden is attributable to population growth and ageing and to socio-demographic changes. According to the National Central Cancer Registry of China (NCCR), an estimated 4292,000 new cancer cases and 2814,000 cancer deaths would occur in mainland China in 2015, with lung, stomach, esophageal, liver and colorectal cancer being the most five common incident cancers and the leading cause of cancer death, for which radiotherapy always plays an important role in the comprehensive therapy. The earliest record of radiation therapy for cancer in China dates back to the early 1930s. The establishment of the Sino-Belgian Radium Institute in 1931 signified the initiation of modern radiation oncology in China. However, the development of cancer treatment has been hampered by several major wars and political turmoil in the following decades until the late 1970s and early 1980s: the era of national economical reform in mainland China. It was at this point when the academic and research bodies started to focus on the availability of radiation oncology service and their access by cancer patients. In the next over 30 years, China has undergone a period of incredible economic growth and radiation oncology, has clearly improved in terms of equipment and its utilization, although the shortage of facilities and workforce remain to be improved. The Chinese Society of Radiation Oncology (CSTRO) started its survey of the personnel and equipment in radiation oncology in mainland China since 1986. The updated survey results of 2015 were recently compiled and analyzed. Comparison of these crucial data clearly demonstrates the increase in the number of the facilities as well as advances in the quality of service (Figures 1 and 2). Based on the report of the third survey (of 1997) (first English-vision survey published in the International Journal of Radiation Oncology * Biology * Physics), there were 453 radiation oncology centers equipped with 286 linear accelerators, 381 cobalt units, 179 deep X-ray machines, and 302 brachytherapy units. These facilities were staffed with 3,440 physicians, 423 physicists, and 2,245 radiation therapists. It is important to note that less than 1,200 physicians were trained at major cancer centers within the radiation oncology specialty. The rest were of other specialties (e.g., surgeons) and received only several months of “practical training” (i.e., mentorship by experienced radiation oncologist with customized lectures) in a few major cancer centers mostly in major cities such as Beijing, Shanghai, and Guangzhou, rather than formal residency training in radiation oncology. The ratio of medical physicists to radiation oncology centers was less than 1 as well. (Figure 1) The two decades after 1997 signifies a rapid advance in the quality of radiation therapy facilities as well. The number of linear accelerators exhibited a nearly 6-fold increase in these 20 years, and more facilities are now equipped with computerized treatment planning systems (increased from 177 to 1,921) as well. On the other hand, the registered radiation oncology centers were established in most of the major cities, increased to 1,431 (a 210% increase from the 1997 survey), which makes radiotherapy much more easily accessed by cancer patients. The number of radiation oncologists increased to 15841 (a 360% increase). Besides, medical physics, a crucial specialty for the quality and safety of the clinical application of radiotherapy, has substantially improved. The number of trained medical physicists has undergone a nearly 7-fold increase to 3,294 in total. (Figure 2) At the same time period for accelerated development regarding radiation therapy capacity, the population and cancer incidence of mainland China had also increased, which resulted in the radiotherapy remained much insufficient. According to the recently cancer statistics in mainland China, the cancer incidence was 4.29 million in 2015. Given that approximately 50% require RT as part of definitive treatment, around 2.15 million Chinese cancer patients need RT annually. This number is most likely higher, since it does not include recurrent and palliative indications (estimates put this number into the 65-75% range for all malignancies), and cover all the area in mainland China. In fact, the numbers of annual new radiotherapy consultation and daily treatment was 919,339 and 76,612 in 2015. Therefore, only 50% patients who would need radiotherapy received radiotherapy in Mainland China in 2015. The current status is caused by two main reasons. First, the ratio of tele-therapy facility (linear accelerator and Co60 combined) per million was 1.49 in 2015, which are quite low compared to 8.2 in the United States, 7.5 in France, 3.4 in the United Kingdom, and 2-3 recommended by the World Health Organization. Second, the distribution of radiotherapeutic resources is uneven by region. For example, the ratio in Beijing, Tianjin, Shanghai, and Shandong municipalities/province, where are considered regions of better economic development, is 3.07, 3.28, 2.19, and 2.28, respectively. Meanwhile, rural and/or less populous regions such as Tibet are often under 1.00. In conclusion, it is still obvious that cancer patients have limited access to radiotherapy facilities as well as qualified radiation oncologist, though remarkably robust development in all facets of radiation oncology over the last 30 years in mainland China. Clearly, much more effort should be made in regards to access to radiation oncology facilities and their service for cancer patients.Figure 1 Figure 1. The growth radiation therapy equipment in China from 1986 to 2015 based on the2015 CSTRO report by Lang et al. Figure 2 Figure 2. The changes in the configuration of radiotherapy team in China from 1986 to 2015 based on the 2015 CSTRO report by Lang et al. References 1. Gu XZH, Feng NY, Yu Y, et al. Investigation report on the composition of equipment and technical level of radiation therapy team in China. Radiat Oncol China. 1989, 3(1): 41-43. [Published in Chinese] 2. Yin WB, Chen B, Gu XZH, et al. General survey of radiation oncology in China. Chin J Radiat Oncol, 1995, 4(4):271-275. [Published in Chinese] 3. Yin WB, Tian FH, Gu XZH. Radiation Oncology in China: the third survey of personnel and equipment in radiation oncology. Int J Radiat Oncol Biol Phys, 1999, 44(2):239-241. 4. Yin WB, Tian FH. Survey report on national radiation therapy personnel and equipment in 2001. Chin J Radial Oncol, 2002, 11(3): 145-147. [Published in Chinese] 5. Chinese Society of Radiation Oncology (Yin WB, Yu Y, Chen B, et All). Fifth nationwide survey on radiation oncology of China in 2006. Chin J Radial Oncol, 2007, 16(1): 1-5. [Published in Chinese] 6. Chinese Society of Radiation Oncology (Yin WB, Chen B, Zhang CL, et al). The sixth nationwide survey on radiation oncology of continent prefecture of China in 2011. Chin J Radiat Oncol, 2011, 20(6): 453-457. [Published in Chinese] 7. Yin WB, Chen B, Tian FH, et al. The growth of radiation oncology in mainland China during the last 10 years. Int J Radiat Oncol Biol Phys, 2008, 70(3): 795-798. 8. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016, 66(2):115-132.

