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    ES06 - Oligometastatic Disease (ID 774)

    • Event: WCLC 2018
    • Type: Educational Session
    • Track: Oligometastatic NSCLC
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 202 BD
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      ES06.01 - Current Clinical Trials in Oligometastases (Now Available) (ID 11374)

      10:30 - 10:50  |  Presenting Author(s): Anne-Marie C. Dingemans

      • Abstract
      • Presentation
      • Slides

      Abstract

      Long-term benefit of local ablative treatment in patients with up to 3-5 metastatic sites was seen in several, mainly retrospective, series[1]. In 2012 our group published the first prospective clinical trial in NSCLC patients with synchronous oligometastases [2]. In this single arm phase II study 40 patients with stage IV NSCLC and < 5 metastases, amendable for LAT (radiotherapy or surgery), were enrolled. The 2- and 3-year survival rates were 23.3% and 17.5% respectively. In the last years the concept of oligometastasic treatment evolved. The continuing interest was pushed by the increasing number of available treatment strategies, with widespread introduction of minimal invasive surgery and stereotactic radiotherapy. Several guidelines have described oligometastatic NSCLC as a separate entity. After years of retrospective data and single arm trials reporting on oligometastatic NSCLC, at ASCO 2016 the first randomized phase II trial was presented. Progression free survival (PFS), the primary endpoint, was shown to be significantly superior when oligometastatic NSCLC patients were treated with LAT compared to follow-up or maintenance therapy after treatment with at least four cycles of platinum containing chemotherapy or three months of EGFR-TKI (EGFR mutation) or crizotinib (ALK-rearrangement). These were selected patients as oligometastatic was defined as no progression after this systemic treatment; a maximum of three remaining metastases were allowed. The median PFS were 11.9 and 3.9 months in the LAT and the control group, respectively (HR 0.35, 95% CI 0.18-0.66) [3]. The question arises whether we need additional evidence or whether the randomized phase II trial of Gomez with PFS as primary endpoint will change daily clinical practice. In the meantime another randomized phase II study was recently published, randomizing EGFR/ALK negative, NSCLC patients with up to six extracranial cancer sites (including primary) without progression after 4-6 cycles of chemotherapy to maintenance chemotherapy with or without LAT (radiotherapy) to all tumor sites[4]. Primary outcome was PFS. This study was stopped after an unplanned interim analysis, performed after publication of the Gomez trial. 29 of the 36 planned patients were randomized. The median PFS was 9.7 months in the radiotherapy arm and 3.5 months in the control group (HR 0.30, 95% CI 0.11-0.82, p=0.01). The phase III part of this study is ongoing (NCT03137771) and OS is the primary outcome measure.

      In addition to both randomized trials, at the 2017 WCLC conference data of a single arm phase II data on pembrolizumab in oligometastatic NSCLC were presented [5]. 45 patients with up to four metastases and no progression after LAT to all known sites were treated with pembrolizumab. The 1-year PFS was 68%.

      Although the PFS difference is impressive in both randomized phase II studies, there are some concerns to implement this strategy in daily practice. Most importantly the total number of patients enrolled in the two trials combined is very limited (78) and the majority had only one metastatic site. Knowing that assessment of local progression might be a challenge in patients treated with radiotherapy, especially SABR, OS data are needed in order to draw firm conclusions. As patients were randomized after first line treatment baseline characteristics were not known and selection bias might have occurred.

      What can we expect in the next years? A search on clinical trial.gov learned that ongoing clinical trials all use different definitions of oligometastatic NSCLC and that they require different staging procedures. One of the ongoing trials is the SARON trial (NCT02417662), patients with oligometastatic NSCLC (defined as up to three metastases, FDG-PET and brain imaging mandatory) are registered before treatment initiation and randomized (when no progression after two chemotherapy cycles), between two additional chemotherapy cycles with or without radical radiotherapy to all tumor sites. The number of metastasis and mediastinal lymph nodes are stratification factors. Primary outcome is OS. Hopefully this trial will complete enrolment as it can give the final answer on whether local ablative treatment will improve OS in oligometastatic NSCLC patients. In addition OLIGO-CARE is initiated, a pragmatic observational basket study to evaluate radical radiotherapy for oligo-metastatic cancer patients, a joint project of EORTC and ESTRO.

      In conclusion, since the trial of Gomez, oligometastatic NSCLC “is there to stay” as some of these patients benefit from systemic treatment combined with LAT. Most trials focus on radical radiotherapy as the LAT modality but optimally trials would also include surgery as an option. However, despite the promising results important aspects have to be addressed. In order to speak the same language we need a uniform definition of oligometastatic NSCLC. The European Organisation of Treatment of Cancer (EORTC) lung cancer group started an initiative to come to a consensus definition of oligometastatic disease for synchronous NSCLC. In addition, these patients have to be accurately staged (i.e FDG-PET and brain MRI/CT), as proposed by the EORTC imaging group[6]. But most important, future trials will have to address predictive factors, as we need a selection tool to identify those patients that will have long-term benefit from LAT.

      References

      1. Ashworth, A., et al., Is there an oligometastatic state in non-small cell lung cancer? A systematic review of the literature. Lung Cancer, 2013. 82(2): p. 197-203.

      2. De Ruysscher, D., et al., Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct01282450). J Thorac Oncol, 2012. 7(10): p. 1547-55.

      3. Gomez, D.R., et al., Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol, 2016. 17(12): p. 1672-1682.

      4. Iyengar, P., et al., Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol, 2018. 4(1): p. e173501.

      5. Bauml, J., et al., OA 17.08 Phase II Study of Pembrolizumab for Oligometastatic Non-Small Cell Lung Cancer (NSCLC) Following Completion of Locally Ablative Therapy (LAT). Journal of Thoracic Oncology. 12(11): p. S1794-S1795.

      6. deSouza, N.M., et al., Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group. Eur J Cancer, 2018. 91: p. 153-163.

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      ES06.02 - Integrating New Systemic Therapy into Trials in OMD (Now Available) (ID 11375)

      10:50 - 11:10  |  Presenting Author(s): Sanjay Popat

      • Abstract
      • Presentation
      • Slides

      Abstract

      Significant progress has been made in the treatment of metastatic non-small cell lung cancer (NSCLC) in recent years. The oligometastatic state has been identified and formally adopted by UICC from IASLC recommendations by the creation of the M1b category of the v8 TNM staging system, defining patients with a solitary site of metastatic disease. Parallel to these changes, rapid technical advances in supportive care, minimally invasive surgery, and advanced technical radiotherapy have been implemented alongside a greater biological understanding of NSCLC. Contemporaneously, advances in therapeutics have transformed the face of advanced NSCLC with the routine implementation of personalized molecular oncology into routine care and marked durable responses observed, alongside the recent implementation of immune-checkpoint inhibitor therapy. With the latter, optimal scheduling with radiotherapy has been brought under the spotlight to identify, characterize, and enhance the abscopal effect for maximal clinical benefit.

