Virtual Library

Abstract not provided

Abstract not provided

Abstract:
The suitable characteristics of the carcinoma for definitive radiotherapy (RT) are that (a) involved areas of the disease can be covered by adequate planning target volume (PTV), and that (b) the tumor cells can be sterilized with under tolerable doses for the surrounding normal tissues. Among non-small cell lung cancer (NSCLC), squamous cell carcinoma (SQ) has the characteristics to grow locally, to spread proximally along the trachea-bronchial trees and to develop regional nodal metastases. In SQ, furthermore, surgical resection is well known to be effective even for locally advanced disease. On the other hand, non-SQ has the tendency to develop distant metastases at early T-stage. In a randomized controlled trial comparing continuous, hyperfractionated, accelerated radiotherapy (CHART) (54Gy/36fr in 12 consecutive days) with conventional RT (60Gy/30fr in 6 weeks), the SQ patients had absolute advantages of CHART in both local progression-free survival (LPFS) and overall survival (OS). Therefore, SQ is considered to be a good candidate for intensive loco-regional treatment. In RTOG 0617 trial of standard-dose versus high-dose conformal RT with concurrent and consolidation carboplatin + paclitaxel with or without cetuximab for patients with stage IIIA/B NSCLC, an EGFR H-score less than 200 (low EGFR expression) was noted more commonly in non-SQ patients whereas an EGFR H score of 200 or more (EGFR-overexpression) was more common in SQ patients (p=0.0003). In patients with an H score of 200 or higher, median OS for the cetuximab group was 42.0 months (95% CI 20.6–not reached) versus 21.2 months (17.2–29.2) for the no-cetuximab group. These results suggested that SQ patients might benefit from the addition of cetuximab to chemoradiation like SQ of the head and neck. Furthermore, on phase II study of nimotuzumab in combination with concurrent chemoradiotherapy for Japanese patients with locally advanced NSCLC, the LPFS was significantly better for SQ patients than for non-SQ patients. The results also suggested that the low in-field relapse rates might be attributed to the radio-sensitizing effect of nimotuzumab and contribute to the improved OS of SQ patients. By contrast, non-SQ patients did not benefit from nimotuzumab because the distant relapse rate was significantly higher for non-SQ than that for SQ. In non-SQ histology, EGFR mutations are well known to often appear especially in adenocarcinoma. Some clinical trials of EGFR-TKI combined with standard platinum-based chemoradiotherapy for EGFR-mutant locally advanced NSCLC are ongoing in Japan. In the future direction, the locally intensified chemoradiotherapy using high-precision RT techniques and advanced radiation sensitizers including molecular targeting drugs may be more important for SQ and newly developed systemic therapies with powers of sterilizing subclinical distant metastases may be more effective for non-SQ among locally advanced NSCLC.

Abstract:
Introduction: Recently, systemic approaches to inperable non-small-cell lung cancer (NSCLC) in stage IV disease have been significantly improved by the introduction of a new treatment modality: immunotherapy with PD-1 antibodies. Currently, nivolumab is registered for the second-line therapy of NSCLC without prerequisite of PD-L1 expression in tumor tissue. Pembrolizumab has been registered for PD-L1 positive (> or = 1% TPS) patients in second-line and for high expressors (> or = 50% TPS) also in the first-line setting. In some countries already platinum-based combination chemotherapy (CTx) plus pembrolizumab is accepted for first-line therapy of medium expressors (1-49% TPS) and also for high expressors. Other PD-L1 antibodies have already achieved positive phase-III results (atezolizumab) or large phase-III trials have finished accrual and final results are awaited (eg. durvalumab). Based on these paradigms, the rationale for combinations with radiotherapy (RTx) in NSCLC is analyzed and trial design of currently ongoing studies as well as reported signals of first results are summarized. Material and Methods: Clinicaltrials.gov has been searched for ongoing and active clinical trials with immmunotherapy and RTx. We divided NSCLC strategies into a) locally advanced and inoperable NSCLC stage III b) advanced and inoperable stage IV NSCLC (episcopal effect) c) combinations of immunotherapy and stereotactic RTx in early disease NSCLC d) oligometastatic disease. Results: a) introduction of PD-1 antibodies into treatment strategies of inoperable stage III NSCLC will get a significant booster efffect by the recently reported outcome signals of the Pacific Trial looking at durvalumab consolidation therapy versus placebo following concurrent CTx/RTx in stage III NSCLC (press release, AZ, May 2017). PFS was signifcantly longer for the administration of durvalumab as maintenance in this situation. We expect presentation of the final results at an important Lung Cancer conference during this fall. Theroretically, intoduction by DNA double-strand breaks in patients following concurrent CTx/RTx or RTx alone could lead to an increase in tumor mutational load and could potentially enhance the efficacy of any PD-1- or PD-L1-antibody therapy. A consolidation therapy of PD-1-antibody treatment following concurrent chemoradiotherapy aiming at cure was found to be a rational strategy to improve long-term survival results in inoperable stage III NSCLC. Other trials ongoing are looking at combinations of RTx with concurrent PD-1 immunotherapy or concurrent CTx/RTx combined with concurrent adminstration of PD-1 antibody therapy.Trials outlines will be summarized and presented. Only one phase-II study including pembrolizumab has maintenenance has already been presented with ist results at ASCO 2017. Treatement was manageable and toxicity acceptable. First signals shown efficacy of this strategy but final survival data are pending. Other clincial trials are currently also looking at combinations of CTx and PD-1-immunotherapy and concurrent RTx. Also other immunotherapy drugs such as CTLA4-antibodies or combinations of both PD-1(eg. nivolumab, pembrolizumab, atezolizumab, durvalumab) and CTLA4-antibodies (ipilimumab, tremelimumab) are also being investigated in stage III NSCLC. b) few trials are also looking to enhance systemic effects of immunotherapy (PD-1/PD-L1 and CTLA-4) and concurrent RTx of tumor lesions. The so called "episcopal effect" is being investigated within several clinical studies. Theoretically, the release of tumor associated antigens (TAA) by RTx given to specific tumor lesions leading to tumor lysis including the release of antigens into the circulation could potentially enhance the systemic immunological effects of checkpoint-inhibitor therapies. Well-selected case reports have given hints to support such thesis but only randomized trials will finally verify if this approach is really valid and worthwhile. c) the stereotactic and, therefore, locally ablative RTx techniques also aiming at early inoperable NSCLC patients could also potentially benefit from combinations with new immunotherapy. Several trials are underway for combinations with nivolumab, pembrolizumab, atezolizumab and durvalumab. Finally, for all mentioned treatment strategies concurrent versus sequential administration of immunotherapy and RTx is a complete open issue. Also, permutations including combinations together with platinum-based CTx and immunotherapy together with RTx have recently become very attractive. d) Last but not least, the patient group of oligometastatic patients (M1a, M1b, M1c with less than four lesions in one organ, eg. brain) seems to be a very interesting group of patients to increase both local as well as systemic control of the treatment. Conclusions: Consolidation durvalumab may potentially become the first strategy to become a new paradigm of treatment for stage III NSCLC. We will have to wait for the final results of that trial to draw more valid conclusions for future treatment strategies. However, based on the inclusion of new immunotherapy with checkpoint inhibitors already into the standard treatment algorithms of stage IV disease in NSCLC it can be predicted that also in other disease settings these innovative approches may finally extend our potential treatment options - at least for well selected patient subsets. Referrences: Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2. Rizvi NA, Mazières J, Planchard D,et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Mar;16(3):257-65. doi: 10.1016/S1470-2045(15)70054-9. Epub 2015 Feb 20. 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 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31. 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 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. doi: 10.1056/NEJMoa1501824. Epub 2015 Apr 19. 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 Apr 9;387(10027):1540-50. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. doi: 10.1016/S0140-6736(16)32517-X. Epub 2016 Dec 13. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. Hellmann MD, Rizvi NA, Goldman JW,et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017 Jan;18(1):31-41. doi: 10.1016/S1470-2045(16)30624-6. Epub 2016 Dec 5. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3. Epub 2016 Oct 10. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015 Apr 3;348(6230):124-8. doi: 10.1126/science.aaa1348. Epub 2015 Mar 12. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2017/imfinzi-significantly-reduces-the-risk-of-disease-worsening-or-death-in-the-phase-iii-pacific-trial-for-stage-iii-unresectable-lung-cancer-12052017.html