Abstract:
The treatment of lung cancer has changed dramatically in the past few years. From a time when treatment decisions were made without regard to histology or genotype, an era of personalized therapy, at least for a subset of patients with lung cancer, is a reality. The treatment of EGFR mutation-positive patients with EGFR inhibitors has resulted in significant improvements in outcomes over standard chemotherapy. Similarly, for patients with ALK- and ROS1-positive non-small cell lung cancer (NSCLC), targeted therapies have proven to be superior. However, for patients with KRAS mutations, which are seen in approximately 25-30% of lung adenocarcinomas, there is no effective targeted therapy option. For nearly 70% of patients with NSCLC, systemic chemotherapy remains the standard approach. The emergence of immune-checkpoint inhibitors has resulted in considerable change in the treatment algorithm for advanced NSCLC. These agents are now preferred salvage therapy after progression following platinum-based chemotherapy. As immunotherapy moves to the first-line therapy setting for advanced NSCLC, it is anticipated that at least 25-30% of the patients without a driver mutation will be treated with immune-checkpoint inhibitors. All of these exciting developments call for careful evaluation of ongoing and planned clinical trials, so that appropriate new priorities are established. The newly established NCI National Clinical Trials Network (NCTN) includes all the adult cancer cooperative groups (ALLIANCE, ECOG-ACRIN, SWOG, & NRG Oncology) is actively engaged in conducting the new generation of clinical trials for lung cancer. Despite, the success with targeted agents in advanced stage NSCLC, patients do not achieve a cure. Using these agents in early stage NSCLC provides the best chance for a cure. The ALCHEMIST study has been launched by the NCTN to evaluate personalized adjuvant therapy for early stage NSCLC. In this study, patients with early-stage lung cancer (stages IB, II and IIIA) are treated with systemic chemotherapy after surgical resection, as per standard of care. Subsequently, their tumor is subjected to molecular testing. Patients with ALK-positive disease are randomized to treatment with crizotinib or placebo. Patients with EGFR mutations are randomized to erlotinib or placebo. Patients who are negative for EGFR and ALK, are randomized to nivolumab or observation. These studies will evaluate the effect of the personalized adjuvant therapy on overall survival and disease-free survival. Another ongoing effort is to understand the therapeutic value of targeted strategies in patients with advanced stage squamous cell lung cancer. The lung-MAP study enrolls patients with advanced stage squamous NSCLC. Following next-gen sequencing, patients with selected targets are treated with an appropriate targeted agent. The study includes a phase 2 component, which can be rapidly adapted to phase 3 if a agent demonstrates the pre-defined level of efficacy. This trial is also designed to accelerate the development of treatments leading to full approval by the FDA by shortening timelines. These individualized treatment approaches based on genotype are likely to answer important questions in a definitive manner. As immunotherapy becomes integrated in the standard treatment paradigms, considerable changes are also warranted for patients without driver mutations. For a subset of patients, as immunotherapy becomes the first line treatment in the advanced stage disease setting, the role of platinum-based chemotherapy in the second line needs to be investigated. It is also important to evaluate the need for continued immunotherapy after disease progression when patients are switched to chemotherapy. Another key question relates to the duration of therapy for patients receiving immune checkpoint inhibitors. Appropriately designed trials to understand the optimum duration of therapy will optimize benefits, reduce toxicity, and decrease cost. Combination strategies using immune checkpoint inhibitors with chemotherapy and other targeted agents is also an important area of priority. The role of biomarkers to select therapy is another critical research priority. We should also make efforts to improve the percentage of patients enrolled to clinical trials. A major reason for this is the stringent eligibility criteria that excludes a significant proportion of patients in order to select the ‘fittest’ candidates for clinical trials. While this is certainly appropriate in early phase drug development, if patients enrolled in clinical trials do not represent the ‘real-world’ patient population, the applicability of the results are limited. The next wave of clinical trials should also take into consideration the impact of new treatments on the overall cost of care and the clinical significance of improvements in efficacy. The national Cooperative groups in the United States are committed to a collaborative approach to address key research questions and improve outcomes for lung cancer.

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Abstract:
　In Japan, several cooperative study groups, such as Japan Clinical Oncology Group (JCOG), West Japan Oncology Group (WJOG), North East Japan Study Group (NEJ), Thoracic Oncology Research Group (TORG), Tokyo Cooperative Cooperative Oncology Group (TCOG), Oncology Group in Kyushu (LOGiK), Okayama Lung Cancer Study Group (OLCSG) and so on are conducting investigator initiated cooperative clinical studies for lung cancer. Phase 3 studies are mainly conducted by JCOG, WJOG and NEJ. JCOG and WJOG are conducting intergroup phase 3 studies for lung cancer. More recently, multi-group phase 3 studies are also started. 　JCOG is a multicenter clinical study group for cancer treatment fully funded by the national research grants in Japan. The goal of the JCOG is to establish effective standard treatments for various types of malignant tumors by conducting nationwide multicenter clinical trials, and to improve the quality and outcome of the management of cancer patients. JCOG consists of 16 subgroups and JCOG Lung Cancer Study Group (JCOG-LCSG) consists of 44 institutions, was established in 1982. JCOG also have JCOG Lung Cancer Surgical Study Group (JCOG-LCSSG) established in 1986. 　Only JCOG is supported by no industries but National Cancer Center and grants of Japan Agency for Medical Research and Development (AMED). Thus, JCOG studies are conducting completely independent from pharmaceutical companies. Other groups are supported by mainly pharmaceutical companies and grants of AMED. JCOG-LCSG has been conducting many randomized trials for small cell lung cancer and elderly non-small cell lung cancer. In case of JCOG-LCSG, protocol concepts are discussing in the group meeting held every 3 months. The protocol concept agreed in the group meeting will discuss in JCOG Protocol Review Committee and finally approved by JCOG Steering Committee. Kawano Y, Okamoto I, Fukuda H, et al. Current status and future perspectives of cooperative study groups for lung cancer in Japan. Respir Investig 52: 339-347, 2014.