      Whilst interactions between systemic chemotherapy and ablative doses of radiotherapy have been established over recent years, significant uncertainty still exist in defining interactions between ablative radiotherapy and novel systemic therapies. Uncertainties include the role of radical consolidation in patients oncogene addicted disease: when to stop tyrosine kinase inhibitor (TKI) therapy and consolidate with radiotherapy, whether to give traditional radical external beam radiotherapy and risk time off systemic therapy, when (or if) to hold and continue TKI therapy during stereotactic body radiotherapy (SBRT), and if to give ongoing TKI therapy post radiotherapy, and if so, for how long. Similarly for patients with advanced NSCLC suitable for immune checkpoint inhibitor (ICI) therapy, are ICIs the optimal induction agent prior to SBRT, and are they the safest, what risks are observed for combining radiotherapy with ICIs, and does site of oligometastatic disease matter. Finally, should ICIs be given with radical radiotherapy or as consolidation.

      In this presentation, I will overview ongoing uncertainties in integrating novel systemic therapies into the radical management of the oligometastatic state, discuss current potential treatment strategies contingent on patient scenarios, and highlight presented data to help routine clinical decision-making.

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      ES06.03 - Developments in SBRT in the Oligometastatic Paradigm in NSCLC (Now Available) (ID 11376)

      11:10 - 11:30  |  Presenting Author(s): Patrick Cheung

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES06.04 - Surgical Considerations in OMD (Now Available) (ID 11377)

      11:30 - 11:50  |  Presenting Author(s): Jessica Donington

      • Abstract
      • Presentation
      • Slides

      Abstract

      Historically, surgery was reserved for palliation in patients with stage IV NSCLC, but since the 1980s there have been reports of prolonged survival following complete resection of primary tumors and metastatic lesions in select patients with low volume metastatic disease. Hellman and Wechselbaum introduced the term “oligometastasis” to describe an intermediate spread of disease, prior to widely metastatic disease and recognized it as a subset where aggressive local treatments were warranted.

      Surgery for metastatic NSCLC is increasing in frequency. An analysis from the National Inpatient Sample uncovered a 5.8% average annual percent increase resections of NSCLC metastases between 2000 and 2011.1This increase is attributed to several factors, including more efficacious and better tolerated chemotherapies including targeted agents, which have slowed the progression of metastatic spread and altered patterns of resistance. Simultaneously, there have been significant improvements in surgical techniques, with increased minimally invasive approaches, making resection better tolerated and negating long interruption from systemic treatments.

      The majority of patients considered for resection of oligometastatic NSCLC fall into three categories, isolated metastasis to the brain, adrenal glands, or contralateral lung. Patients who have previously undergone resection of early stage NSCLC and subsequently develope isolated oligometastasis and good performance status should be considered for curative intent resection. Similarly patients with oliogometastsis de novo should be evaluated for curative resection in addition to systemic therapy.

      Isolated Brain Metastasis

      Some of the oldest series on surgical treatment of oligometastatic NSLC relate to treatment of isolated brain metastasis.2,3 Up to one quarter of all patients with stage IV NSCLC harbor brain metastasis. Adenocarcinomas are associated with higher rates of brain metastasis, but in 10% of patients with metastatic adenocarcinoma the brain is the only site of involvement.4 Aggressive curative intent treatment of the primary and metastatic site is encouraged in those with good performance status and in whom both sites are amenable to complete resection or ablation. Curative intent local treatments can only be considered after a thorough search for disease at other sites. Mediastinal lymph node involvement portends poor prognosis and therefore invasive mediastinal staging is recommended prior to starting treatment. Brain MRI is recommended in addition to PET/ CT because of increased sensitivity. Multiple brain metastasis are not an absolute contraindication to this aggressive treatment approach, but most recommend three or fewer lesions.5 Treatment of the brain lesion can be by resection or radiosurgery ablation.

      Five year survival following definitive treatment of isolated brain metastasis and primary NSCLC is 15%, and not significantly impacted by synchronous or metachronous presentation. Prognosis is improved in patients who are younger, female, have lower t-stage, and good performance status. Adjuvant whole brain radiation therapy (WBRT) following resection or radiosurgery is recommended. Randomized data on WBRT in this setting is limited, but the sole trial demonstrated a significant decrease brain recurrence.6 There is also no randomized data specifically addressing the use of adjuvant chemotherapy following complete resection of stage IV disease, but with strong evidence supporting adjuvant chemotherapy for completely resected stage II and III, it is recommended.

      Isolated Adrenal Metastasis

      In well-selected patients with isolated adrenal metastasis from NSCLC, survival following complete resection is 25%.7 Similar to those with isolated brain metastasis, mediastinal lymph node involvement portend poor prognosis so invasive staging is recommended. Histology and laterality appear to have no impact on survival and adjuvant chemotherapy is recommended. Synchronous and metachronous tumors have similar long-term survival rates, despite younger age distribution in patients with synchronous presentation.7 Operative mortality is extremely low in reported series and the majority of patients die of disease progression.

      M1a Disease

      The appearance of bilateral NSCLC lesions with the same histology is a staging challenge. In the absence of other disease it is difficult to distinguish bilateral primary tumors from stage IVa disease. Analysis of mutational status and genetic clonality difference are being investigated, but not clinically reliable at this time.The clinical judgement of an experienced multi-modality team is essential, 4 and the criteria described by Martini and Melamed in 1975 remains relevant.8 As with isolated brain and adrenal metastasis, an exhaustive search for additional metastatic disease and invasive mediastinal staging are recommended prior to considering resection. Parenchymal sparing resections are typically recommended when possible in this setting.

      Conclusion

      Most agree that favorable biology is the primary driver of prognosis in the setting of oligometastasis and the true impact of local interventions on prognosis is unclear. But in an era when local treatments carry minimal morbidity and mortality, the lack of clarity should not translate into a denial of intervention in well-selected patients , but rather another treatment option to prolong survival.

      References

      1. Bartlett EK, Simmons KD, Wachtel H, et al. The rise in metastasectomy across cancer types over the past decade. Cancer 2014.

      2. Wronski M, Arbit E, Burt M, Galicich JH. Survival after surgical treatment of brain metastases from lung cancer: a follow-up study of 231 patients treated between 1976 and 1991. Journal of neurosurgery 1995;83:605-16.

      3. Nakagawa H, Miyawaki Y, Fujita T, et al. Surgical treatment of brain metastases of lung cancer: retrospective analysis of 89 cases. J Neurol Neurosurg Psychiatry 1994;57:950-6.

      4. Kozower BD, Larner JM, Detterbeck FC, Jones DR. Special treatment issues in non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e369S-99S.

      5. Fuentes R, Bonfill X, Exposito J. Surgery versus radiosurgery for patients with a solitary brain metastasis from non-small cell lung cancer. The Cochrane database of systematic reviews 2006:CD004840.

      6. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. Jama 1998;280:1485-9.

      7. Tanvetyanon T, Robinson LA, Schell MJ, et al. Outcomes of adrenalectomy for isolated synchronous versus metachronous adrenal metastases in non-small-cell lung cancer: a systematic review and pooled analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008;26:1142-7.

      8. Martini N, Melamed MR. Multiple primary lung cancers. The Journal of thoracic and cardiovascular surgery 1975;70:606-12.