Abstract:
Chemotherapy combined with radiation therapy has become standard treatment for inoperable non-small cell lung cancer (NSCLC). The combination was first proposed in the 1970s. Although induction (neoadjuvant) chemotherapy followed by radiation therapy was initially considered preferable owing to concerns about toxicity, it eventually became clear that concurrent treatment was more effective. Similarly, low-dose radiation therapy was thought to be the safest, and radiation oncologists were loath to use any dose/fractionation regimen that exceeded standard approaches with radiation therapy alone. Chemotherapy evolved in a similar fashion. At first, single agents were used, followed by tests of various combinations of different drugs, with eventual acceptance of 2-drug combination regimens, usually consisting of a platinum compound with another agent. These regimens were combined with standard radiation therapy, usually to a dose of 60 Gy in 30 fractions using three-dimensional conformal radiation therapy (3D CRT), planned on the basis of computed tomography (CT); this combination produced tolerable adverse effect profiles that were less severe than those after the previous standard of 2D treatments based on plane radiography. The next iteration of external-beam radiation therapy was intensity-modulated radiation therapy (IMRT), which involves directing multiple beamlets at the tumor while limiting the doses to surrounding critical structures. IMRT, which depends on CT imaging for staging and treatment planning, also allowed higher fraction sizes and total doses to be tested in attempts to increase tumor control. However, use of higher total doses has had potentially intimidating results in clinical trials. In a recent prospective clinical trial of the Radiation Therapy Oncology Group (RTOG 0617) in which standard-dose 60 Gy in 30 fractions given over 6 weeks was compared with high-dose 74 Gy in 37 fractions over 7 1/2 weeks, the higher total dose actually led to poorer local control. It has been hypothesized that failure to adequately cover the gross tumor volume in the high-dose arm resulted in the higher local failure rate. For small (T1 or T2) tumors of the lung, investigators have tested very-high-dose treatments based on 3D targeting of every fraction, an approach that requires 3D imaging capability. In the United States, achieving such precise targeting has required collaborations with medical physicists in the delivery of each fraction. The next generation of radiation therapy, stereotactic body radiation therapy or SBRT, began as a treatment for lesions in the brain. In Sweden, Leksell and colleagues developed an approach that came to be known as stereotactic radiation therapy. Considered an alternative to surgical resection, stereotactic radiation therapy was predicated on immobilizing the patient with a stereotaxic frame, using multiple cobalt-60 sources in a helmet-like configuration, and administering the radiation in a single fraction. Because the goal of this approach was controlled necrosis rather than a surgical defect, this approach also came to be known as stereotactic radiosurgery. Approximately 25 years later, a similar approach was developed in which linear accelerators were used to deliver SBRT. Similar principles were used: precise imaging with of the tumor with CT and, more recently, with fluorodeoxyglucose positron emission tomography; careful and secure immobilization with various body frames; management of respiratory motion for lesions in the thorax; intensity-modulated treatment planning; and image-guided targeting. From 1 to 5 or even 10 fractions are delivered in this manner, with both the treating physician and collaborating physicist attending each treatment to ensure consistent image guidance. This approach allows the delivery of very high biological doses. SBRT has been shown to result in local control rates of 85% to 95% for tumors up to 4 cm in diameter. Proton beam therapy is the latest means to control NSCLC, particularly for tumors that are larger than the T1 or T2 tumors usually treated with SBRT. Protons differ from photons in their interactions with tissues in the body; protons are heavy particles that produce different ionization tracks and deposit most of their energy at the end of their range. Where they come to a stop is a function of their energy when they enter the body. Protons have lower energy than photons until they reach their prescribed depth, at which point they produce a peak of ionizations, the Bragg peak. This Bragg peak can be spread out to cover the tumor in depth, and the beam can be shaped in the other two dimensions by electronic or physical means to achieve a high-dose volume that has the same size and shape of the tumor. Properly directed proton therapy essentially delivers no dose beyond the gross tumor volume. The relative biologically effective dose (RBE) of proton beam therapy is approximately the same as that of x-rays, so the effects of the doses in the tumor and the surrounding normal tissues (organs at risk) are well understood. Proton beam therapy and chemotherapy interact in predictable ways, and so the toxicity patterns are similar to those with chemotherapy and photons. However, proton therapy seems to have less severe effects on blood counts. In clinical trials to date, whether with IMRT, SBRT, or protons, the greatest need seems to be to enhance the effectiveness of the systemic treatment. Considerable interest has been expressed in combining each of these radiation delivery methods with immunotherapy. The occurrence of an occasional abscopal effect with radiation therapy has given rise to cautious enthusiasm for further exploration of this area.

Abstract not provided

Abstract:
Antigen-specific immunotherapy or cancer vaccination has been studied in several large phase III trials in NSCLC in different stages [1]. Agents consisted of two major components: immunogenic tumor-associated antigens, combined with a strong adjuvant to generate the tumor directed attack. Overall, the results of these trials have been disappointing. One of these phase III trials was MAGRIT, the largest therapeutic clinical trial ever performed in NSCLC. The MAGRIT trial (MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy[2]. Other major trials in this setting, such as RADIANT, studying adjuvant erlotinib [3], and ECOG 1505, studying the addition of bevacizumab cisplatin-based adjuvant chemotherapy [4], proved to be negative. As adjuvant cisplatin-based chemotherapy can be hard to tolerate for many patients [5], a less toxic and effective therapy to improve the outcome in this group was of great interest. Melanoma associated antigen (MAGE)-A3 was an interesting target because it is almost exclusively expressed on tumor cells, and not expressed in normal tissue (except in male germline cells, which however do not present the antigen). The MAGE-A3 vaccine was a recombinant protein antigen-based vaccine, containing the recombinant fusion protein (MAGE-A3 and protein D of Haemophilus Influenzae) in combination with an immune response enhancing adjuvant. Clear responses to this compound had been noted in early experience in patients with metastatic melanoma [6]. For NSCLC, the proof of concept study was a double-blind, placebo-controlled, randomized phase II trial [7]. Patients with completely resected MAGE-A3-positive stage IB-II NSCLC were randomly assigned to either MAGE-A3 vaccine (N=122) or placebo (N=60), 5 administrations q3 weeks followed by 8 administrations q3 months. No adjuvant chemotherapy was given, as this therapy was not established in the study interval. Disease-free interval (DFI) was the primary endpoint. After a median post-resection period of 70 months, there was a trend in favor of MAGE-A3, with a Hazard Ratio (HR) for DFI 0.78 (95%CI 0.49-1.24; two-sided P=0.295). No significant toxicity was observed, resulting in very high therapy compliance. Furthermore, a possible gene signature (GS), predictive of clinical activity of the MAGE-A3 vaccine in previous metastatic melanoma experience [6], could be validated in early-stage NSCLC [8]. Actively treated GS-positive NSCLC patients showed a favorable DFI compared with placebo-treated (HR 0.42, 95% CI 0.17-1.03; P=0.06), whereas among GS-negative patients, no such difference was found (HR 1.17, 95% CI 0.59-2.31; P=0.65). This led to the large double-blind, randomized, placebo-controlled phase III trial MAGRIT (ClinicalTrials.gov, number NCT00480025) [9]. MAGE-A3 positive patients with completely resected stage IB, II or IIIA NSCLC, and adjuvant chemotherapy as clinically indicated, were 2:1 randomly assigned to the MAGE-A3 vaccine or placebo. Randomization and treatment allocation was done centrally via internet with stratification for chemotherapy versus no chemotherapy. A minimization algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. Between Oct 18, 2007, and July 17, 2012, a total of 13,849 surgical patients in 443 centers in 34 countries were screened for MAGE-A3 expression, 4210 had MAGE-A3 expression, and 2,272 were treated (active vaccine 1,515; placebo 757). 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. At the time of the report, median follow-up was 38.1 months in the MAGE-A3 group and 39.5 months in the placebo group. In the overall population, median disease-free survival (DFS) was 60.5 months (95% CI 57.2–not reached) in the MAGE-A3 vaccine group and 57.9 months (55.7–not reached) in the placebo group (hazard ratio 1.02, 95% CI 0.89–1.18; P=0·74). In the predefined subgroup patients who did not receive chemotherapy, median DFS was 58.0 months (95% CI 56·6–not reached) in the MAGE-A3 group and 56.9 months (44.4–not reached) in the placebo group (hazard ratio 0.97, 95% CI 0.80–1.18; p=0·76). Because of the absence of treatment effect, the predictive gene signature could not be further studied. The frequency of grade 3 or worse adverse events was similar: 246/1515 (16%) in the MAGE-A3 group and 122/757 (16%) in the placebo group. It was concluded that adjuvant treatment with the MAGE-A3 vaccine did not increase DFS compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC, and the further development of the MAGE-A3 vaccine for NSCLC was stopped. REFRERENCES 1. Decoster L, Wauters I, Vansteenkiste J. Vaccination therapy for non-small cell lung cancer: Review of agents in phase III development. Ann Oncol 2012; 23: 1387-1393. 2. The International Adjuvant Lung Cancer Trial Collaborative Group, Arriagada R, Bergman B et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004; 350: 351-360. 3. Kelly K, Altorki NK, Eberhardt WE et al. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small cell lung cancer (RADIANT): A randomized, double-blind, phase III trial. J Clin Oncol 2015; 33: 4007-4014. 4. Wakelee HA, Dahlberg SE, Keller SM et al. Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non-small cell lung cancer (NSCLC): Results of E1505. J Thorac Oncol 2015; 10 Suppl 2: 66S. 5. Alam N, Shepherd FA, Winton T et al. Compliance with post-operative adjuvant chemotherapy in non-small cell lung cancer. An analysis of National Cancer Institute of Canada and intergroup trial JBR.10 and a review of the literature. Lung Cancer 2005; 47: 385-394. 6. Kruit WH, Suciu S, Dreno B et al. Selection of immunostimulant AS15 for active immunization with MAGE-A3 protein: Results of a randomized phase II study of the European Organisation for Research and Treatment of Cancer melanoma group in metastatic melanoma. J Clin Oncol 2013; 31: 2413-2420. 7. Vansteenkiste J, Zielinski M, Linder A et al. Adjuvant MAGE-A3 immunotherapy in resected non-small cell lung cancer: Phase II randomized study results. J Clin Oncol 2013; 31: 2396-2403. 8. Ulloa-Montoya F, Louahed J, Dizier B et al. Predictive gene signature in MAGEA3 antigen-specific cancer immunotherapy. J Clin Oncol 2013; 31: 2388-2395. 9. Vansteenkiste JF, Cho BC, Vanakesa T et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; 17: 822-835.