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Abstract:
Over the recent decade, we witnessed important progress in the treatment of patients with advanced NSCLC in three domains. First, cytotoxic chemotherapy, where histology-directed chemotherapy with cisplatin-pemetrexed, followed by pemetrexed maintenance therapy in appropriate candidates, has resulted in a median overall survival (OS) of 16.9 months in adenocarcinoma [1]. Second, the use of tyrosine kinase inhibitors (TKIs) in tumors driven by specific molecular pathways, such as EGFR, ALK and others, has largely improved progression-free survival (PFS) compared to the one with chemotherapy in randomized studies, and had led to OS times of several years in many of these patients [2]. Third, immunotherapy with immune checkpoint inhibitors (ICI) directed against the immunosuppressive molecules programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has been in clinical trials since 2009. At present, the anti-PD-1 antibodies nivolumab (a fully human IgG4 antibody) and pembrolizumab (an engineered humanized IgG4 antibody) have been approved for NSCLC by different regulatory agencies worldwide. EMA approved nivolumab for advanced NSCLC after prior chemotherapy, and pembrolizumab for advanced NSCLC in adults whose tumors express PD-L1 and who have received at least one prior chemotherapy regimen. At the time of writing of this contribution, there were no public randomized study data on the use of these agents in 1[st] line therapy, we will therefore concentrate on the relapse therapy setting. Despite the real progress made by ICI therapy, we must realize that at present only about 20% of the patients respond to single-agent ICI treatment, while 50% have early progression (Checkmate 017 [3]; Checkmate 057 [4]). Moreover, the cost of these drugs is considerable. Hence it is important to define optimal candidates in clinical practice. Elements in this decision are a) clinicopathological factors; b) possible predictive biomarkers; and c) the availability of other treatment choices. As for (a) clinicopathological factors, there is no evidence that age, gender or ethnicity determine activity of ICIs. Smoking history, on the other hand, is strongly associated with better response rate to ICI therapy. Although EGFR oncogene pathway activation has been linked to upregulation of PD-L1 in tumor cells, response rates to ICIs in these patients are generally reported to be lower. In e.g. Checkmate 057, the overall response rate was 19%. It was 22% in smokers vs. 9% in non-smokers, 18% in EGFR-wildtype vs. 11% in EGFR-mutant tumors. Further understanding and refinement of the use of ICIs in tumor with an oncogene driver is needed. (b) A multitude of potential predictive biomarkers of response to PD-1/PD-L1 pathway inhibitors have been reported. In particular, PD-L1 expression in tumor and/or immune cells, the presence of TILs (tumor-infiltrating lymphocytes, CD8+ T-cells in particular), and the overall mutational load in the tumor cells have been linked to activity of ICIs [5]. PD-L1 expression on tumor cells, determined by immunohistochemistry (IHC) staining is by far the one most close to clinical practice for selecting optimal candidates for immunotherapy. This biomarker is quite distinct and less powerful than e.g. EGFR mutation as predictor of efficacy of EGFR TKIs. EGFR mutation is limited to the tumor, it is located in a distinct pathway, and is a yes/no phenomenon. PD-L1 IHC, on the other hand, relates to the tumor and its micro-environment, is only one of the many checkpoints in a complex interaction, and is a gradual phenomenon. Nonetheless, as can be noted from the figure, in most datasets of phase III studies – except Checkmate 017 – PD-L1 IHC predicts efficacy of ICI therapy. We added the large phase I study Keynote 001 to the figure as a very illustrative example: Over the categories of PD-L1 expression, response rate increased from 8% in the lowest to 45% in the highest category [6]. In the Keynote 010 phase III study, the hazard ratio of OS versus chemotherapy was 0.76 in the low-, but 0.54 in the high-expression group [7]. In the Checkmate 057, the OS hazard ratio even was 1.00 in all patients with tumors having PD-L1 <10%. Thus, except for the Checkmate 017 dataset, PD-L1 IHC enriches the response rate and differential OS benefit vs. chemotherapy, and can be used to designate these expensive agents to the optimal candidates. (c) Docetaxel single-agent chemotherapy was the comparator in the phase III studies on relapse therapy. In the meanwhile, progress has been made in conventional relapse therapy as well. In the LUME-Lung 1 trial, the combination of docetaxel and the triple angiogenesis inhibitor nintedanib resulted in a significantly better OS than docetaxel alone – with a difference in median OS of 2.3 months – in patients with adenocarcinoma [8]. In the REVEL study, patients treated with docetaxel plus ramucirumab, a VEGF receptor 2 inhibiting monoclonal antibody, had significantly better OS than those treated with docetaxel alone across all NSCLC histologies [9]. In conclusion, the choice of ICI therapy for relapsing NSCLC needs to be considered in the available treatment options for these patients, and this can be based on clinicopathological factors, predictive biomarkers, and comparison of efficacy of various treatments in specific subgroups. While PD-L1 is not a biomarker with the strength such as e.g. EGFR mutation, it helps to optimize the response rate and differential OS benefit of ICI therapy vs. chemotherapy, and to and can be used to designate these expensive agents to the optimal candidates. Figure Figure 1 References 1. Paz-Ares LG, De Marinis F, Dediu M et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after first-line treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013; 31: 2895-2902. 2. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-957. 3. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous cell non-small cell lung cancer. N Engl J Med 2015; 373: 123-135. 4. Borghaei H, Paz-Ares L, Horn L et al. Nivolumab versus docetaxel in advanced nonsquamous non-small cell lung cancer. N Engl J Med 2015; 373: 1627-1639. 5. Rizvi NA, Hellmann MD, Snyder A et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348: 124-128. 6. Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med 2015; 372: 2018-2028. 7. Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016; 387: 1540-1550. 8. Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): A phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014; 15: 143-155. 9. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665-673.