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    JCSE01 - Perspectives for Lung Cancer Early Detection (ID 779)

    • Event: WCLC 2018
    • Type: Joint IASLC/CSCO/CAALC Session
    • Track: Screening and Early Detection
    • Presentations: 20
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 07:30 - 11:15, Room 202 BD
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      JCSE01.02 - Necessity for Early Detection in Lung Cancer and Initial Attempts for Early Detection (Now Available) (ID 11395)

      08:00 - 08:20  |  Presenting Author(s): Annette Maree McWilliams

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.03 - CT Screening for Early Detection (NLST, UKLS, NELSON, ITALUNG, DANTE, Others) (Now Available) (ID 11396)

      08:20 - 08:40  |  Presenting Author(s): Matthijs Oudkerk

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.04 - Risk Modeling for the Early Detection of Tin Miner Lung Cancer in China (Now Available) (ID 11397)

      08:40 - 09:00  |  Presenting Author(s): You-lin 13910410711 Qiao

      • Abstract
      • Presentation
      • Slides

      Abstract

      Result of National Lung Cancer Screening Program has demonstrated a 20% reduced lung cancer mortality with low-dose computed tomography among current or former smokers with a smoking history of 30 or more pack-years[1]. Selecting high risk population for LDCT screening is a key issue for lung cancer screening. Many studies have suggested that lung cancer risk model which incorporating these factors can be more accurate to identify high risk individuals suitable for LDCT screening than the NLST criteria[2]. Thus, more precise evaluation of association between these factors are warranted to developing lung cancer risk models.

      In this study, we developed and internal validated a lung cancer risk model with data of a occupational screening cohort in Yunnan, China with the aim to exploring potential improvement of yield of lung cancer screening with Chest X-ray and Sputum cytology due to the improved risk stratification. This study was a prospective occupational cohort study among tin miners from Yunnan Tin Corporation (YTC) initiated in 1992[3]. Participants were tin miners aged 40 or over and had at least 10 years of underground work or smelting history. Participants also had received annual lung screening from 1992 to 1999, and were annually followed up through December 31, 2001. Previous studies suggested that age, education level, smoking, occupational radon and arsenic exposure, prior chronic bronchitis were risk factors of lung cancer risk in this cohort[4-6]. During the study period, a total of 443 lung cancer deaths were confirmed among 9295 participants. To reduce the potential information bias, 69 lung cancer death with 1 year since enrollment were not included into the analysis.

      To stratified those with higher lung cancer risk, we increased the age criteria from 40 to 50 years old(model 0), then further developed three risk prediction models with multivariate logistic regression respectively, and the predicted probability of lung cancer death for each participants were also calculated based on logistic regression model respectively(table1). The goodness of fit, discrimination and calibration ability of the model performance were evaluated with -2log likelihood, area under the receiver operator characteristic curve (AUC) (C-index) and Hosmer-Lemeshow test. We found that the model incorporated age, gender, smoking, educational prior chronic bronchitis, occupational radon and arsenic had the best discrimination performance with area under ROC as of 0.821(95%CI:0.805-0.836) (figure1a). The calibration performance of this model was also good(Hosmer–Lemeshow type χ2=5.413,p=0.773)(figure1b). The areas under ROC curve of model 2 and model 3 were significantly better than those of model1 and model 0(all p<0.001), however, no difference was found between model 2 and model 3. Besides, Bootstrapping techniques were used for internal validation of the model 3 to Correct for this overfit or optimism, and discrimination C-statistic from C-statics was the same to the original data.

      We stratified the participants into 4 quintiles for the predicted risk of death from lung cancer. The cumulative lung cancer death rate from quintile 1 with lowest risk to quintile 4 having the highest risk increased from 11.51, 47.66, 625.41 to 1732.37 per 105 person-years, while only 2.5% of all lung cancer deaths were in quintile 1 and 2. Similarly, in 210 screen-detected lung cancer deaths, the proportion in quintile 1 and 2 was only 2.4%.

      In conclusion, we have developed and internal validated a lung cancer risk model based on personal and occupation covariates in this occupational population, and this model showed good accuracy for the identification of lung cancer and might assist in identifying individuals at high risk of developing lung cancer in lung cancer screening in this occupational cohort.

      [1] Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011. 365(5): 395-409.

      [2] Tammemägi MC. Application of risk prediction models to lung cancer screening: a review. J Thorac Imaging. 2015. 30(2): 88-100.

      [3] Qiao YL, Taylor PR, Yao SX, et al. Risk factors and early detection of lung cancer in a cohort of Chinese tin miners. Ann Epidemiol. 1997. 7(8): 533-41.

      [4] Lubin JH, Qiao YL, Taylor PR, et al. Quantitative evaluation of the radon and lung cancer association in a case control study of Chinese tin miners. Cancer Res. 1990. 50(1): 174-80.

      [5] Fan YG, Jiang Y, Chang RS, et al. Prior lung disease and lung cancer risk in an occupational-based cohort in Yunnan, China. Lung Cancer. 2011. 72(2): 258-63.

      [6] Yao SX, Lubin JH, Qiao YL, et al. Exposure to radon progeny, tobacco use and lung cancer in a case-control study in southern China. Radiat Res. 1994. 138(3): 326-36.

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      JCSE01.05 - Biomarkers and Liquid Biopsy for Early Detection of Lung Cancer (Now Available) (ID 11398)

      09:00 - 09:20  |  Presenting Author(s): K.C. Allen Chan

      • Abstract
      • Presentation
      • Slides

      Abstract

      The analysis of circulating DNA released by tumor cells, frequently known as liquid biopsy, provides a convenient and noninvasive way for the assessment of cancers. The most common application of liquid biopsy is to guide the choice of treatment in lung cancers. The detection of EGFR mutations in the plasma of patients with advanced lung cancers is useful for predicting the response to EGFR TKI treatment. Because of its noninvasive nature and quick turn-around time, liquid biopsy has been proposed to be a first line investigation for the assessment of EGFR mutational status. Another potential application of liquid biopsy is for the screening of early cancers. However, there is a lack of information regarding the biological feasibility of this approach as it is unclear if a small tumor would release sufficiently large amount of DNA into the circulation to allow early detection of the cancer. In this regard, we used nasopharyngeal cancer (NPC) as a model to address this biological question. As NPC is closely related to Epstein-Barr virus infection, we developed plasma EBV DNA as a marker for NPC. From 2013 to 2016, we screened over 20,000 asymptomatic men for NPC using a sensitive plasma EBV DNA assay. Subjects with positive test results were further investigated with nasal endoscopy and MRI. Through this arrangement, we identified 34 cases of NPC and almost half of them had stage I disease. Compared with historical cohorts, patients identified by screening had much improved progression-free survivial with a hazard ratio of 0.1. This study clearly demonstrates that a small early cancer can release sufficiently large amount of DNA into the circulation to allow sensitive detection by liquid biopsy. To apply these results to non-viral-associated cancers, we developed a generic cancer test based on copy number aberrations and altered methylation in plasma DNA. This test successfully detect various types of cancers, including lung cancer.