Abstract:

Abstract:
A well-known mechanism of resistance to EGFR-TKIs is MET upregulation. MET inhibitors were developed to overcome and prevent this resistance mechanism. Onartuzumab is a monoclonal antibody that binds the extracellular domain of MET. By blocking the interaction with its HGF ligand, activation of the MET signaling pathway does not occur and tumor growth is halted. The clinical evaluation of onartuzumab followed the traditional phase I, II and III registration pathway. In the randomized Phase II trial of erlotinib and placebo versus erlotinib and onartuzumab the trial failed to meet the co-primary endpoint of PFS in the intent to treat population but was positive for the co-primary endpoint of PFS in 66 patients with MET positive tumors defined as IHC > 2+ expression (HR, .53; P .04) (1). Overall survival was also significant (HR, .37; P .002). Objective response rate (ORR) was reported as 8.6% and 3.2% for onartuzumab versus placebo, respectively. Based on these results a randomized placebo controlled phase III trial was launched in patients with MET expressing tumors (2). Surprisingly this trial did not meet its OS primary endpoint and numerically favored the placebo arm. A total of 499 patients were enrolled. The median OS was 6.8 months for onartuzumab versus 9.1 months for placebo (HR, 1.27; 95% CI, 0.98 to 1.65; P = .067). Median progression-free survival was 2.7 months versus 2.6 months (HR, 0.99; 95% CI, 0.81 to 1.20; P = .92) and the ORR was 8.4% compared with 9.6% respectively. When a trial is negative scrutinizing all aspects of the trial and its predecessor trial to determine if there were instructive signals is needed. In this case, reported patient characteristics were similar between the two trials but other patient variables such as the frequency of patients with brain metastases, sites of metastases, and time from previous therapy were not provided. However a large magnitude of difference would be required to significantly alter the results which is unlikely. Adverse events profiles were unrevealing. There were differences related to the MET biomarker that may have influenced the phase III results. In the phase II trial MET IHC expression was retrospectively determined compared to its prospective determination in the phase III trial and its use as a stratification factor. Although the frequency of MET 2+ versus 3+ IHC expression was similar in the two trials, the retrospective nature of the analysis in the phase II trial with its inherent imbalance in patient characteristics may have been misleading especially in the context of the small sample size. Had this been a randomized biomarker selected Phase II trial with a larger sample size we might have seen a different outcome. The assay itself was not a factor. Rigorous validation of the MET IHC assay was conducted. The assay was performed at Genentech for the phase II study and these investigators carefully trained the central laboratories personnel performing the assay for the phase III trial. A robust quality check and audit program was followed. A frequently asked question is whether IHC accurately characterize drivers of MET dysregulation that would result in EGFR tyrosine kinase inhibitor (TKI) resistance and onartuzumab responsiveness. In an exploratory biomarker analysis from the Phase II study MET IHC remained the most robust predictor of efficacy for the combination (3). In the phase III trial a detailed EGFR and MET pathway analysis that included MET and EGFR FISH, EGFR amplification and EGFR, KRAS BRAF, PIK3CA mutational analysis failed to find a biological explanation for onartuzumab inactivity (3). An analysis of MET Exon 14 splicing mutations was not conducted because these mutations had not been discovered at the time of study conduct. Although it would be intriguing to know the frequency of these mutations and their association to onartuzumab activity this is unlikely to be performed. The subgroup results supported further investigation of onartuzumab in a MET positive population but the results were modest. The statistically significant 1.4 month improvement in median PFS is not clinically significant and objective response rates were similar between the arms. Driving the phase III design was the impressive 8.8 month improvement in median OS for the combination but without strong efficacy signals in ORR and PFS to account for this survival outcome suggests other factors were at play such as subsequent therapies and warrants caution. The dilemma with encouraging preliminary data is what is the optimal next study design especially in this instance where the findings were modest? Too many times we have seen positive phase II trials lead to negative phase III results. While a phase III trial is the quickest route to a definitive answer it is done at the price of hundreds of patients. This is particularly highlighted by this study where the combination was approaching an inferior overall survival. Alternative design strategies such as a randomized Phase II/III design that can better balance benefit and risk for our patients and still achieve the goal should be considered. Criteria should be established to help investigators select the appropriate design. References 1. Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH Jr, Blumenschein GR Jr, Krzakowski MJ, Robinet G, Godbert B, Barlesi F, Govindan R, Patel T, Orlov SV, Wertheim MS, Yu W, Zha J, Yauch RL, Patel PH, Phan SC, Peterson AC. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2013, 31:4105-14. 2. Spigel DR, Edelman MJ, O'Byrne K, Paz-Ares L, Mocci S, Phan S, Shames DS, Smith D, Yu W, Paton VE, Mok T. Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non-Small-Cell Lung Cancer: METLung. J Clin Oncol. 2017, 35:412-20. 3. Koeppen H, Yu W, Zha J, Pandita A, Penuel E, Rangell L, Raja R, Mohan S, Patel R, Desai R, Fu L, Do A, Parab V, Xia X, Januario T, Louie SG, Filvaroff E, Shames DS, Wistuba I, Lipkind M, Huang J, Lazarov M, Ramakrishnan V, Amler L, Phan SC, Patel P, Peterson A, Yauch RL. Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib±onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin Cancer Res. 2014, 20:4488-98.

Abstract not provided

Abstract:
In this talk I will cover reasons why phase III trials are "negative" and what can be done to increase the rate of true positive results. Reasons for failure in phase III include inactive agents, poor statistical design, and inadequate implementation. With targeted agents including immunotherapy, additional issues of statistical design arise, as well as assay reliability. I will review the trials discussed in this section (PROCLAIM, MAGRIT, METLung, CheckMate026) with a view towards assessing the reasons these trials might have been negative, and make some suggestions for future trials.

Abstract not provided

Abstract not provided

Abstract:
The significant activity of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) checkpoint inhibitors in heavily pre-treated patients with advanced non–small-cell lung cancer (NSCLC) marked the beginning of a new era of immunotherapy. Recently published randomised clinical trials’ data have led to the approval of 3 PD-1/PD-L1 inhibitors—nivolumab (Opdivo; Bristol-Myers Squibb Company), pembrolizumab (Keytruda; Merck Sharp & Dohme Corp), and atezolizumab (Tecentriq, Genentech/Roche)—for the treatment of advanced NSCLC after first-line therapy. Furthermore, pembrolizumab was recently approved by the FDA as a first-line therapy for patients with advanced NSCLC. However, the overall response rates to these agents in an unselected population are reportedly low, thus emphasising the need for predictive biomarkers that identify beneficial candidates. The recently approved tests for anti-PD-1/PD-L1 therapy in NSCLC include the assessment of PD-L1 expression using immunohistochemistry (IHC) as a companion diagnostic test (22C3 for pembrolizumab) and 2 complementary diagnostic tests (28-8 for nivolumab and SP142 for atezolizumab). Another PD-L1 assay is being currently tested in clinical trials (e.g. SP263). In addition to commercial assays, laboratories and research institutions may establish their own laboratory-developed tests (LDTs) using various antibodies available, most notably the E1L3N clone. Hence, the PD-L1 expression status, as well as its predictive and prognostic value, differ considerably based on the antibody clones, platforms, and interpretation criteria used. However, the current assays evaluating the predictive role of tumour PD-L1 expression remain without harmonization in terms of the staining analysis and scoring system. The intratumoural heterogeneity in PD-L1 expression is another important issue. At present, PD-L1 testing is mainly conducted on biopsy specimens, which may not represent the tumour as a whole, and it may lead to false results, particularly in cases where testing is conducted using small tissue specimens, such as bronchial or transthoracic biopsy specimens. The resulting false-negative results could lead to the under-treatment of patients. In this presentation, I’d like to introduce 1) the results of comparison study between 4 different PD-L1 IHC and scoring systems in the surgically resected early stage lung cancer specimen 2) the correlation of PD-L1 expression between TMA specimens and the corresponding resected specimen to better understand the intratumoral heterogeneity.

Abstract not provided

Abstract not provided

Abstract:
This presentation will discuss 3 discoveries that radically changed our understanding of lung cancer. It will also address the challenges faced in communicating these life-saving “bench to bedside” discoveries to patients. In 2007, the National Science Foundation (NSF) released a report on the meaning of “transformative research” (TR) as follows: "Transformative research involves ideas, discoveries, or tools that radically change our understanding of an important existing scientific or engineering concept or educational practice or leads to the creation of a new paradigm or field of science, engineering, or education. Such research challenges current understanding or provides pathways to new frontiers.” Discoveries that changed our understanding of lung cancer: 1. PD-1/PD-L1: The discovery of PD-1 leads to development of PD-1/PD-L1 inhibitors i.e. immunotherapy. 2. Gene Defects: The discovery of gene defects/mutations leads to understanding that lung cancer is in fact many lung cancer mutations and leads to development of targeted therapies and precision medicine. 3. National Lung Cancer Screening Trial (NLST): The NLST lead to the conclusion that low dose CT scans can detect lung cancer earlier and lead to better treatment options and increased survivorship for lung cancer. In the United States, according to a recent study by Northwestern University’s Kellogg MBA program, the public is dangerously uninformed about our nation’s second leading cause of death; only behind heart disease. Lung cancer accounts for more deaths than any other cancer. More than breast, prostate and colon cancer combined! An estimated 155,870 deaths are expected to occur in 2017 in the United States, accounting for about 26% of all cancer deaths. However, federal funding for lung cancer research per death was just $1,680 compared to $24,846 for breast, $12,644 for prostate and $6,344 for colon. Not surprisingly, lung cancer has the lowest 5-year survival rate of the other most common cancers: only 18%, versus prostate at 99%; breast at 89%; and colorectal at 65%. It is clear that lung cancer is the leading cause of cancer death, and yet, it is tragically underfunded in terms of research. We will explore communication tactics including multimedia public awareness campaigns, public service announcements and social media most effective in raising the voice of lung cancer and the impact of “transformative research” in the community.