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Abstract:
Immunotherapy (IT) has become one of the most potent new treatments for all cancers, particularly non small lung cancer. However, it has a unique toxicity profile different than most therapies (chemotherapy; biologic; targeted therapy) than most oncologists are familiar with, specifically immune related adverse events; irAE. These toxicities may be acute but also can occur weeks and months after starting or even stopping therapy. Given the prolonged duration that patients may be exposed to these drugs, they become important to manage over a short and long period. Further, given the responses and the relative milder toxicity compared with traditional chemotherapy agents, the older patient population may be exposed to these agents at a somewhat higher frequency. The use of immunomodulatory drugs to counter irAE toxicity will be discussed as to how it affects efficacy of immunotherapy. This lecture will focus on: Timeframe and monitoring for immune related toxicity (with special attention paid towards pulmonary, gastrointestinal and endocrinopathies) using the appropriate immunosuppressive drugs Management of toxicities related to IT Decision making on re-exposure to drug after iRAE Patient education Toxicities associated with combination IT drugs that may be used in the future or on clinical trials

Abstract:
“How Can Immunotherapy be Implemented In a Cost-Effective Strategy?” Christoph Zielinski, Director, Clinical Division of Oncology and Chairman, Department of Medicine I, and Comprehensive Cancer Center, Medical University Vienna – General Hospital, Vienna, Austria, Central European Cooperative Oncology Group (CECOG) When talking about immunotherapy and its cost-effectiveness, the story of disharmony between the magnitude of clinical benefit and the cost-effectiveness of certain drugs clearly emerges. I will try to illustrate this by the following arguments and data: The total health care costs of cancer per person varies widely within EU countries not only concerning outpatient and primary care, but also inpatient care and particularly drug expenditures. Cancer drug-related health care costs, thus differ between less than € 10.- per person up to over € 50.- per person. This divergence has been described previously and put into context with cancer outcomes (1) as well as cancer-associated mortality (2). Therefore, the European Society for Medical Oncology decided to create a magnitude of clinical benefit scale (ESMO-MCBS) “in order to promote high quality, rational, responsible and affordable cancer care wanting to highlight treatments which bring substantial improvements to the duration of survival and/or the quality of life of cancer patients” (3). It was intended that the scale was used for accelerated reimbursement evaluation. Factors taken into account for the ESMO-MCBS were particularly overall survival and/or progression-free survival as assessed by hazard ratios, quality of life, toxicity of the compound in question and the prognosis of the individual condition. Costs were not analysed in view of their significant heterogeneity across Europe. While generating two different scales for the curative versus the non-curative setting, a couple of rules were followed regarding the performed analyses: the priority was a strong level of evidence from large phase III studies with a careful analysis of each control arm and the identification of endpoints. For the required HR, the lower limit of the 95% CI was used to take into account the variability of the estimate. Before being published, the scale and its outcomes were broadly tested and evaluated in and by various institutions. The first full-length field testing (FT-MCBS) of the ESMO-MCBS was published recently (4) in which the results of non-small cell lung cancer (NSCLC) corresponded well with the original ESMO-MCBS. Regarding the use of the immune checkpoint inhibitor Nivolumab, the FT-MCBS generated the highest grade (i.e. “5”) for squamous NSCLC according to data generated within the Checkmate 017-Trial whereas a grade “4” was given for non-squamous NSCLC, as assessed in the Checkmate 057-Trial. Thus, the immune checkpoint inhibitor Nivolumab has acquired the highest or almost highest degree in the magnitude of clinical benefit, as assessed by the FT-MCBS scale. Soon after market introduction, concerns about the financial toxic dose of immune checkpoint inhibitors emerged leading to the rejection of NICE of Nivolumab in the second-line-treatment of NSCLC, whereas – in contrast - the Scottish authorities decided to include Nivolumab into their reimbursement strategies. Very recent analyses on this very topic showed that Nivolumab was not cost effective versus Docetaxel in the second-line-treatment of NSCLC based upon data generated in Checkmate 057-Trial. However, cost effectiveness could be very well reached by including and stratifying patients according to PD-L1 testing and the use of Nivolumab in PD-L1 overexpressing tumors on one side or – in statistical models - by the reduction of drug costs on the other. Either of these strategies would improve the cost effectiveness of Nivolumab (5, 6) Scientifically, however, the doubt remains to linger whether PD-L1 would be an optimal biomarker resulting in appropriate decision making for the choice of compound optimally suitable for the treatment of NSCLC without unjustly excluding patients who might have benefitted due to other factors from treatment: Thus, it is well known that certain somatic mutations occur more frequently in very special tumors than in others (7). Along this line, the efficacy of Nivolumab correlated with higher non-synonymous mutation burden in the Checkmate 063-Trial population (8). Therefore, it seems correct to conclude that we still have a long way to go to fully understand biomarkers predictive for the outcome of an optimal treatment of NSCLC with immune checkpoint inhibitors. Accordingly, appropriate analyses necessary for biomarker identification might translate into cost effectiveness. Such analyses might result in a primarily increased diagnostic cost, but lead to an ameliorated patient selection and, thus, ameliorated cost effectiveness in the appropriate use of immune checkpoint inhibitor treatment in NSCLC. In the meantime, the scientific community remains fascinated by the insights and results which are generated by the use of these compounds in a variety of diseases including NSCLC. References 1. Jedrzejewski M. et al., The Oncologist 20: 28, 2015; 2. .Ades F. et al., Ann. Oncol. 24: 2897, 2013; 3. N.I. Cherny et al., Ann. Oncol. 26: 1547, 2015; 4. B. Kiesewetter et al., ESMO Open 1: e000066, 2016; 5. K. Matter-Walstra et al., J. Thoracic Oncol., 2016, ePub.: http://dx.doi.org/10.1016/j.jtho.2016.05.032; 6. P.N. Aguiar et al., J. Clin. Oncol. 34, abstr. 9033, 2016; 7. L.B. Alexandrov et al., Nature. 22: 415, 2013; 8. N.A. Rizvi et al., Science 2015, ePub.: pii:aaa1348