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      JCSE01.06 - Incorporating Artificial Intelligence for Early Detection of Lung Cancer (Now Available) (ID 11399)

      09:20 - 09:40  |  Presenting Author(s): Jie Hu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.09 - Cluster Trial: Ph2 Biomarker-Integrated Study of Single Agent Alpelisib, Capmatinib, Ceritinib and Binimetinib in advNSCLC (Now Available) (ID 11678)

      10:15 - 10:25  |  Presenting Author(s): Qing Zhou  |  Author(s): Yi-Long Wu, Xu-Chao Zhang, Hai-Yan Tu, Bin Gan, Bin-Chao Wang, Chong-Rui Xu, Hua-Jun Chen, Ming-ying Zheng, Zhen Wang, Xiao-Yan Bai, Yue-Li Sun, Andrea Myers, Xueting Lv, Yajnaseni Chakraborti, Sylvia Zhao, Jin -Ji Yang

      • Abstract
      • Presentation
      • Slides

      Background
      Several genetically altered signaling pathways have been profiled in NSCLC, enabling advanced management of NSCLC using targeted therapies. This study investigated the therapeutic spectrum of NSCLC with uncommon molecular alterations by allocating patients to treatment arms based on molecular aberrations; targeted therapies alpelisib (PI3Kαi), capmatinib (METi), ceritinib (ALKi), and binimetinib (MEKi) were evaluated.The study was based on the umbrella design. Key objectives: investigate feasibility of using one trial for different agents based on biomarker-integrated analysis, assess anti-tumor activity, characterize safety, tolerability and PK profiles of individual agents. Key eligibility criteria: age ≥18 years; ECOG PS ≤2; failed prior treatment/unsuitable for chemotherapy. Documentation of locally determined molecular alterations before treatment allocation was required (alpelisib, 350 mg QD: PIK3CA mutation/amplification; capmatinib, 400 mg BID (tablet): MET IHC overexpression/amplification; ceritinib, 750 mg QD: ALK or ROS1 rearrangement; binimetinib, 45 mg BID: KRAS, NRAS or BRAF mutation).Sixty-six patients with advNSCLC were enrolled (median age 58 years; 65.2% male: alpelisib, n=2; capmatinib, n=16; ceritinib, n=26; binimetinib, n=22). As of Feb 28, 2018, 10 patients in ceritinib and 2 in binimetinib arms were ongoing. Twenty-four patients had confirmed partial responses (36.4%): alpelisib, 0%; capmatinib, 18.8%; ceritinib, 73.1%; binimetinib, 9.1% (Figure). Longest mPFS (14.4 months) was in ceritinib arm. Among the most common treatment-related AEs: alpelisib: malaise, hyperglycemia, dysgeusia; capmatinib: nausea, anemia, peripheral edema, decreased appetite; ceritinib: diarrhea, vomiting, ALT/AST elevation; binimetinib: mouth ulceration, AST, blood CPK increased, rash. Most AEs were grade 1/2.

      abstract #1.jpg

      Objective responses/tumor shrinkage were observed in the study; highest ORR and mPFS were observed with ceritinib, although patient numbers differed between arms. All treatments were well tolerated; no new safety signals were observed. This study demonstrated the feasibility of an umbrella trial and importance of precision medicine in the management of advNSCLC with uncommon molecular alterations.

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      JCSE01.10 - A Ph3 Study of Niraparib as Maintenance Therapy in 1L Platinum Responsive Extensive Disease Small Cell Lung Cancer Patients (Now Available) (ID 11679)

      10:25 - 10:35  |  Presenting Author(s): Shun Lu  |  Author(s): Liyan Jiang, Xinghao Ai, Junling Li, Xiaorong Dong, Dan Zhang, Qi Liu

      • Abstract
      • Presentation
      • Slides

      Background
      Small cell lung cancer (SCLC) accounts for 15% of lung cancer, characterized by early dissemination and rapid development of chemo-resistant disease after platinum response (60-80%). Less than 2% of extensive disease SCLC (ED-SCLC) patients survive 5 years. The bi-allelic loss or inactivation of TP53 and RB1 is common in SCLC, the poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA damage repair enzyme, is highly expressed in SCLC, and SCLC is sensitive to platinum based chemotherapy, suggesting that the defect in DNA damage repair pathways plays an important role in SCLC. ZL2306/ Niraparib is a highly selective PARP-1/2 inhibitor which was exclusively licensed for development in China by Zai Laboratory from TESARO. In SCLC PDX model, niraparib demonstrated anti-tumor activities as monotherapy. In addition, niraparib demonstrated promising tumor growth inhibition in maintenance post platinum treatment in platinum sensitive SCLC PDX models. Clinically, in phase III NOVA study, niraparib demonstrated clear clinical benefit as maintenance treatment by significantly extending progression free survival in all platinum-sensitive recurrent ovarian cancer patients regardless gBRCA or HRD status which led to the approval by FDA and EMA in ovarian cancer. It is suggested that niraparib maintenance therapy could provide potential clinical benefit in platinum responsive SCLC. ZL-2306-005 is a randomized double-blind multi-center phase 3 study to evaluate the efficacy and safety of niraparib versus placebo as maintenance therapy in ED-SCLC patients who have had responses to platinum based chemotherapy.Approximately 590 Chinese patients with histologically or cytologically confirmed ED-SCLC who have achieved either complete response or partial response to their platinum based chemotherapy to their newly diagnosed disease will be randomized (2:1) to 2 groups, receiving either ZL-2306 or placebo in ZL-2306-005 study. Patients need to complete 4 cycles of etoposide + cisplatin/ carboplatin. All patients will be stratified by gender, LDH level and history of prophylactic cranial irradiation. ZL-2306 will be started with 300mg PO QD for patients with a baseline body weight ≥77 kg and a baseline platelet count ≥150,000/μL, or 200 mg PO QD for patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL based on RADAR analysis in NOVA study. Patients will remain on treatment until disease progression or intolerable toxicity. The co-primary endpoints are PFS assessed by independent central radiologic review and OS; the secondary endpoints are PFS assessed by investigator, CFI, QoL, safety and tolerability.

      Section not applicable

      Section not applicable

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      JCSE01.11 - Dynamic ctDNA Monitoring Revealed Novel Resistance Mechanisms and Response Predictors of Osimertinib Treatment in East Asian NSCLC Patients (Now Available) (ID 14716)

      10:35 - 10:45  |  Presenting Author(s): Jianhua Chang  |  Author(s): Zhihuang Hu, Dongmei Ji, Shannon Chuai, Weina Shen, Junning Cao, Jialei Wang, Xianghua Wu

      • Abstract
      • Presentation
      • Slides

      Background

      Advanced NSCLC patients, harboring EGFR T790M, exhibit marked diversity in tumor behavior and response to AZD9291, yet a discriminable molecular profile remains elusive. In addition, although EGFRC797S was involved in 30% of AZD9291 resistance cases in Western patients, mechanisms for the rest patients remain unclear, especially for the East Asian population. We utilized circulating tumor DNA (ctDNA) profiling to conduct dynamic monitoring in patients undergoing AZD9291, thus characterizing mutational heterogeneity and genomic evolution.

      Longitudinal plasma samples were collected before, during and post of the AZD9291 treatment in Chinese NSCLC patients with acquired T790M mutation. A ctDNA panel, spanning 160KB of human genome, was used to perform capture-based targeted sequencing that comprises critical exons and introns of 168 genes. The EGFR mutation abundance and dynamic changes of allele fraction (AF) were analyzed with progression-free survival (PFS) after AZD9291 treatment.

      A total of 61 samples were collected longitudinally from 14 patients, of which 9 have experienced progressive disease (PD). Six patients exhibited a rebound of ctDNA prior to radiographic PD, suggesting the potential of ctDNA in early detection of PD. Several acquired mutations were detected with the AZD9291 resistance, including newly identified EGFR G796S, L792H/F/R/V, V802F, V843I mutations, expect for the previously reported RB1 and EGFR C797S, L718Q mutations. Patients with a higher ratio of T790M and EGFRactivating mutation at baseline had a significantly longer PFS (9.6m vs 4.5m, p=0.008). A lower ratio of EGFRactivating mutation AF compared to baseline at first follow-up was significantly correlated with a longer PFS (8.5m vs 5.0m, p=0.027). Furthermore, patients harboring other known driver mutations in addition to T790M at baseline had an inferior PFS (4.9m vs 7.8m, P=0.039).