Abstract:
A Harmonized Strategy for Lung Cancer Awareness Month – November 2016 In early 2016, IASLC proposed a common strategy for the benefit of all lung cancer organizations during Lung Cancer Awareness Month. It was agreed by advocates and advocacy groups that IASLC is in a unique position to lead this unified effort among advocacy organizations. This campaign was supported by independent educational grants from Merck & Co., Inc., Eli Lilly and Company and Helsinn. Objectives for the common strategy for Awareness Month: Inform the public that everyone can get lung cancer (e.g. break down stigma) and share stories. Raise money, increase resources for research. This was done via individual organizations, not a common donor campaign, so we do not necessarily have metrics on funds raised. Reduce mortality & suffering by communicating to the public the exciting scientific advancements, which provide HOPE and PROGRESS in lung cancer. The joint public awareness campaign, supported by all the organizations, included the development of a common logo (seen above); common infographics featuring clear messages and vibrant photos showing people living their lives with lung cancer. The campaign shared stories that represented the demographics of spouses/caregivers/family and tried to show the diversity of all types who will get lung cancer. The common website (www.LCAM.org) was the focus and link shared during LCAM. We developed an advertising and public awareness campaign that included both print, digital and social media outlets. The advertising campaign included print advertising in New York Times and Wall Street Journal (Rocky Mountain Edition); a digital campaign featuring banner ads and video “pre-roll” ads; and a social media campaign utilizing both organic and paid campaigns. Key Metrics: More than 60 Survivors & Caregivers shared their stories on . More than 20 partners participated in the campaign. More than 25,000 pins, t-shirts, bracelets and posters were distributed in November.

Facebook	Twitter	LCAM Youtube Channel
9,500 Likes in November 2016	#LCAM Impressions - over 51M in November	15 Videos (:30 Seconds to 2 minutes long)
38,000 Likes as of January 31, 2017	Daily Tweets of Survivor Stories	Over 2,000 Views
28,000+ Post Likes/Shares/Clicks	Over 100 Followers
	Re-tweets by Alec Baldwin, US Actor

Digital Analytics	Print Ads
Over 30,000 Website Visitors	1/2 page full color ad New York Times - Page A8
Video and Web Banner Impressions - More than 18M	NYT Circulation = 651,458
Video Views & Web Banner Clicks - 78,202	(2) 1/2 page full color ads WSJ Rocky Mountain Edition
Click-through-rate 8x industry benchmark	WSJ Rocky Mountain Edition Circulation = 45,000
View-through-rate of 80-84%

Major Highlights/Activities: Organized Kickoff Event at the National Press Club in Washington, DC on November 1[st] 3 Travel Awards granted for LCAM 2016 Meeting in September 2016 2017 Objectives: Expand to include more global partners – Latin America, Asia, Rest of World Expand to include more Cancer Center/institutional partners Improve the diversity of the participants Improve website technology and social sharing Include more scientific advances linked with survivor stories Expand media kit and social sharing tools Increase sponsorship to support an expanded campaign Thank you to our Partners! Caring Ambassadors Dusty Joy Foundation (LiveLung) LUNGCAN Free Me From Lung Cancer Free To Breathe Lung Cancer Foundation of America Lungevity Lung Cancer Research Foundation Chris Draft Family Foundation Faces of Lung Cancer Clifton Mountain Foundation Bonnie J. Addario Foundation American Lung Association Lung Cancer Initiative of North Carolina Lung Cancer Europe Women Against Lung Cancer Europe Patient Power Rexanna’s Foundation Upstage Lung Cancer University of Colorado Cancer Center …and many lung cancer survivors and researchers Special thanks to the LCAM 2016 working group: Janet-Freeman Daily, Dusty Joy Donaldson, Cynamon Frierson and Mary Henningfield. Participants: A consortium of individuals, including lung cancer survivors, and more than 20 different advocacy organizations in the USA and Europe, with IASLC coordinating the effort. There is potential for a worldwide campaign in the future.

Abstract:
In May 2015, I attended a conference for lung cancer patients in Washington DC. There were close to 200 patients in attendance, but only five with my specific diagnosis: ROS1+ Adenocarcinoma. We saw what a minority we were within the lung cancer community and knew it would be up to us to find and create our own “tribe.” The five of us met up in the hotel bar to discuss how we might find other ROS1+ patients to share knowledge and improve our survival odds. Our first step was to create an online presence. Upon returning home from the conference, Tori Tomalia, Janet Freeman-Daily and I started a private Facebook group for people with ROS1+ cancer. We welcomed patients and caregivers and invited them to share their diagnosis stories, treatment paths and other experiences related to having ROS1+ cancer. We combed the internet searching for other ROS1+ patients, and we spoke to our doctors and friends in the lung cancer community to try to spread the word. In the first few months, membership ramped up fairly slowly, but we were a close knit group, sharing critical information, and making a difference in each other’s lives. The more I learned, the more it became apparent that essentially no one was conducting research focusing on ROS1+ cancer. We had gotten lucky that the ROS1 fusion was similar enough to the ALK mutation (which occurs with more frequency and has a larger patient population), that ROS1 had been able to piggyback on the ALK research. But no one was specifically examining ROS1, and while the first generation ALK research generated Crizotinib, a therapy that proved exceptionally effective for ROS1, some of the most exciting second generation ALK research was not looking as promising for ROS1. Obviously, this was disconcerting. So, while attending WCLC in Denver in September of 2015, Janet and I pulled Dr. Ross Camidge (Univ. of Colorado) aside to ask him one very important question: How can we get ROS1-specific research going? His answer: Organize. Research cannot happen without a cohort of patients to study, and gathering enough ROS1+ patients is difficult for researchers. Dr. Camidge’s words lit a fire under us. Janet, Tori and I decided to increase our efforts to recruit ROS1 patients to our Facebook group. All three of us published blogs, redoubled our efforts scouring the web and contacting doctors, and sought out other media opportunities. Within a couple of months, we’d doubled our membership, including many international patients, and we decided it was time to seek outside help. I contacted Bonnie Addario, a long-term lung cancer survivor and founder of the Addario Lung Cancer Foundation (ALCF). I knew Bonnie was a strong proponent of “patient centric” research, and I also knew the ALCF (and its sister organization, Addario Lung Cancer Medical Institute (ALCMI)) had successfully launched the “Young Lung Study” the previous year. Since both young lung cancer, and ROS1+ lung cancer, are minorities in the lung cancer space, requiring researchers to cast an international net to gather a critical mass, I felt that the ALCF and ALCMI had demonstrated both the interest and experience necessary to help shepherd a global ROS1 research effort. Luckily, Bonnie agreed, and soon the ALCF and ALCMI joined our team. As patients and caregivers, we began calling ourselves the “ROS1ders” (pronounced “ross-wonders”). A core group of about 5 ROS1ders did most of the work, but we would check in with the broader Facebook group for feedback periodically. By December 2015, the ROS1ders delivered a list of our research priorities to ALCF. Dr. Guneet Walia, ALCF’s Senior Director of Research and Medical Affairs then began reaching out to researchers and industry--and the Global ROS1 Initiative (the “Initiative”) was born. The first project of the Initiative was an epidemiological survey. ROS1ders worked together with Dr. Walia and a Stanford University researcher to develop a survey, designed to uncover commonalities which might indicate causes for the ROS1 oncogene, and help direct where to focus future research. Over 100 ROS1ders from around the world filled out the survey. Data analysis is underway, and a second generation follow-up survey is coming. Guneet discussed some of the initial findings of this study at WCLC 2016 in Vienna. Our second project is even more ambitious. Only a few models of ROS1 cancer exist. To encourage more research into ROS1 cancer, we are partnering with researchers and organizations to create new ROS1 cancer models (both cell lines and mouse models) using fresh biopsy and surgery specimens donated by ROS1ders. Models created by ROS1der donations will be made available (freely or at minimal cost) to academic researchers. Orchestrating the Initiative is a major undertaking. A group of the most involved ROS1ders and ALCF and ALCMI members have weekly conference calls. In between calls, each of us work on our individual pieces, such as meeting with researchers, negotiating contracts, writing content for websites, speaking at conferences, and fundraising. Since this project is the first of its kind, it’s not surprising that sometimes we face hiccups and hurdles. Patients, caregivers, researchers, advocacy organizations and industry are learning how to work with each other as peers, and occasionally the learning curve is steep. The global nature of our project adds legal complexities, language barriers and time zone juggling to the mix. We are all evolving and changing the way research can be done. The Initiative is a groundbreaking example of international patient-driven research. Its success reflects the collaborative efforts of so many dedicated to achieving something truly special. From its inception at a hotel bar in Washington DC to today, ROS1der voices have been involved every step of the way. We hope the Initiative not only changes the lives of ROS1ders, but paves the way for other motivated patient groups to pursue their own goals. We are so proud and excited to see our vision manifest.