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Abstract:
Advances in modern technologies allows for an increasing opportunities in surgical and medical education. The main advantages for e-learning process are: accessibility and flexibility. A range of platforms offers educational programs accessible at work or home with total temporal and spatial freedom. Trainees are allowed to access their learning environment at a convenient time and relevant to their own training needs. Several techniques are available: web-based data, interactive online modules, and virtual reality. This is especially true within surgical training where the development of new techniques constantly evolves. The rapid and constant evolution in oncology knowledge’s makes it relevant for e-leaning process. E learning allows trainees to apply and be assessed on the new information in a safe setting. In addition, all contents can be discussed and debated around the medical world without any limits. The level of trainees recall can be significantly increased by e-learning techniques because it stimulates multi-sensory experiences. E learning offers also large possibilities for decision making based on available information and interactive decision-making process. Surgical e-learning programs include the development of knowledge, technical skills, non-technical skills and decision-making process. The content of all the e-learning modules should be relevant; best available, up to date and critically appraised evidence should supports the information contained within the modules. E-learning surgical programs should be based on an understanding of educational principles, peer review resources associated to creativity. It could be highly interactive. Immersive questions and answers for clinical setting permit to trainee to progress through scenarios and makes the relevant decisions and choices. Trainees have to evolve with their decisions and receive feedback as to the choices they have made. These interactive models can be created with text on the page or with simulators. E-learning modules should be used as a complementary tool to traditional learning methods. Authors will present their e-learning thoracic platform created at September 2013 : “Tenon Thoracic Institute“ (www.tenon-thoracic-institute).This e-leaning thoracic platform develops several e-learning tools: live from OR with interactive discussion with faculty, round table with exerts, didactic session for young trainees. All the aspects around thoracic pathology are treated: oncology, surgery, anaesthesiology, radiology, etc. Authors will discuss the relevance of such a platform, the lack of its content and future e-leaning projects.

Abstract:
The following is in part the STS, TSDA and AATS combined response to ACGME (collated and written up by Dr. Ara Vaporciyan) regarding the effect of Duty hour regulations on resident education in Thoracic Surgery in North America. A greater reliance on midlevel providers and physician extenders. This has impacted the profession in terms of additional cost from their much higher salaries, which are anywhere from 50% to 100% higher, but also a subtle but steady transfer of bedside teaching previously focused on the trainee to bedside teaching focused on the mid-level provider. Limited exposure to our field. Our profession still fills the bulk of its training position from general surgery graduates. Duty hour restrictions have contracted the ability of those programs to provide elective rotations in thoracic and cardiac. Limited exposure translates into limited interest and diminished applications. Quality of Surgical and postoperative teaching. This is where we have felt the greatest impact. We, like all surgical professions, have developed an increasing variety of procedures necessitating expansion of our case log requirements. This puts pressure on trainees to participate in every available case. Appropriate cases are harder to find due to increasing case complexity and outcome reporting. Therefore, the inability to scrub on just one or two of these cases can be significant. While some large surgery programs have implemented float pools to ensure that all cases provide someone a learning experience most CT training programs are small and cannot implement that solution Even more difficult to overcome is when a trainee misses a rare postoperative event. As a high acuity specialty our patients will frequently develop rapid changes in their condition which, if not recognized, can quickly become catastrophic. Most occur in the immediate postoperative period at night. The use of mid-level providers and other services to cover call in an effort to preserve a trainee’s ability to do cases the next day prevents them from taking part in the bedside assessment and management of these rare events. One solution is to lengthen training to allow more opportunities but there is concurrent pressure to reduce what is already one of the longest training paradigms (up to 9 years for congenital surgeons without considering any time for research). Alternatively simulation has been used but these are expensive and are not easily implemented at all programs.. Finally, issues of patient safety and outcomes. While there is no clear study demonstrating documented impact on patient safety there are many surveys of resident and faculty perceptions of patient safety. The majority of these, especially in surgery, have shown that the perception is that safety is compromised. The increased number of handoffs, especially of high acuity cases, is frequently the target of that perception. The subtle aspects of the intraoperative findings cannot always be accurately communicated in a handoff. While patient safety data is not conclusive there is data on worse outcomes in spinal and meningioma surgery post implementation of duty hour regulations. These data may serve to corroborate the perceived concerns.