      Several novel resistance mechanisms were identified by ctDNA monitoring in the East Asian patients treated with AZD9291. Relative AF of T790M, changes of AF after treatment and the presence of concurrent driver mutations at baseline could predict clinical benefit of AZD9291 treatment.

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      JCSE01.12 - Discussant Oral Abstracts (Now Available) (ID 11681)

      10:45 - 11:00  |  Presenting Author(s): Daniel S.W. Tan

      • Abstract
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      Abstract not provided

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      JCSE01.13 - Discussant Poster Abstracts (Now Available) (ID 11682)

      11:00 - 11:15  |  Presenting Author(s): Bob T. Li

      • Abstract
      • Presentation
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      Abstract not provided

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      JCSE01.14 - Effects of Neoadjuvant Chemotherapy on the Expression of Programmed Death Ligand-1 and Tumor Infiltrating Lymphocytes in Lung Cancer Tissues (ID 14703)

      11:15 - 11:15  |  Presenting Author(s): Xu Wang  |  Author(s): Wenyu Sun, Kewei Ma

      • Abstract

      Background
      Immune checkpoints programmed death 1(PD1)and its ligand PD-L1,PD-L2 pathways can mediate negative synergistic stimulation signals.Immunotherapy combined with chemotherapy can increase the objective response rate of cancer patients,but the mechanism of combination therapy is not clear.This study aims to analyze the changes of PD-L1,PD-L2 in lung cancer tissues and the changes of TILs ( CD4+,CD8+,CD28+,and CD56+ lymphocytes ) surrounding the tumor before and after neoadjuvant chemotherapy(platinum-based),in order to provide a theoretical basis for relevant clinical studies.Tumor samples were obtained from 26 patients who confirmed primary lung cancer before and after NAC from 2009 to 2016 in the First Hospital of Jilin University. The expression of PD-L1, PD-L2 in lung cancer specimens were assessed by IHC. 5%,10%,20%,30%,50% expression thresholds were used to define PD-L1, PD-L2 positive status, respectively. Of 16 patients ( since the biopsy tissue specimens were limited, only 16 cases of biopsy and postoperative tissue specimens were collected), the expression of TILs around the tumor before and after NAC were assessed by IHC. We analyze the changes of PD-L1 and PD-L2 in lung cancer tissues before and after NAC, the correlation between the changes of PD-L1 in lung cancer tissues and tumor shrink rate, the interval from the end of NAC to operation, pathological type, gender and smoking status. Of 16 patients, the changes of TILs around the tumor before and after NAC were also evaluated. P<0.05 was considered statistically significant.

      1. When using 5%, 10%, and 20% as expression threshold to define PD-L1 positive status, PD-L1 was up-regulated after NAC (P=0.008,P=0.016,P=0.016). However, there were no obviously statistical significance about the expression of PD-L1 when using 30%, 50% expression threshold. The expression of PD-L2 were not show any statistical significance before and after NAC.

      2. Of 16 patients, the expression of CD4+, CD8+ and CD28+ lymphocytes increased after NAC (P=0.014,P=0.038,P=0.021), whereas the change of CD56+ lymphocytes was not statistical significant.

      3. There were no significant difference between the changes of PD-L1 and tumor shrink rate, interval from the end of NAC to operation, pathological type, gender and smoking status .

      1. NAC up-regulates the expression of PD-L1 in lung cancer tissues when the expression thresholds are 5%, 10%, and 20%.

      2. NAC up-regulates the expression of CD4+, CD8+, and CD28+ lymphocytes.

      3. No correlation exists between the variation of PD-L1 and tumor shrink rate, interval from the end of NAC to operation, pathological type, gender and smoking status.

      a9ded1e5ce5d75814730bb4caaf49419

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      JCSE01.15 - Molecular Characteristics of ALK Primary Point Mutations Non-Small-Cell Lung Cancer in Chinese Patients (ID 14704)

      11:15 - 11:15  |  Presenting Author(s): Chunwei Xu  |  Author(s): Jinhuo Lai, Wenxian Wang, Quxia Zhang, Wu Zhuang, Yunjian Huang, Youcai Zhu, Yanping Chen, Gang Chen, Meiyu Fang, Tang Feng Lv, Yong Song

      • Abstract
      • Slides

      Background
      Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified in lung cancer at 3-7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. While the genetic locus of ALK primary point mutations NSCLC patients is unclear. The aim of this study is to investigate mutations and prognosis of NSCLC harboring ALK primary point mutations.

      A total of 339 patients with non-small-cell lung cancer were recruited between July 2012 and December 2015. The status of ALK primary point mutation and other genes were detected by next generation sequencing.


      ALK gene primary point mutation rate was 8.55% (29/339) in non-small cell lung cancer, including V163L (3 patients), F921Gfs*16 (2 patients), K1416N (2 patients), A585T (2 patients), P1442Q (1 patient), A348T (1 patient), K1525E (1 patient), S737L (1 patient), P115L (1 patient), Q515E (1 patient), E314D (1 patient), R395H (1 patient), S1219F (1 patient), S341G (1 patient), P1543S (1 patient), G129V (1 patient), Q167H (1 patient), L550F (1 patient), T1012M (1 patient), D302Y (1 patient), H755Q (1 patient), H331Q (1 patient), G1474E (1 patient) and E119D (1 patient), and median overall survival (OS) for these patients was 20.0 months. Among them, 27 patients with co-occurring mutations had a median OS of 20.0 months, and median OS of the 2 patients without complex mutations was 8.5 months. Statistically significant difference was found between the two groups (P=0.02). Briefly, patients with (n=8) or without (n=21) co-occurring EGFR mutations had a median OS of 24.0 months and 20.0 months respectively (P=0.73); patients with (n=21) or without (n=8) co-occurring TP53 mutations had a median OS of 20.0 months and 17.0 months respectively (P=0.83).

      EGFR and TP53 gene accompanied may have less correlation with ALK primary point mutation in NSCLC patients. Results of ongoing studies will provide a platform for further research to offer individualized therapy with the purpose of improving outcomes. a9ded1e5ce5d75814730bb4caaf49419

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      JCSE01.16 - Positive Correlation Between Whole Genomic Copy Number Variant Scoring and the Grading System in Lung Non-Mucinous Invasive Adenocarcinoma  (ID 14705)

      11:15 - 11:15  |  Presenting Author(s): Zheng Wang  |  Author(s): Shenglei Li, Lin Zhang, Lei He, Di Cui, Chenglong Liu, Yuyan Gong, Bi Liu, Xiaoyu Li, Wang Wu, David Cram, Dongge Liu

      • Abstract
      • Slides

      Background
      Grading systems of Lung adenocarcinoma have been proposed by Sica and Kadota in stage I tumors,but the predominant architectural subtypes grading system is applicable for resection samples mostly. The correlation between the histological subtypes and grading with whole genomic copy number variation(WGCNV) is unknown, and was investigated in lung non-mucinous invasive adenocarcinoma (LNMIA) at this study.The predominant histological subtype from 58 resection specimens of LNMIA and 20 para-cancerous lung tissues were collected by laser microdissection from HE staining FrameSlides PEN-Membrane slides.7 of 58 specimens,two predominant subtypes in one cancerous nodule were collected simultaneously. Whole genome amplification followed by high-throughput sequencing was used to deteted WGCNV with the para-cancerous lung tissues as normal reference set and WGCNV was scored by a particular formula.
      abstract #1.jpgabstract #2.jpg

      The letters above the figure show the results of Chi-squared test, and same letters mean no significant difference.