Abstract:
Background/History A lung cancer diagnosis can be devastating to both the patient and their loved ones. Often times, lung cancer patients and caregivers report feeling isolated and hopeless. In 2004, there were very few events across the United States which connected the lung cancer community. One advocate, whose husband was fighting lung cancer, sought to change that and held the very first Shine a Light event in November 2004 in Santa Rosa, CA. Little did they know, this local event would turn into a movement. In 2006, a few advocates in Boston held a similar Shine a Light on Lung Cancer Vigil—a “rally” for lung cancer on the steps of the Massachusetts state house, to honor and remember those who have been touched by the disease and to raise awareness during Lung Cancer Awareness Month (LCAM). In 2008, they were determined to grow this event and offer local communities an opportunity to connect with others impacted by this disease and Lung Cancer Alliance was there to help them achieve their vision. Purpose Shine a Light on Lung Cancer’s primary purpose was and continues to be raising awareness about lung cancer and connecting the community. The events are always free to attend and free to host as we want to eliminate any barriers to participation. Shine a Lights began as “vigils”, and have always incorporated a moment of silence and the literal act of shining a light—whether that be a glow stick, flashlight, candle, or illumination of a room or building—to remember those we’ve lost to this disease. In 2014, Lung Cancer Alliance decided to drop the word “vigil” from the program title, as vigils often connote a feeling of sadness or mourning, and the purpose of Shine a Lights were to provide hope, support and inspiration to all those impacted. Each Shine a Light program still incorporates a moment of silence and shining of lights, however, we focus that moment to celebrate the survivors in attendance, while also remembering those who have passed away from this disease. This signature element of Shine a Lights can often be emotional and is typically the culminating activity of the event. Shine a Lights are also a great platform for local media attention. In an effort to leverage this attention, from 2008 through 2015, we encouraged organizers to host their event on the official Shine a Light date (voted on by past organizers and ultimately chosen by LCA). However, due to lack of national coverage and confusion from potential organizers on the official date, in 2016, we stopped choosing an official national date. Impact The impact of our Shine a Light on Lung Cancer program has far exceeded our initial expectations. The initiative continues to grow and evolve year after year and we continually adapt and improve the program based on feedback from organizers and attendees. When Shine a Light began, events were typically organized by individuals in communities who wanted to do something during Lung Cancer Awareness Month. They incorporated survivors, caregivers, physicians and local notable members of their communities (i.e. news reporters, local politicians, and entertainers) into their programs, to educate attendees about lung cancer and inspire action with a unifying national call to action. In 2013, Lilly Oncology came on board as a national title sponsor and their sales force began to spread the word about these unique events to their customers—healthcare providers. Shine a Lights are a great way for nurse navigators to celebrate their patients during Lung Cancer Awareness Month and highlight their programs and services—particularly on the heels of Breast Cancer Awareness Month—and especially with our “event in a box”. Organizers complete a very simple online LOA which contains all of their event information, after which they receive access to our online resources (i.e. template flyers, programs, sponsor logos, media outreach instructions, and more). In October, each organizer will receive their Shine a Light “kit” in the mail, which contains bracelets, flashlights, a poster and educational materials for their attendees. Although we had had a handful of Shine a Lights taking place in healthcare facilities before 2013, with Lilly’s involvement, the numbers grew. Simultaneously, we noticed Shine a Lights which were hosted by individuals were becoming more unique and personalized to their local community (i.e. paint and sip parties, yoga classes, and backyard barbecues). Because of this natural distinction, we evolved the program in 2016 to include Shine a Light, traditional events hosted by a healthcare facility during LCAM, and Shine a Light Your Way, unique awareness and fundraising events hosted by individuals in their local communities throughout the year. Due to this split, our traditional Shine a Light numbers saw a slight dip in 2016 as they no longer included events being hosted by individuals, but we anticipate continued growth in 2017 as the program evolves. Future Goals In 2016, 166 Shine a Light events were held in 38 states. Our goal for 2017 is to reach 200+ events in all 50 states and Washington, DC. We are also looking to make an even bigger global impact in 2018. The first international Shine a Light was held in partnership with the Australian Lung Foundation in 2011 and we have had seven unique countries host at least one Shine a Light since then. We hope to expand our national reach while bringing this unique program to many more worldwide, and continue connecting the lung cancer community—offering hope and inspiration, letting those who are impacted know they are not alone.

Abstract:
It is estimated that in 2015, approximately 3 million people in Italy have received a cancer diagnosis during their lifetime. While in men cancer has decreased of 2.5%, in women the cases have risen from 168,000 to 176,000. Epidemiological data of lung cancer reveal a dramatic increase of the incidence and mortality in women, mainly due to the tobacco consumption in the female population during the past 60 years and since the 1980s, the gap between the two genders has narrowed. Nowadays lung cancer represents a global women’s health issue and every year more women die due to lung cancer than for breast, ovarian and uterine cancer all together and receiving a cancer diagnosis together with the communication about treatment and care can lead to a series of extremely stressful and frightening events that cause both patients and their relatives to suffer emotionally. Psychological distress, depression and anxiety are related to poor quality of life in all its shapes and forms, including the physical-side. The disease and the treatments alter the patient body image and consequently change the personal identity; the body is no longer recognized and accepted in its new condition, and this may undercut the sense of femininity and diminish the confidence in the physical appearance and the self-esteem. It gets difficult for a woman to face the daily life because she is exposed to the external world with a body revealing visible signs of the illness and care. For addressing these issues, it is necessary to implement an holistic approach and this is one of the objectives behind the active commitment of WALCE (Women Against Lung Cancer in Europe) since 2006, when it was established. In 2009, it started the collaboration with “La forza e il sorriso – L.G.F.B. Italia”, the Italian version of a well-known program called “Look Good ... Feel Better®”, launched in US in 1989 and currently active in 26 countries worldwide. It is a free make-up workshop project for women diagnosed with cancer who are undergoing chemotherapy, radiotherapy or other cancer treatments. Beauty workshops are offered to help women to cope with treatment side effects and to regain the femininity and the self-confidence in their body with the aim to improve their quality of life by simple beauty techniques to enhance the appearance. Following this positive experience, WALCE designed a lung cancer awareness campaign, called: “How to beauty your day”, a make-up session program for women of all ages affected by cancer with the aim to reach little and peripheral hospitals in Italy, where the initiative “La forza e il sorriso” has not been provided yet and hospitals, where no general support programs for women with cancer have been developed. This initiative was launched in November 2010, during the World Lung Cancer Awareness Month and in some way it recalls the other one, but with some new addition. Together with the beauty sessions, educational events are organized with the aim to improve and reinforce the knowledge of people about the disease, the current treatment options, the side effects and any other related issues. This program was firstly carried out just in Italy and later on, it was expanded in other European countries (Spain, Serbia and Greece). From November 2010 to November 2016, WALCE organized 76 make-up workshops in several Italian locations and in Europe, in collaboration both with cancer centres and no profit organizations working in these areas; about 750 ladies attended the make-up workshops, guided by 7 voluntary beauticians and with the support of a psycho-oncologist. At the end of the session, the women are invited to complete a survey to assess the event and benefits received. The general response received until now is positive; most of participants declare to have learnt useful advice and to be very enthusiastic, whereas very few are a little doubtful. The most common adjectives used to describe patient feelings at the end of the experience are: beautiful, happy, positive, pretty and attractive. From the survey results, it seems that most of the ladies don’t think about the illness during the event and meeting other women in a similar situation is considered a positive experience. Cancer patients tend to better cope with the illness when self-confidence and self-esteem are regained. The sense of well-being shared in a relaxed atmosphere, acknowledging social, emotional and psychological needs and being amongst other ladies who feel the same fears or anxieties, has proven to be an incentive to fight against cancer. Figure 1 Pikler VI, Brown C: Cancer Patients’ and Partners’ Psychological Distress and Quality of Life: Influence of Gender Role. Journal of Psychosocial Oncology, 28:43–60, 2010 Honda K, Goodwin R: Cancer and mental disorders in a national community sample: Findings from the national comorbidity survey. Psychotherapy and Psychosomatics, 73: 235–242, 2004 Tuinstra J, Hagedoorn M, Van Sonderen E et al: Psychological distress in couples dealing with colorectal cancer: Gender and role differences and intracouple correspondence. British Journal of Health Psychology, 9: 465–478, 2004 Fife B, Kennedy V, Robinson L: Gender and adjustment to cancer: Clinical implications. Journal of Psychosocial Oncology, 12: 1–21, 1994 Phillips C: Images, femininity and cancer: an analysis of an international patient education programme. Health, 13: 67, 2009

Abstract:
Any Differences in the Management of Elderly Patients with Lung Cancer between East and West? Lung cancer is one of the commoner cancers in the world, accounting for 1.6 million cases annually. In many western countries, lung cancer rates have declined in contrast to the predicted increase in the incidence of lung cancer in Asia, especially among males. Many patients with lung cancer are older and this applies to all parts of the world. There are relatively few data for the older age group, since many studies have an age restriction, such that there can be uncertainty in the extrapolation of trial findings to the average older person. On the other hand it is clear that there are differences in lung cancer in the East and the West including genetic and biological differences such as smoking habits between genders, genetic aberrations such as the frequency of EGFR gene mutations, in addition to cultural and local preferences. Moreover clinical trials are often performed either in the East or the West, as are studies of lung cancer in the older population, such that extrapolation may be needed. In the work up of suspected lung cancer, the older patient may be less tolerant of diagnostic tests given the ageing process and potential concurrent co-morbid disease, especially smoking related diseases which can differ between East and West. In addition in terms of treatment apart from well-known somatic mutation differences, ethnic differences in efficacy and toxicity from therapies may differ, in addition to non-patient factors such as affordability, cultural sensitivities and preferences. Thus the challenge in interpreting and applying research and clinical trials data is includes the relative paucity of data on the older population as well as uncertainty whether the data that is available on the older population applies equally to those in the East and the West, even allowing for known biological differences. This presentation will examine knowledge gaps and differences that should be considered for the management of the older person with the lung cancer from the East and West, in the setting of cultural and genetic uniqueness.