Abstract:
Last decades have shown an impressive advance in terms of biological knowledge in cancer. Traditional way to bring new ideas/hypotesis into clinical trials was overcoming by this fact. New agents directed against specific molecular targets have important impact in terms of response rate (RR), response duration (RD), progression free survival and eventually overall survival (OS) as well as quality of life (QoL). If you have an interesting idea/hypotesis, today you have to take on account several points that can exclude it. Select population becomes a very important issue. How to do this? Selecting a target, a tumor, both, other conditions? Following the tradition of research phases, Phase I refers to measure safety and pharmacokinetics assesing maximum tolerated dose (MTD) but a number of new agents have a non reachable MTD because they have a low toxicity. On the other hand, phase II refers to the assesing of efficacy in a certain tumor as well as safety, but, in the case of new agents you may select a tumor (as ussual), a specific target no matter wath tumor carry it (basket), or other conditions. In this phase measurement of response is important as a precedent of next phase trials and the challenge is the method you will use to do it. New inmunotherapeutic agents probably need a different way to do this. Also, to have predictive biomarkers for most of these agent will help to select the potential population that will achieve the more benefit and avoid futile toxicity and a waste of time and resources. We have to remember that biological effects not always means clinical benefit. Breaking barriers, for phase III comparator selection, primary and secondary end points as well as inclusion and exclusion criteria become a very important point and are different in the traditional way and in a proposed new way. OS is the gold standard end point but there are many more very important like PFS, RR, DoR, QoL. Again, measurement methods are very important and may be different related with biological mechanism and length of response for different agents than chemotherapy. As phase III trials select (include and exclude) patients troughout very strict criteria and there are some late toxicities that can be as important as the acute and subacute toxicities, phase IV trials are very important because they represent better the daily patient we see at office practice and is a powerfull pharmacovigilance mechanism. Sanctuaries have to be consider as far as the prevalent tumors have a very frequent involvement of Central Nervous System and these patient are mostly excluded from clinical trials at the beggining. Ethics is a fundamental point as far as the most important objective is the patient safety and treatment accesibility. If we went troughout these restriction points and our idea/hypotesis has survive, we can follow the development of trials around wasting less time and resources.

Abstract:
Introduction: Published and officially approved medical research is based on evidence and subsequently, statistical methods are an essential part in proving the usefulness of results. The translation in statistical terms in most cases is to build hypotheses and their alternatives to be tested. Clearly, medical researchers need some sound understanding of statistical principles which can be taken, however, not as a matter of course. The aim of the contribution is to communicate among readers of medical journals and reports statistical matters focusing on basic statistical considerations to enable a better understanding. [1] Essentials of statistical analysis and reporting: (i) Making the information content of the research results visible in summarizing and prescinding them in tables, graphs, and figures. (ii) Assessing and quantifying any associations of reported measures like possible differences in the outcome of treatment actions etc., and using confidence intervals to express the uncertainty of those associations. (iii) Building hypotheses and their alternatives to prove that these associations have a real biomedical basis which is performed by statistical testing under a given level of significance (p-values). Important is the design of the research project: In randomized trials comparisons are an inherent part of those associations whereas in nonrandomized studies no direct conclusion can be driven that any association not due to chance indicates a causal relationship. Methods: Randomization is a process in which each of the patients has the same but not necessarily the equal chance to be assigned to predefined treatment arms ensuring that the treatment arms are comparable with respect to known or unknown risk factors. Hence, it is a method to remove selection and accidental bias and to guarantee the validity of statistical tests. Main design issues of studies are the formulation of the primary aim, the question of blinding, and the boundary conditions of sample size calculations. [2] Tables of baseline data and outcome events are part of most medical journal papers concerning treatments. Generally the first table displays the patients’ characteristics including some demographic variables and variables related to the primary aim. The main outcome events are forming the key table of every paper stratified by treatment groups. Categorical variables are shown as number and percent by group. Continuous variables can either be presented by mean and the standard deviation or by median and the interquartile range. Latter is preferred if the data are scattered and far from normal distribution with the implication that in the sequel non-parametric tests should be favored. For composite events like severe toxicities, progression of disease, and death the number of patients experiencing any of them plus the number in each component should be given, since we have the effect of multiple events. In focus are often variables displaying the time to the first event (e.g. progression of disease which can happen more than once during treatment history). For time driven events in the sequel analysis of general survival times are applied leading to special statistics and graphs. The Kaplan-Meier plot is the most used graph to show time-to-event outcomes as death, time to progression, disease free interval etc. In general the graph displays the steadily increasing difference in incidence rates of the outcome for two or more treatment arms. To make the process clearer, the numbers at risk in each group should be shown at regular time intervals in the time axis. Individuals who did not reach the endpoint are censored (e.g. still alive, lost to follow-up) and should be marked in the plot. The conditional probabilities of Kaplan-Meier statistics indicate the probability of experiencing the endpoint under consideration beyond a certain length of follow-up. Estimation of treatment effects is to measure the magnitude of the difference between treatments on patient outcomes. Normally this is done by a point estimate showing the actual difference observed. Inherent in this kind of statistics is that the bigger the trial, the more precise the point estimate will be. Such uncertainty is usually expressed by a 95% confidence interval in which this percentage of the sample will be found. The primary aim of the study determines the type of estimate required. Namely, there are three main types of outcomes: (a) Binary (dichotomous) response, e.g. dead or alive, progressive or non-progressive, success or failure, respectively. (b) Time to event outcome most measured in intervals, e.g. time from randomization to death, time of inclusion in the study to treatment failure. (c) Quantitative outcome as the reduction of a certain percentage of tumor loads at a given time point (e.g. a seen reduction of 30% after exactly 6 months). Estimates based in percentage are indicated if a binary outcome has to be judged in terms of absence or presence. Then a confidence interval of the proportion of interest can be given. Relative risks are the ratio of two percentages and can be converted to relative risk reduction. Alternatively relative odds can be applied which is a cross-product relationship and shows the relation of chance. Relative risk and relative odds are sometimes called risk ratio and odds ratio instead. The absolute difference in percentage is taken as a measure of absolute risk reduction. Estimates for time-to-event outcomes are used in all survival statistics as time to death, time to progression etc. The Kaplan-Meier plot depicts the first time of the occurrence of the event but does not in itself provide a simple estimate summarizing the treatment difference. The Kaplan-Meier estimate at the end of plotted time or at any other time between can be taken as cumulative rate of the leading event. That is only a time point estimate. Instead, the most common approach is to use a Cox proportional hazards model to obtain a hazard ratio and its 95% confidence interval. The hazard ratio can be thought of as the hazard rate in one group divided by the hazard rate in the other group averaged over the whole follow-up period. Examples from medical trials will be used to explain the statistical principles shown here. References [1] Pocock SJ, McMurray JJV, and Collier TJ: Making sense of statistics in clinical trial reports. J Am Coll Cardiol 2015; 66(23):2648-2662. [2] Pilz LR, Manegold C: Endpoints in lung cancer trials: Today's challenges for clinical statistics. MEMO 2013; 6(2): 92-97.