      WGCNV median scores of 5 histological subtypes of LNMIA with three tiered architectural grades are shown in Table1. The WGCNV scores have a positive correlation with either histological subtypes and architectural grading system (Figure1 A and B). The differences of WGCNV scores are detected betweem two predominant subtypes in one cancerous nodule.

      GWCNV scores display a positive correlation with three tiered architectural grading system and may has a potential value to predict prognosis in LNMIA. a9ded1e5ce5d75814730bb4caaf49419

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      JCSE01.17 - Weekly Nab-Paclitaxel Plus Carboplatin as Neoadjuvant Therapy for IIIA-N2 Lung Squamous Cell Carcinoma: A Prospective Phase II Study (ID 14706)

      11:15 - 11:15  |  Presenting Author(s): Changli Wang  |  Author(s): Yu Zhang, Jian Quan Zhu, Dongsheng Yue, Xiaoliang Zhao, qiang Zhang, Hui Chen

      • Abstract
      • Slides

      Background
      To evaluate the safety and antitumor activity of weekly nab-paclitaxel combined with carboplatin in patients with advanced stage IIIA-N2 NSCLC patients with squamous histologyFrom April 2015 to August 2017, 36 treatment-naive, pathologically diagnosed IIIA-N2 lung squamous cell carcinoma patients were enrolled and given two cycles of weekly nab-paclitaxel (100mg/m2, day1,8,15 of a 21-day cycle) plus Carboplatin (AUC = 5 at day 1, q3w) as neoadjuvant therapy. Then resectability was assessed and surgery was performed for resectable lesions. Post-operative adjuvant chemotherapy regimens is the combination of Nab-paclitaxel (100mg/m2, qw x 6) and carboplatin (AUC 5, Q3W x 2) for patients with PD, adjuvant chemotherapy regimen will be changed. The primary objective is the safety and efficacy, and the secondary objectives are quality of life and the role of prognostic biomarker SPARC.

      Of 36 patients, 3 stopped treatment due to patient decision. 33 were finally evaluated and 1 is still on treatment. Significant tumor volume shrinkage was seen in some patients after the neoadjuvant therapy. 66.7% patients achieved partial response (PR), 21.2% patients achieved stable disease (SD). Disease control (PR +SD) rate was 87.9%. Finally, 23 patients underwent surgical resection, the respectability rate was 69.7%. 12.1% occurred disease progress and failed to achieve resection, including 3 with local progress and 1 with pulmonary metastatic nodule; Among 22 PR pts, 4 failed to achieve resection, in which 1 was due to heart function, the other 3 due to personal unwillingness. 2 of 7 with stable disease failed to achieve resection; the pathological improvement in T stage and N stage before and after treatment was 81.8% (18/22) and 50% (11/22) respectively. The major adverse event was neutropenia (grade I and II) and no serious AE was found.

      Nab-paclitaxel in combination with Carboplatin showed promising ORR rate and resection rate in of IIIA-N2 lung squamous cell carcinoma. The regimen could be a new chemo option as the neoadjuvant treatment. PFS and OS data will be reported after follow up completing.

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      JCSE01.18 - A Multicenter Survey of One Year Survival Among Chinese Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer (CTONG1506) (ID 14707)

      11:15 - 11:15  |  Presenting Author(s): Qing Zhou  |  Author(s): Ping Yu, Yong Song, Xin Zhang, Gongyan Chen, Yi Ping Zhang, Jianhua Chen, Zhuang Yu, Yi Hu, Xia Song, Diansheng Zhong, Guosheng Feng, Lulu Yang, Lujing Zhan, Luan Di Yao, Yun Chen, Yue Gao, Yi-Long Wu

      • Abstract
      • Slides

      Background
      Previous results of CTONG1506 study showed that gene aberration test rate was increasing in Chinese NSCLC patients and first-line treatment was standardized accordingly. This survey further described one year survival of patients with different gene aberration status and under different first-line treatments.

      CTONG1506 was a two-year series cross-sectional study. Patients with advanced nonsquamous NSCLC who were admitted from August 2015 to March 2016 and who received first-line anti-cancer treatment at one of 12 tertiary hospitals across China were included. Data extracted from medical charts were entered into medical record abstraction forms, which were collated for analysis. Survival information was collected one year after patients were admitted to hospital. One year survival rate and its 95% confidence interval were analysed by Kaplan-Meier method.

      A total of 707 patients were analysed, with mean age of 57 years and 56.7% were male. Among the 487 patients who had survival data, 192 were EGFR- mutation positive (86 mutated in exon 19 [one year survival rate 0.90, 95% CI: 0.81-0.94] and 88 mutated in exon 21 [one year survival rate 0.84, 95% CI: 0.75-0.90]), 27 patients were ALK positive and 164 patients were EGFR and ALK wild type. Most EGFRmutation positive patients (128/192) received tyrosine kinase inhibitors (TKIs) as first-line treatment and most EGFR wild type patients (155/175) received first-line chemotherapy (Chemo). Pemetrexed was the most common non-platinum chemotherapy-backbone agent (120/155) in platinum doublet regimens. One year survival rates are shown in the table.

      abstract 12337 ctogn1506 one-year survival.png

      This national-wide real world study of tertiary hospitals in China revealed that a majority of (>75%) advanced nonsquamous NSCLC patients survived more than one year and was comparable to well-controlled clinical trial results, indicating survival benefits by gene aberration status guided standard of care. This result may be further validated by our on-going two-year survey.

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      JCSE01.19 - ALTER-0303 Study: Tumor Mutation Index (TMI) For Clinical Response to Anlotinib in Advanced NSCLC Patients at 3rd Line (ID 14708)

      11:15 - 11:15  |  Presenting Author(s): Baohui Han  |  Author(s): Jun Lu, Wei Zhang, Bo Yan, Lele Zhang, Jie Qian, Bo Zhang, Shuyuan Wang

      • Abstract
      • Slides

      Background

      Anlotinib is an effective multi-targeted receptor tyrosin kinase inhibitor (TKI) for refractory advanced Non-Small Cell Lung Cancer (NSCLC) therapy at 3rd line. ALTER-0303 clinical trial has been revealed that Anlotinib significantly prolongs progression free survival (PFS; Anlotinib: 5.37 months vs Placebo: 1.40 months) and overall survival (OS; Anlotinib: 9.63 months vs Placebo: 6.30 months) with the objective response rate (ORR) of 9.18% and the disease control rate (DCR) of 80.95%. Here, we sought to understand the gene mutation determinants for clinical response to Anlotinib via next generation sequencing (NGS) upon cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) at baseline.