Abstract:
Chemotherapy Treating the elderly with advanced NSCLC remains a major challenge. ELVIS (Elderly Lung Cancer Vinorelbine Italian Study) was the first elderly-specific phase III randomized trial to be conducted in advanced NSCLC; this study demonstrated improved survival and quality of life in patients 70 years of age and older, receiving weekly vinorelbine compared to best supportive care. The most studied non platinum-based regimen has been the combination of gemcitabine plus vinorelbine, which proved active and well tolerated in several phase II trials. However, in a large phase III randomized Multicenter Italian Lung cancer in the Elderly Study (MILES), which enrolled about 700 patients, combination chemotherapy with gemcitabine and vinorelbine failed to improve outcomes (response rate, time to progression, survival or quality of life) compared to single agent chemotherapy with either vinorelbine or gemcitabine. Based on these trials, single agent chemotherapy, until relatively recently, was considered the standard of care in PS 0-2 elderly advanced NSCLC patients. However, over the past two decades, retrospective analyses of randomized phase III trials and multiple phase II studies have confirmed the activity and tolerability of cisplatin-based and carboplatin-based chemotherapy in fit elderly patients. In aggregate, these trials suggested that the elderly fared as well or nearly as well as their younger counterparts with respect to response rate and survival, albeit with more toxicity. A randomized phase III trial led by Quoix et al in advanced NSCLC patients between the ages of 70 and 90 with PS 0-2 showed superiority in all outcome parameters for carboplatin and weekly paclitaxel versus either single agent gemcitabine or vinorelbine. Response rate was nearly triple at 29% vs 11% (p <0.0001) with progression-free survival of 6.1 mos vs 3.0 mos (p < 0.0001), median survival of 10.3 mos vs 6.2 mos (p=0.00004), and 1-year overall survival rate of 45% vs 26% (p < 0.001). Quality of life was preserved or improved with the combination regimen. Survival benefit was seen in those 80 years of age and older (n = 114; HR 0.56 [95% CI: 0.37 -0.85], p = 0.0067), and in individuals with PS 2 (n = 122; HR 0.65 [95% CI: 0.44 – 0.95] p =0.027). More recently, in a retrospective subset analysis of elderly individuals enrolled on a phase III study of carboplatin plus either conventional solvent based (sb) paclitaxel administered every three weeks or nanoparticle, albumin-bound (nab) paclitaxel given weekly, the latter regimen resulted in a significant improvement in overall survival at 19.9 mos vs 10.4 mos (p = 0.009). To date, there has been no formal, prospective, phase III comparison of weekly sb- vs weekly nab- paclitaxel in combination with carboplatin in advanced NSCLC in the elderly or any other population. At ASCO 2017, ABOUND 70+ showed that therapy with carboplatin and weekly nab-paclitaxel x 3, followed by a one week break (Arm B) was well tolerated with no dilution in efficacy compared to the “uninterrupted” weekly nab-pacliaxel regimen (Arm A) used in the phase III trial: median PFS (Arms A and B) 3.9 vs 7.0 mo (HR 0.49; 95% CI, 0.30 - 0.79; P = 0.003), confirmed ORR 23.9% vs 40.3% (P = 0.037), and median OS 15.2 vs 16.2 mo (HR 0.76; 95% CI, 0.46 - 1.26; P= 0.292). In addition, the feasibility of cisplatin-based chemotherapy was also reported during ASCO 2017. The results from two separate phase III randomized trials (MILES 3 and 4) led by Gridelli et al comparing single agent gemcitabine to cisplatin+gemcitabine in squamous cell histology or single agent pemetrexed to cisplatin+pemetrexed in non-squamous cell NSCLC, showed a significant improvement in ORR (15.5% vs 8.5%, p=0.02) and PFS (4.6 mos vs 3.0 mos, p=0.005, HR 0.76) and suggested a non-significant trend toward improved median OS (9.6 vs 7.5 mos, p= 0.136, HR: 0.86) in patients receiving the platinum-based combinations. In clinical practice, non-platinum monotherapy remains the standard treatment for unfit elderly patients with advanced NSCLC, but a carboplatin-based combination is a reasonable option for those who are fit enough. Bevacizumab and targeted therapies: E4599 showed a survival advantage for combination bevacizumab and paclitaxel/carboplatin (PCB) vs chemotherapy alone, though a subsequent analysis of those over 70 years of age suggested that this benefit was diluted in older patients. More nuanced analyses by Wakelee and Ramalingam suggested that males of any age sustained a survival benefit, while women up to the age of 60 also realized an OS advantage. It was only in women > 60 years of age where this benefit seemed to be lost, in part because the control arm performed better in this group. A more recent joint analysis pooling the data from the experimental arm of E4599 and the “control” arm of POINT BREAK, both featuring combination PCB, and comparing these data to PC alone (E4599), showed that a survival benefit was sustained up to age 75 with median survival (MS) of 13.4 vs 10.2 mos (HR, 0.78; 95% CI, 0.68–0.89). However, above the age of 75 in a limited cohort (n=157), combination PCB offered no advantage: MS of 9.6 mos vs 13.0 mos for those < 75 yo (HR, 1.05; 95% CI, 0.70–1.57). As for tyrosine kinase inhibitors (TKIs), a retrospective analysis of the elderly enrolled on BR 21, which compared erlotinib to placebo in the 2nd and 3rd line setting in advanced NSCLC showed a consistent response (OR%), progression-free survival (PFS) and OS benefit, albeit a bit more toxicity in older subjects. More recently, in patients with actionable mutations or translocations, phase III trials have demonstrated a consistent OR% and PFS advantage for erlotinib, afatinib, and crizotinib compared to standard front-line or second line chemotherapy regardless of age. Sub-analyses using 65 to 75 as cut points consistently show similar benefits, although the individual comparisons for the elderly have been frequently underpowered to demonstrate statistical significance. In the EURTAC trial comparing erlotinib to platinum-based chemotherapy in patients with exon 19 or 21 mutations, the magnitude of PFS benefit for the TKI was very similar in those above and below 65 years of age: amongst 88 individuals > 65, the HR was 0.26 (95% CI: 0.16 – 0.51), while it was 0.49 for 85 subjects < 65 years of age (95% CI: 0.25- 0.75). In Lux Lung 3, which compared afatinib to cisplatin/pemetrexed in advanced, treatment-naïve patients with EGFR mutations, PFS favored afatinib over chemotherapy in 135 patients 65 years of age and older (HR 0.64, 95% CI: 0.39 – 1.03), not too different from the benefit seen in 211 patients under the age of 65 (HR 0.53, 95% CI 0.36- 0.79). More recently, the J-ALEX trial demonstrated a statistically significant and clinically meaningful PFS advantage for alectinib vs standard crizotinib in TKI-naïve ALK (+) NSCLC. Amongst 207 enrollees, 22 subjects were 75 years of age and older; the hazard ratio for alectinib’s PFS benefit in this very small population was impressive at 0.28, but because of small numbers and an under-powered comparison, the 95% confidence intervals overlapped unity (0.06 – 1.19), and so the putative difference was not statistically significant. Immunotherapy Novel immunotherapy with check-point inhibitors nivolumab, pembrolizumab and atezolizumab have yielded an overall survival benefit compared to standard docetaxel in second-line setting of advanced NSCLC with less toxicity. As of 2017, PD1/PDL1 inhibitors have effectively replaced chemotherapy in the second line setting independent of histology. In these trials, the benefits have been confirmed consistently in subgroup analysis of the elderly, particularly in those between 65 and 75 years of age. Representation of those above 75 years of age in these studies, unfortunately, has been relatively sparse. In some series, there is no indication of increased toxicity of nivolumab in older patients. To date, there are no ongoing elderly-specific trials evaluating immunotherapy in advanced NSCLC. Summary: Elderly NSCLC patients who are fit for clinical trials do reasonably well in comparison to their younger counterparts. However, extrapolating clinical trial data to the general population, is problematic. Clearly, more evidence is required, particularly among octogenarians and patients with multiple chronic conditions. Older patients are at risk for tolerating chemotherapy poorly because of comorbidity and organ dysfunction; in this regard, modified comprehensive geriatric assessments may help facilitate appropriate treatment selection.

Abstract:
Thymic malignacies are distintive by being relatively rare and by their generally more indolent behavior; nevertheless all thymomas are malignant tumors. Progress in the understanding of these tumors has been limited until recently. The advent of several regional and international collaborative groups (e.g. the Japanese Association for Research on the Thymus [JART] and the International Thymic Malignancy Interest Group [ITMIG] has provided an infrastructure to facilitate progress, and the field has advanced significantly. The level of understanding available now makes the previously common approach of empiric management of thymic malignancies inappropriate. Three major categories of thymic malnignancies with different biologic behavior are distinguished: thymoma, thymic carcinoma (TC) and Neuroendocrine tumors of the thymus (NETT, also known as thymic carcinoid). Thymomas are subdivided into 5 histotypes with slightly different clinical features, but these clinical differences are small and mixed histotypes are frequent. Through international collaboration, the first fromal stage classification system has been developed. Many patients with thymic malignancies have associated autoimmune conditions, most prominently myathenia gravis. Chest CT with intravenous contrast is the primary imaging modality for patient evaluation. A combination of patient demographics, clinical and imaging features allows a reliable clinical diagnosis of a thymic malignancy to be made in most patients; this can be supplemented with a needle biopsy if needed. However, the ability of imaging to accurately define the degree of local invasion or pleural dissemination is limited. In general, surgical exploration is warranted (in a facility prepared to handle resection of all possibly involved structures) unless imaging clearly demonstrates unresectable invasion. A complete resection of all involved structures is the cornerstone of treatment. The role of adjuvant radiotherapy after an R0 resection remains unclear, especially after resection of more invasive tumors or int he case of TC/NETT. It is easier to argue for adjuvant RT after an R1 resection or an R0 resection with close margins. Surgeons should be prepared to resect involved structures; a planned subtotal (debulking) resection is not recommended. When more invasive thymic tumors raise questions about the ability to achieve an R0 resection, preoperative chemo- or chemoradiotherapy is typically given. Recurrences are relatively low after complete resection. Longer-term (5- and 10-year) survival rates with aggressive multimodality treatment are fairly good, evin in tumors that invade major mediastinal structures or demonstrate pleural dissemination. When resection is not possible, management with palliative chemotherapy (± RT) can be useful. Several regimens have been shown to be active, and an optimal chemotherapy regimen has not been identified.