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Clinical trials in cancer have typically investigated agents or regimens in selected groups of patients based primarily on histology and clinical characteristics (e.g., tumor stage, performance status, prior treatment, etc). The major goal of those trials was to demonstrate statistically significant improvement in outcome with minimum p-value of 0.05, as compared with the control arm. In the majority of cases, this approach resulted in only small incremental improvements in overall survival. In some cases, even without any improvement in survival, a certain regimen became the foundation for adding novel targeted agents only based on the favorable toxicity profile and has been widely used in practice over the last two decades. More recently, targeted therapies administered to patients with biologically relevant biomarkers, such as activating EGFR mutations and ALK alternation, have produced substantial improvements in outcomes and rapidly changed the treatment paradigm of lung cancer. In addition, newer treatment modalities such as immune check-point inhibitors and antibody-drug conjugates are emerging as highly effective therapies that are providing improvements in patient outcome. In fact, between 2004 and 2015, 14 new drugs were approved by the FDA for NSCLC. However, the relevance of statistical significance has increasingly been challenged when the treatment effect is small. [1,2] To resolve this issue, there has been growing consensus to raise the bar of efficacy for approving new cancer drugs.[3,4] The critical question is what is clinically meaningful and how can this outcome be measured. The FDA considered OS to be the standard clinical benefit endpoint that should be used to establish efficacy of a treatment in patients with locally advanced or metastatic NSCLC.[5] The FDA also has recognized that PFS may be appropriate as the primary endpoint to establish efficacy for drug approval if the trial is designed to demonstrate a large magnitude for the treatment effect as measured by both the hazard ratio and absolute difference in median PFS and an acceptable risk-benefit profile of the drug is demonstrated. The remaining question is, “What is clinically meaningful?” Modest benefits could be considered worthwhile if associated with moderate costs and toxicity, whereas a new drug with a very high cost and/or substantial toxicity is worthwhile only if it produces sizeable clinical benefits. To address this issue, the ASCO Cancer Research Committee convened four disease-specific working groups, including the lung cancer working group. The Committee generally agreed that relative improvements in median OS of at least 20% are necessary to define a clinically meaningful improvement in outcome.[3] For lung cancer, it was recommended that one experimental agent in non-squamous NSCLC should be considered practice changing if it increases PFS by at least 4 months and OS by 3.5-4 months with a corresponding death risk reduction of 20-24%. Due to less favorable prognosis, the desired benefit in squamous NSCLC was 3 months increase in PFS and 2.5-3 months increase in OS with a death risk reduction of 20-23%.[3] Obviously, if a new treatment is to be introduced into clinical practice, it is not sufficient to demonstrate that it is "better than” or “non- interior to” the standard therapy. As cancer care costs continue to increase at an unsustainable rate, oncology professionals need to focus more on delivering value-based patient care rather than simply practicing evidence-based patient care. In addition, it has become increasingly clear that the traditional fee-for-service model will no longer serve the interest of all the parties involved, including the pharmaceutical company.[6] It seems to be a matter of time that the fee-for-service system will be replaced with the value-based reimbursement system. Reference 1. Sobrero A, Bruzzi P. Incremental advance or seismic shift? the need to raise the bar of efficacy for drug approval. J Clin Oncol 2009;27:5868–73. 2. Ocana A, Tannock IF. When are "positive" clinical trials in oncology truly positive? J Natl Cancer Inst 2011;103:16–20. 3. Ellis LM, Bernstein DS, Voest EE, Berlin JD, Sargent DJ, Cortazar P, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol 2014;32:1277–80. 4. Sobrero AF, Pastorino A, Sargent DJ, Bruzzi P. Raising the bar for antineoplastic agents: How to choose threshold values for superiority trials in advanced solid tumors. Clin Cancer Res. 2015;21:1036-43. 5. United States, Department of Health and Human Services, Food and Drug Administration (FDA). Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics Guidance for Industry (published April 2015) : Available online: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM259421.pdf, 2015. 6. Eaton KD, Jagels B, Martins RG. Value-based care in lung cancer. Oncologist. 2016;21:903-6.

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Abstract:
Expectations from a Young Investigator Over the last two decades, research has pushed lung cancer investigations from the shallows of cancer treatment to one of the most innovative positions in oncology. The improvements in molecular diagnostics, in targeted therapy and immunotherapy with the linked creeping decline of traditional chemotherapy act as a model for many other tumor entities. Joined by this paradigm shift is a demographic change to young investigators who start their career in the innovative fields of lung cancer research instead of thinking in the traditional chemotherapy-based fashion. Nevertheless, in order to detect the needs and expectations from young investigators, even the definition of "young" is hard to handle, and subjective expectations might be biased by the socioeconomic background of the investigator. We therefore set out to find a way to present more robust and reliable data on the topic. We created an online questionnaire covering age, experiences, interests, and of course needs and expectations of young investigators. The expectations focus on research topics, treatment options, mentorships and social networking. The questionnaire will be forwarded to 20 investigators in the EU, Asia, South America and the US with link to the emerging fields of lung cancer research, in order to forward it to participants who they consider young in both clinical and preclinical investigations. For subgroup analyses, we will include students with interest in this field, too. Results will be analyzed by the presenters. The poll will be open until one week of the WCLCs Young Investigator's Scientific Mentoring Session, and results of this interim analysis will be presented by this talk. Nevertheless, all participants of the WCLC 2016 are invited to answer the questionnaire during the Conference, and a final data cut will be made at December 10th, 2016. We are aware of the potential biases in online polls. A valid e-mail address and the source of the online link (i. e., who was the "supervisor") are necessary. As an incentive to participate properly, we offer all participants to be part of the "WCLC young Investigator Expectations Network (WIEN)" which will coauthor the final manuscript. As we question the expectations of how lung cancer research will work in five years, it is intended to repeat the poll in a regular manner, maybe yearly. We expect a view on the expectations from young investigators worldwide and a feeling of their needs for the future.