      Totally 437 advanced NSCLC patients enrolled in ALTER-0303 study, and 294 patients received Anlotinib therapy. Of the 294 patients, 80 patients were analyzed in the present study. Capture-based targeted ultradeep sequencing was performed to obtain germline and somatic mutations in cfDNA and ctDNA. Response analyses upon discovery cohort (n = 62) and validation cohort (n = 80) were performed by use of germline and somatic (G+S) mutation burden, somatic mutation burden, nonsynonymous mutation burden, and unfavorable mutation score (UMS), respectively. Based on the above independent biomarkers and their subtype factors, tumor mutation index (TMI) was developed, and then used for response analysis.

      Our data indicated that the patients harbouring less mutations are better response to Anlotinib therapy (G+S muatation burden, cutoff = 4000, Median PFS: 210 days vs 127 days, p = 0.0056; somatic mutation burden, cutoff = 800, Median PFS: 210 days vs 130 days; p = 0.0052; nonsynonymous mutation burden, cutoff = 50, Median PFS: 209 days vs 130 days; p = 0.0155; UMS, cutoff = 1, Median PFS: 210 days vs 131 days; p = 0.0016). TMI is an effective biomarker for Anlotinib responsive stratification (Median PFS: 210 days vs 126 days; p= 0.0008; AUC = 0.76, 95% CI: 0.62 to 0.89) upon discovery cohort and validation cohort (Median PFS: 210 days vs 127 days; p = 0.0006). Lastly, integrative analysis of TMI and IDH1 mutation suggested a more promising result for Anlotinib responsive stratification upon validation cohort (Median PFS: 244 days vs 87 days; p < 0.0001; AUC = 0.90, 95% CI: 0.82 to 0.97).This study provide a biomarker of TMI to stratify Anlotinib underlying responders, that may improve clinical outcome for Anlotinib therapy on refractory advanced NSCLC patients at 3rd line. Clinical trial information: NCT02388919. a9ded1e5ce5d75814730bb4caaf49419

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      JCSE01.20 - Outcome in Small Cell Lung Cancer Patients with Cerebral Recurrence After Prior Prophylactic Cranial Irradiation  (ID 14710)

      11:15 - 11:15  |  Presenting Author(s): Lei Zhao  |  Author(s): Jindong Guo, Xuwei Cai, Xiaolong Fu

      • Abstract
      • Slides

      Background
      Prophylactic cranial irradiation (PCI) is a standard therapy for both limited small cell lung cancer (SCLC) and extensive SCLC patients with good responses to first-line treatment. The aim of this study was to examine outcomes in SCLC patients in a single institution who underwent cerebral recurrence after prior PCI.

      We retrospectively examined the medical records of 219 consecutive SCLC patients who had initially received PCI(25 Gray in 10 fractions) between June 2007 to June 2017. Data were analyzed with regard to age, sex, smoking status, treatment, disease stage, data of PCI, time to cerebral recurrence, site of cerebral recurrence, re-irradiation after cerebral recurrence and time to death. Survival was estimated by the Kaplan-Meier method. Multivariate analyses were performed by the log-rank and Cox’s proportional hazard model test.

      Of the 219 patients undergoing PCI, 180(82.2%) were LD-SCLC and 39(17.8%) were ED-SCLC. The median age was 59 years and the median follow-up time was 23.7 months. The median overall survival (OS) of all patients from the time of diagnosis was 39.0 months (95%CI, 29.6–48.4), in LD-SCLC it was 47.0 months (95%CI, 35.4–58.6), and in ED-SCLC it was 19.0 months (95%CI, 17.0–21.0). The difference was statistically significant with P=0.000.

      Forty-six patients (21.0%) were diagnosed with cerebral recurrence. 30(65.2%) of these presented with oligometastatic disease and 16(34.8%) had non-oligometastatic disease. Cox multivariate analysis identified disease stage (P=0.043) was the only significantly favorable prognostic factor for cerebral recurrence. The median survival time from PCI was 21.0 months (95%CI, 12.5–29.5), in oligmetastatic disease it was 35.0 months (95%CI, 19.0–51.0), and in non-oligometastatic disease it was 16.0 months (95%CI, 12.1–19.9). The difference was statistically significant with P=0.007. Meanwhile, the median time from PCI to cerebral recurrence was 11.0 months (95%CI, 9.5–12.5), in oligmetastatic disease it was 11.0 months (95%CI, 6.7–15.3), and in non-oligometastatic disease it was 10.0 months (95%CI, 8.4–11.6). There was no statistical significance between the two.

      Among forty-six patients with cerebral recurrence, 34 patients underwent re-irradiation using either Re-WBRT (11patients, 23.9%) or SRS /SRT (23patients, 50.0%), another 12 patients (26.1%) did not accept radiotherapy to brain. The median survival time from cerebral recurrence was 10 months (95%CI, 4.1-16.0) for re-irradiation and 4 months (95%CI, 2.3-5.8) for no radiotherapy group, respectively. The difference was statistically significant with P=0.000.

      PCI remains standard therapy for SCLC patients with good responses to first-line treatment. Cerebral recurrence is inevitable, however, cerebral re-irradiation after recurrence is proven to be beneficial for survival.


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      JCSE01.21 - Different Responses to Osimertinib in Primary and Acquired EGFR T790M-Mutant NSCLC Patients (ID 14711)

      11:15 - 11:15  |  Presenting Author(s): Shuyuan Wang  |  Author(s): Bo Zhang, Baohui Han

      • Abstract
      • Slides

      Background
      Primary EGFR T790M could be occasionally identified by routine molecular testing in tyrosine kinase inhibitor TKI-naive non-small cell lung cancer (NSCLC) patients. This study was aimed to compare clinical characteristics of primary and acquired T790M mutations and their responses to Osimertinib in NSCLC patients.
      We collected clinical characteristics of patients diagnosed with epidermal growth factor receptor (EGFR) mutation from 2012 to 2017 in Shanghai Chest Hospital. For patients with primary and acquired T790M mutations, the responses to Osimertinib were analyzed.Primary T790M was identified in 1.03% (61/5900) of TKI-naive patients. Acquired T790M was detected in 45.50% (96/211) of TKI-treated patients. T790M always coexisted with sensitizing EGFR mutations. Primary T790M was always coexisted with 21L858R (45/61) whereas acquired T790M was coexisted with 19del (61/96). Among them, 18 patients with primary T790M mutation acquired Osimertinib and 75 patients with acquired T790M mutation received Osimertinib. The median progression-free survival (mPFS) of Osimertinib in primary T790M group was greatly longer than that in acquired T790M group (18.0 months:95% CI:15.0-21.0 VS 10.0months:95% CI:8.3-11.7, P=0.016). The DCR of both groups were 89.3% and 100%. In primary T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 15.7m and 24.0 m, respectively. In acquired T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 11.0m and 10.0m, respectively.

      Primary and acquired T790M-mutation patients showed different molecular characteristics. Both of them may respond to Osimertinib. However, primary T790M patients showed greater survival benefits from Osimertinib than acquired T790M patients.