Abstract:
Extragonadal germ cell tumors (EGCTs) are among the most perplexing and embryologically intriguing entities in clinical oncology. They represent only 2-5% of adult germ cell malignancies. Their histology is identical to germ cell tumors (GCTs) derived from primary gonadal sites. However, their biology, especially primary mediastinal non-seminomatous GCT (PMNSGCT), is substantially different. PMNSGCT represents a clinically and biologically distinct subset of EGCT. It carries a poor prognosis with 40-50% overall survival after platinum-based chemotherapy and surgery (1-3). The cure rate is even worse if there is metastatic disease of the lung, liver, or supraclavicular lymph nodes with only 25% overall survival. In contrast, mediastinal seminomas have a good prognosis with 88-90% overall survival (4,5). Survival outcome for PMNSGCT is dependent on successful chemotherapy and expert thoracic surgery to remove residual disease when feasible. Patients presenting with anterior mediastinal tumor do not have a testis primary and there is no need to evaluate with testis ultrasound. The significant elevation in tumor markers including human chorionic gonadotrophin (hCG) > 1,000 U/1 and/or any elevation in alphafetoprotein (AFP) confirms the diagnosis of NSGCT and no biopsy is needed. The patient should be treated with 4 courses of platinum-based triple chemotherapy. We recommend using etoposide (VP-16), ifosfamide and cisplatin (VIP x 4) as the standard chemotherapy for PMNSGCT followed by surgical resection (2). Patients with normal tumor markers or mild elevation in hCG require a biopsy to establish the diagnosis of pure seminoma vs. NSGCT vs. other etiology such as thymic malignancy or lymphoma. Between 1980 and 2013, 221 patients with PMNSGCT who underwent postchemotherapy surgery at Indiana University were retrospectively reviewed. Our initial experience was entirely with BEP x 4. Because of our clinical observation of unacceptable pulmonary toxicity, we subsequently substituted ifosfamide for bleomycin. One hundred sixty-six patients received BEP and 55 received VIP. There were 11perioperative deaths when bleomycin was part of the preoperative chemotherapy (6.6%). By contrast, we saw no perioperative deaths on the VIP arm. Furthermore, 30 patients (18.1%) had prolonged ventilator use for greater than 48 hours. Only 2 patients (3.6%) had this complication on the VIP arm (6). A phase III intergroup study of 181 patients with poor-risk germ cell tumors, including patients with PMNSGCT, demonstrated equivalent survival in patients with VIP compared to BEP. Given the high rate of postoperative pulmonary failure and mortality after BEP, we feel these results strongly support our present policy of preferring to use VIP chemotherapy in patients with PMNSGCT before major thoracic surgical procedure. Surgical resection of residual disease after chemotherapy is an integral part of the management of patients with PMNSGCT. Surgical resection after chemotherapy serves to assess response, remove chemotherapy-resistant disease and direct additional chemotherapy. Viable teratoma or germ cell cancer is present in 30-47% of patients who undergo resection post-chemotherapy (7,8). Chest CT scan every 4 months for 2 years, then every 6 months for years 3-5 is recommended if teratoma or malignant transformation of teratoma is present in the surgical specimen. However, if there is persistent germ cell cancer in the surgical specimen, then patients should receive 2 post-operative courses of etoposide and cisplatin (EP). Surgical treatment for relapsed PMNSGCT in the presence of rising tumor markers after chemotherapy is controversial. Our preferred treatment option is surgery, if feasible, especially if carried out by experienced thoracic surgical oncologists. We recently reported our results with surgery alone in 35 patients with relapsed PMNSGCTs with rising serum AFP (32 patients) or hCG (3 patients). Seven (20%) of 35 patients remained continuously disease-free, with median followup of 64 months (range, 25-220 months) (10). If surgery is not feasible, then high dose chemotherapy in an experienced center is a reasonable approach. Mature teratoma is the most common GCT in the mediastinum. Patients present with large circumscribed anterior mediastinal mass with normal serum hCG and AFP. The treatment of mature teratoma is surgical resection and there is no role for chemotherapy unless elevated tumor markers are present. Mediastinal pure seminomas comprise 30-40% of malignant mediastinal GCT. Mediastinal seminoma carries an excellent prognosis and should be treated with good-risk chemotherapy regimen (3 cycles of bleomycin, etoposide, and platinum or 4 cycles of EP) with no surgical resection needed. References: International Germ Cell Consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997; 15:594-603. Kesler KA, Rieger KM, Hammoud ZT, et al.: A 25-year single institution experience with surgery for primary mediastinal non-seminomatous germ cell tumors. Ann Thorac Surg 2008; 85:371-378. Rivera C, Arame A, Jougon J, et al.: Prognostic factors in patients with primary mediastinal germ cell tumors, a surgical multicenter retrospective study. Interact Cardiovasc Thorac Surg 2010; 11:585-589. Bokemeyer C, Nichols CR, Droz JP, et al.: Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. J Clin Oncol 2002; 20:1864-1873. Hartmann JT, Nichols CR, Droz JP, et al.: Prognostic variables for response and outcome in patients with extragonadal germ cell tumors. Ann Oncol 2002; 13:1017-1028. Ranganath P, Kesler KA and Einhorn LH: Perioperative morbidity and mortality associated with bleomycin in primary mediastinal non-seminomatous germ cell tumor. J Clin Oncol 2016; 34:4445-4448. 2016. Vuky J, Bains M, Bacik J, et al.: Role of postchemotherapy adjunctive surgery in the management of patients with non-seminoma arising from the mediastinum. J Clin Oncol 2001; 19:682-688. Kesler KA, Rieger KM, Ganjoo KN, et al.: Primary mediastinal non-seminomatous germ cell tumors; the influence of postchemotherapy pathology on long-term survival after surgery. J Thorac Cardiovasc Surg 1999; 118:692-700. Hinton S, Catalano PJ, Einhorn LH, et al.: Cisplatin, etoposide , and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors. Final analysis of an intergroup trial. Cancer 2003; 97:1869-1875. Radaideh SM, Cook VC, Kesler KA, Einhorn LH: Outcome following resection for patients with primary mediastinal non-seminomatous germ cell tumors and rising serum tumor markers postchemotherapy. Ann Oncol 2010; 21:804-807.

Abstract:

Abstract not provided

Abstract:
Around one-third of all malignancies are attributable to tobacco smoking. Diagnosis of cancer is a turning point in life and an alarming signal, motivating for smoking cessation. This is particularly true for patients with tobacco-related malignancies, such as cancers of the lung, head and neck, esophagus, pancreas, uterine cervix, kidney, bladder or stomach. Indeed, the quit and quit attempts rates shortly after cancer diagnosis are relatively high, nevertheless a significant proportion of patients continue to smoke or relapse after initial quit attempts. In consequence up to one-third to one-half of cancer patients or cancer survivors continue to smoke, and the smoking rates in cancer survival do not significantly differ from those in the general population[1,2]. Most smoking cessation efforts have been aimed at primary prevention, whereas the importance of stopping smoking in people diagnosed with cancer have been given less attention. In consequence, the provision of tobacco cessation treatment for cancer tobacco users is still not widely available. Patients with tobacco-related cancers feel more guilt and shame resulting from previous smoking, and tend to underreport their current tobacco dependence[3-5]. Many believe that there is no point to stop smoking once being diagnosed with cancer. Additionally, some health care professionals, in fear of increasing patients’ guilt and stress, do not encourage them to stop smoking. Patients who continue smoking experience several adverse effects. Apart from disease site and stage, abstinence from smoking is the strongest and independent predictor of survival in cancer patients who have ever smoked. Several studies have consistently shown that continued tobacco use compromises the effectiveness and increases the complication rates of three main cancer treatments: surgery, chemotherapy and radiotherapy[6]. In patients managed with surgery, continued cigarette smoking is associated with increasing risk of necrosis, slower wound healing, higher surgical site infection rates and prolonged hospitalization[7]. Components of tobacco smoke significantly impact clearance and delivery of many cytotoxic agents, resulting in their decreased efficacy and higher toxicity[8]. Current, compared to former smokers and patients who stopped smoking before starting treatment, have lower response rates to radiation therapy and acerbated radiation side effects, such as oral mucositis, xerostomia, weight loss and fatigue[9,10]. Smoking after a cancer diagnosis results in higher risk of developing secondary cancers, poorer general health and increased all cause mortality[11,12]. In consequence, patients who continue to smoke after cancer diagnosis almost double their risk of dying, compared to those who quit. A deleterious impact of continued smoking on survivorship is particularly high for tobacco-related cancers. Cancer survivors who continue to smoke have also poorer emotional and social functioning, vitality and quality of life[13-15]. In conclusion, quitting smoking and prevention of smoking relapse represent an important opportunity to mitigate cancer treatment complications and to improve survival, general health and quality of life. It also allows avoiding much of the excess risk of secondary cancers and other tobacco-related diseases. Enhanced focus on smoking cessation and its active promotion among cancer patients may increase their motivation to quit. All cancer patients, irrespective of treatment setting, should be screened for tobacco use and advised on benefits of tobacco cessation. Patients who continue to smoke should be offered individualized pharmacologic and behavioral therapy to assist in the quitting process. References Bellizzi KM, et al. Health behaviors of cancer survivors: examining opportunities for cancer control intervention. J Clin Oncol. 2005; 23:8884–93. Burke L, et al. Smoking behaviors among cancer survivors: an observational clinical study. J Oncol Pract. 2009;5:6-9. LoConte NK, et al. Assessment of guilt and shame in patients with non-small-cell lung cancer compared with patients with breast and prostate cancer. Clin Lung Cancer. 2008;9:171-8. Warren GW, et al. Accuracy of self-reported tobacco assessments in a head and neck cancer treatment population. Radiother Oncol. 2012; 103:45–8. Morales NA, et al. Accuracy of self-reported tobacco use in newly diagnosed cancer patients. Cancer Causes Control. 2013; 24:1223–30. Toll BA, at al. Assessing tobacco use by cancer patients and facilitating cessation: an American Association for Cancer Research policy statement. Clin Cancer Res. 2013; 19:1941–8. Sorensen LT, et al. Smoking as a risk factor for wound healing and infection in breast cancer surgery. European Journal of Surgical Oncology. 2002; 28:815–20. O'Malley M, et al. Effects of cigarette smoking on metabolism and effectiveness of systemic therapy for lung cancer. J Thorac Oncol. 2014;9:917-26. Browman GP, et al. Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med. 1993; 328:159–63. Browman GP, et al. Association between smoking during radiotherapy and prognosis in head and neck cancer: a follow-up study. Head Neck. 2002; 24:1031–7. Stewart BW, et al. Cancer and tobacco: Its effects on individuals and populations, in Robotin M, Olver I, Girgis A (eds): When Cancer Crosses Disciplines: A Physician’s Handbook. London, United Kingdom, Imperial College Press, 2010. Parsons A, et al: Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: Systematic review of observational studies with meta-analysis. BMJ 2010; 340:b5569 Berg CJ, et al. Correlates of continued smoking versus cessation among survivors of smoking-related cancers. Psychooncology. 2013;22:799-806. Garces YI, et al. The relationship between cigarette smoking and quality of life after lung cancer diagnosis. Chest. 2004; 126:1733–41. Duffy SA, et al. Effect of smoking, alcohol, and depression on the quality of life of head and neck cancer patients. General Hospital Psychiatry. 2002; 24:140–7.