Abstract:
All oncologists are part of the mentor-mentee relationship at some point of their career. Mentoring can be considered one of the critical factors in achieving a successful career. The importance of a good mentor is best described by the sentence of Robert S.Kerbel: “I have been extremely fortunate if not blessed, with having series of outstanding mentors [1].” In spite of the importance of mentoring, what makes good mentors and mentoring is often not well defined [2]. According to Nature’s guide for mentors, one of the most important characteristics of a good mentor is his/her orientation towards mentee’s long-term career development as a main focus of mentoring. In this way, the mentor becomes a “mentor for life” and not only temporary supervisor [2]. According to mentees, a good mentor has some distinct personal characteristics like enthusiasm, passion, positivity, compassion and understanding. Beside these, some others like appreciating individual differences, being respectful and unselfish are also very important. To properly advise and guide mentees in their work, mentors should be able to see their individual characteristics and support their personal strengths. Showing respect means that the protégée is not only seen as an workforce, but also as a genuine collaborator. Regarding unselfishness: letting the mentee be the first author of a common article, even if the mentor provided the initial idea is a good example [2]. Personal characteristics aside, abilities to become a good mentor can be gained by following some useful rules. Mentors should be generally available and have an “open door” policy instead of restricted and limited dedicated time. Availability should also be shown by quickly answering e-mails and phones calls. They should be inspirational and show optimism on every-day issues but – even more importantly - when facing failure. Mentors should find a balance between doing and letting do, should support mentees in analytical thinking and adapt to their needs according to the progress of the protégée (e.g. different mentoring at the beginning and the end of the PhD course). They should celebrate successes with the mentee [2, 3]. Scientific mentors have the obligation to teach, encourage and support students in some specific activities in which skills are essential in the world of science. Examples are writing and oral presentations. Supporting writing with fast and accurate reviews, while resisting the temptation of rewriting instead of the student is one of the main goals. Extensive mentoring regarding oral presentations is also needed due to the fact, that not many students have a natural gift for presenting. Mentors should also try to provide as many opportunities for oral presentations as possible. Involving students in mentors’ networking should also be a continuous process [2]. How to choose a good mentor is a question that should be carefully addressed. In selecting mentors, trainees should follow some recommendations. They should look for possible mentors online, see which mentors possibly have the same interests, e-mail previous mentees inquiring about their experience with the mentor and afterwards meet the potential mentor in person at work. Trainees should carefully look for signs of poor mentorship, like no available time for one-to-one conversation, repressed and stressed co-workers that show no respect for their head, the potential mentor [2, 4]. Even if some trials report objective data, evaluating mentorships can be challenging since it is a complex interpersonal interaction. In a trial reported by Badawi the majority (74%) of mentors and mentees report the experience as rewarding, worth their time and effort, many (58%) achieve their goals in a timely manner and plan to continue (89%) their collaboration after the mentorship period is finished [5]. High satisfaction with the mentorship experience is commonly reported in other surveys. DeCastro conducted a trial on 1708 clinicians-researchers and only 10% of them were not satisfied with the experience, without differences between male and female mentees [6]. Some surveys, like the one reported by Dhami, show the importance of formal mentorship. Satisfaction with the mentorship experience was greater in mentees included in formal mentorship compared to those who had an informal one (72% vs. 36%, p<0.01) [7]. Formal mentoring influences also on research productivity. In the survey of Riechelman, responders with mentors were more involved (more available time dedicated) in academic research compared to those without mentors [8]. A model mentor is involved in the fruitful career development of the mentee and broadly shares the knowledge, skills and expertise that the mentee needs. As the mentee advances and gains independence, a good mentor is able to guide him/her toward new opportunities and facilitates the mentee’s growth [9]. 1. Kerbel, R.S., Some guidelines for building a successful career in cancer research. Cancer Biol Ther, 2003. 2(1): p. 111-4. 2. Lee, A., C. Dennis, and P. Campbell, Nature's guide for mentors. Nature, 2007. 447(7146): p. 791-7. 3. Powers, P.J., Engaged mentors offer inspiration and open doors. Am J Med, 2006. 119(1): p. 3. 4. Purcell, E.P., et al., Research to reality (R2R) mentorship program: building partnership, capacity, and evidence. Health Promot Pract, 2013. 14(3): p. 321-7. 5. Badawy, S.M., et al., Early career mentoring through the American Society of Pediatric Hematology/Oncology: Lessons learned from a pilot program. Pediatr Blood Cancer, 2016. 6. DeCastro, R., et al., Mentoring and the career satisfaction of male and female academic medical faculty. Acad Med, 2014. 89(2): p. 301-11. 7. Dhami, G., et al., Mentorship Programs in Radiation Oncology Residency Training Programs: A Critical Unmet Need. Int J Radiat Oncol Biol Phys, 2016. 94(1): p. 27-30. 8. Riechelmann, R.P., et al., The influence of mentorship on research productivity in oncology. Am J Clin Oncol, 2007. 30(5): p. 549-55. 9. Gitlin, S.D. and M.L. Lypson, For Residents and Fellows: What to Look for in a Laboratory Research Mentor. J Cancer Educ, 2015.

Abstract not provided