Abstract not provided

Abstract not provided

Abstract:
The National Lung Screening Trial (NLST) demonstrated that screening for lung cancer could reduce lung cancer (LC) mortality by 20%[1]. Screening with low-dose CT (LDCT) resulted in more early stage lung cancers and fewer late-stage cancers as compared to chest X-ray screening. It has been estimated that 12,000 lung cancer deaths could be averted each year if all eligible Americans were to undergo LDCT screening[2]. An Italian screening study with LDCT reported that stopping smoking reduces overall mortality by 39% compared with current smokers[3]. Tanner and associates also reported a 20% LC mortality reduction in the NLST in the chest X-ray arm (control arm) in the absence of smoking for 7 years[4]. The maximum mortality benefit was seen in the absence of smoking in combination with LDCT that resulted in a LC mortality reduction of 38% (HR=0.62). Accordingly, current-screening programs must include tobacco cessation counseling and treatment to current smokers[5]. The US Preventive Services Task Force has approved LDCT screening in high-risk individuals (asymptomatic persons aged 55 to 80 years who have a 30-pack-year or more smoking history and have quit within the past 15 years)[6]. However, from 2010-2015 less than 5% per year of those eligible are currently undergoing LDCT screening. Of the 6.8 million smokers eligible for LDCT screening, only 262,700 received it[7]. In the last two years a large number of centers have ramped up their screening programs in the US. Another issue is that of all lung cancers patients in the United States only 30-40% of these individuals were actually eligible for LDCT screening based on the NLST criteria for screening[8]. Tammemagi et al developed an LC-risk-prediction model based on the PLCO (Prostate, Lung, Colon, Ovarian) screening trial[9]. At a six-year LC risk of ≥1.5%, this risk prediction model detected 12% more LC and screened 8.8% fewer individuals than those using the NSLC screening criteria[10]. The number needed to screen to detect one LC was 255 with this model as compared with 320 in the NLST. None of the never-smokers in the PLCO trial had a risk of >1.5%. Do not screen never-smokers! In an effort to detect more lung cancers at an earlier stage, additional risk factors need to be included in screening programs and evaluated for their efficacy. Young and colleagues evaluated a subset of the NLST participants who had pulmonary function testing (PFT) and observed a two-fold increase in lung cancer incidence with COPD[11]. There was a linear relationship between increasing severity of airflow limitation and risk of lung cancer[12]. The heritability of lung cancer is not well explained. The OncoArray Consortium has identified 18 genetic susceptibility loci for LC across histological types[13]. Dr. Stephen Lam in Vancouver, BC is testing this 18-gene array as a risk factor in an international screening trial. The European Study of Cohorts of Air Pollution Effects (ESCAPE) identified particle matter (PM 10 and PM 2.5) as having significant association with LC risk (HR 1.22 and 1.18 respectively)[14]. The hazard ratios (HR) associated with adenocarcinoma was 1.51 and 1.55 respectively. Satellites are able to measure air pollution and have good correlation with simultaneous ground measurements ( accessed 8/4/2017). There is extensive research into biomarkers for risk of lung cancer that might be of use in screening for LC or in identifying risk of malignancy in indeterminate pulmonary nodules. Sources of biomarkers to date have included breath, sputum, urine and blood. Categories of blood biomarkers have included micro-RNA, proteins, circulating tumor DNA and autoantibodies. A randomized prospective trial (RCT) in Scotland is evaluating an autoantibody panel against tumor antigens for early detection of LC[15]. The trial randomized 12,000 high-risk participants to the blood test alone or routine care (no screening). Those with a positive blood test undergo a CT chest scan. Results of this RTC should be available in late 2018. If we (IASLC) are going to decrease the mortality of lung cancer then we must promote tobacco use intervention and implement LC screening so that more LCs are detected in an early and more curable stage. The optimal paradigm for screening has yet to be developed and is likely to vary in different countries. The NLST was a starting point and reveals that is can be accomplished. Continued innovations and research are required. References 1) The National Lung Cancer Screening Trial Research Team. NEJM (2011); 365:395-409 2) Ma et al. Cancer (2013); 119:1381-5 3) Pastorino et al. J Thorac Oncol (2016); 11:693-699 4) Tanner et al. Amer J Resp Crit Care Med (2016); 193:534-541 5) Tammemagi et al. JNCI (2014); 106:doi.1043/jnci/dju168 6) Moyer et al. Ann Int Med (2014); 160:330-338 7) Jemal and Fedewa. JAMA Oncol, published online February 2, 2017 8) Wang et al. JAMA (2015); 313:853-855 9) Tammemagi et al. NEJM (2013); 368:728-736 10) Tammemagi et al. PLOS (2014); 11e 1001764 11) Young et al. Amer J Resp Crit Care Med (2015); 192:1060-1067 12) Hopkins et al. Annals Amer Thorac Society, published online January 11, 2017. 13) McKay et al. Nature Genetics (2017); 49:1126-1132 14) Raaschou-Nielsen et al. Lancet Oncol (2013); 14:813-822 15) Sullivan et al. BMC Cancer (2017); 17:187-196

Abstract:
In the era of multidetector CT and lung cancer screening with low-dose CT, there are increasing number of incidentally or screen detected pulmonary nodules. Because a pulmonary nodule is an important finding of lung cancer, how to manage these nodules has become an essential issue in dealing with lung cancer, which explains why many guidelines on this topic are available. In this talk, overview of several well-established guidelines or protocols of International Early Lung Cancer Action Program (IELCAP), the American College of Chest Physicians (ACCP), National Comprehensive Cancer Network (NCCN), Fleischner Society, British Thoracic Society (BTS), and Lung CT screening Reporting and Data System (Lung-RADS) will be introduced. Nodule management protocols are different whether nodules are detected at screening programs or incidentally. Screening programs target high-risk subjects who need consistent monitoring, whereas incidentally detected lung nodules represent a different population that needs a varied clinical management. ACCP, BTS, and Fleischner Society guidelines deal with incidental nodules, while IELCAP and Lung-RADS are protocols for screening programs. NCCN guidelines state both issues with separate algorithms. Most pulmonary nodule guidelines have common components: risk factor assessment, nodule size, and nodule consistency. Baseline and annual repeat protocols are different at screening programs. Risk factors include age, smoking history, family history, previous cancer history, occupation exposure, etc. Nodules smaller than certain thresholds (NCCN, < 4 mm; ACCP and BTS, < 5 mm; Fleischner, IELCAP, and Lung-RADS, < 6 mm) do not require routine follow-up. The management for larger nodules varies with guidelines, but 8 mm and/or 15 mm are frequently recommended thresholds for more workups. Nodules can be classified into solid, part-solid, and pure ground-glass nodule according to their consistency. Because the likelihood of malignancy and growth rates are quite different depending on the nodule consistency, this classification is important in nodule management. Nodule volumetry and risk-prediction models such as the Brock University tool, currently employed in BTS guidelines, may be used more frequently in future guidelines. While the Fleischner Society, IELCAP, and Lung-RADS guidelines are relatively straightforward focused on the initial workup, ACCP, NCCN, and BTS guidelines also deal with the further workup and treatment. Some studies have shown that there is high awareness and adoption of these guidelines, but there are varying degrees of conformance with these recommendations. With the accumulation of large data, these guidelines will be more meticulous and evidence-based. Computerized tools that can assess both clinical and radiologic information will facilitate handling the issue of nodule management. References I-ELCAP protocol documents at http://www.ielcap.org/protocols Gould MK, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e93S-e120S. NCCN guidelines at https://www.nccn.org/professionals/physician_gls/f_guidelines.asp Callister ME, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax. 2015 Aug;70 Suppl 2:ii1-ii54. MacMahon H, et al. Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology. 2017 Jul;284(1):228-243. Lung-RADS at https://www.acr.org/Quality-Safety/Resources/LungRADS