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      JCSE01.22 - Differential Molecular Mechanisms Associated with Dramatic and Gradual Progression in NSCLC Patients with Intrathoracic Dissemination (ID 14713)

      11:15 - 11:15  |  Presenting Author(s): Ying Chen  |  Author(s): Bao Hua, Wei Li, Chao Zhang, Wen-Fang Tang, Ao Wang, Xue Wu, Jing-Hua Chen, Jian Su, Yang W. Shao, Yi-Long Wu, Wen-Zhao Zhong

      • Abstract
      • Slides

      Background
      Lung cancer is a highly heterogeneous disease with diverse clinical outcomes. The pleural cavity is a frequent metastasis site of proximal lung cancer. Better understanding of its underlining molecular mechanisms associated with dramatic and gradual progression of pleural metastasis in patients with non-small cell lung cancer (NSCLC) is essential for prognosis, intervention and new therapy development.We performed whole-exome sequencing (WES) of matched primary lung adenocarcinoma and pleural metastatic tumors from 26 lung cancer patients with dramatic progression (DP, n=13) or gradual progression (GP, n=13). Somatic alterations at both genome-wide level and gene level were detected. Kaplan-Meier survival analysis and multivariate Cox regression models were applied to analyze the association between different somatic alterations and clinical parameters.We first analyzed the differences in somatic alterations between AP and RP group in the primary tumors, and identified higher somatic copy number alteration (SCNA) level in DP group compared to GP group, which is significantly (p=0.016) associated with poorer progression-free survival (PFS). More specifically, patients with chromosome 18q loss in the primary tumor showed a trend (p=0.107) towards poorer PFS. PTEN (p=0.002) and GNAS (p=0.002) mutations are enriched in the primary tumors of DP group, and are associated with poorer PFS. Furthermore, pleural metastatic tumors harbor a relatively higher level of mutation burden (p=0.105) and significantly increased SCNA (p=0.035) compared to the primary tumors.NSCLC patients in the attenuated progression group have more stable genomes. High level of genomic instability, GNAS and PTENmutations, as well as chromosome 18q loss are associated with rapid progression. a9ded1e5ce5d75814730bb4caaf49419

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      JCSE01.22a - Tislelizumab Combined With Chemotherapy as First-Line Treatment in Chinese Patients With Advanced Lung Cancer (ID 14702)

      11:15 - 11:15  |  Presenting Author(s): Jie Wang  |  Author(s): Jun Zhao, Zhijie Wang, Zhiyong Ma, Jiuwei Cui, Yongqian Shu, Zhe Liu, Ying Cheng, Shiang Jiin Leaw, Jian Li, Fan Xia

      • Abstract

      Background
      Immune checkpoint inhibitors have shown efficacy in patients with NSCLC as monotherapy and in combination with chemotherapy. Tislelizumab is a humanized IgG4 monoclonal antibody to PD‑1 specifically engineered to minimize FcϒR binding on macrophages, possibly minimizing negative interactions with other immune cells. In a phase 1 study, tislelizumab was generally well tolerated and showed antitumor activity; 200mg IV Q3W was established as the recommended dose.

      This multi-arm phase 2 study, consisting of safety run-in and dose-extension phases, assessed tislelizumab in combination with platinum-based chemotherapy (by tumor histology) as a potential first-line treatment for Chinese patients with lung cancer. All patients received tislelizumab at 200mg Q3W in combination with 4–6 cycles of platinum-doublet until disease progression. Nonsquamous (nsq) NSCLC patients received pemetrexed + platinum Q3W for 4 cycles followed by pemetrexed maintenance, while squamous (sq) NSCLC patients received paclitaxel + platinum (A) or gemcitabine + platinum (B) Q3W, and small-cell lung cancer (SCLC) patients received etoposide + platinum Q3W. Tumor response (RECIST v1.1) and safety/tolerability were evaluated.

      As of 21 Feb 2018, 48 patients (median age, 62 years [range: 36–75], 71% male, 71% current/former smokers) received tislelizumab treatment (median, 3 cycles [range: 1–7]); 44 patients remain on the study. Across the four cohorts, confirmed and unconfirmed partial responses were observed in 13 and 9 patients, respectively (Table). The most frequent AEs were chemotherapy-related hematologic toxicities. The most commonly reported grade ≥3 treatment-related AEs were neutropenia (20.8%) and anemia (12.5%); the most common grade 3 immune-related AEs were pyrexia (6.3%) and rash (6.3%). One sq‑NSCLC patient experienced a fatal myocarditis/myositis following one cycle of paclitaxel/cisplatin; all other treatment-related AEs were managed/resolved by study-drug interruption (n=15) or discontinuation (n=4) and appropriate treatment.

      Best Overall Response (Patients With ≥1 Post-Baseline Tumor Assessment)

      nsq-NSCLC (n=9)

      sq-NSCLC [A] (n=12 )

      sq-NSCLC [B] (n=5 )

      SCLC (n=8)

      Total

      (N=34)

      PR

      4 (44.4)

      9 (75)

      4 (80)

      5 (62.5)

      22 (64.7)

      Confirmed PR

      1 (11.1)

      4 (33.3)

      4 (80)

      4 (50)

      13 (38.2)

      Unconfirmed PR

      3 (33.3)

      5 (41.7)

      0 (0)

      1 (12.5)

      9 (26.5)

      SD

      3 (33.3)

      2 (16.7)

      1 (20)

      2 (25)

      8 (23.5)

      PD

      1 (11.1)

      0 (0)

      0 (0)

      1 (12.5)

      2 (5.9)

      NE

      1 (11.1)

      1 (8.3)

      0 (0)

      0 (0)

      2 (5.9)

      Data presented as n (%).

      Abbreviations: nsq-NSCLC, non-squamous non-small cell lung cancer; NE, not evaluable; PD, progressive disease; PR, partial response; SCLC, small cell lung cancer; SD, stable disease; sq-NSCLC, squamous non-small cell lung cancer.

      Tislelizumab, in combination with platinum doublets, demonstrated preliminary antitumor activity and was generally well tolerated in patients with advanced lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419

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    MA01 - Early Stage Lung Cancer: Questions and Controversies (ID 894)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 202 BD
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      MA01.01 - Proposal on Incorporating Lymphovascular Invasion as a T-Descriptor for Stage I Non-Small Cell Lung Cancer (Now Available) (ID 12754)

      10:30 - 10:35  |  Presenting Author(s): Shuyuan Wang  |  Author(s): Bo Zhang, Jianlin Xu, Rong Qiao, Baohui Han, Bo Yan, Yu Dong

      • Abstract
      • Presentation
      • Slides

      Background

      Lymphovascular invasion (LVI) and Visceral Pleural Invasion(VPI) have been reported to be risk factors for stage I Non-Small Cell Lung Cancer (NSCLC). However, only VPI was incorporated into the current 8th Tumor–Node–Metastasis(TNM) classification. This study aimed at exploring the prognostic impact of LVI on TNM staging in Pathological Stage I NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed 2600 consecutive p-stage I NSCLC patients in the Shanghai Chest Hospital (2008-2012). By using the Kaplan–Meier method and Cox proportional hazard regression model, we identified the correlations between LVI, VPI and clinical outcomes in p-stage I NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      Of all p-stage I NSCLC 2600 patients, 221 were pathologically diagnosed with LVI and 815 pathologically with VPI, respectively. It was observed that patients with LVI had an unfavorable lung cancer specific survival (LCSS) (hazard ratio [HR]: 1.883; 95% confidence interval [CI]: 1.351-2.625; P < 0.001) and recurrence-free survival (RFS) (HR: 2.025; 95% CI: 1.560-2.630; P < 0.001). The 5-year RFS rates of patients with LVI was significantly worse than those without LVI (61.2% VS 82.7%, P< 0.001). Patients with LVI exhibit similar prognosis (HR: 2.538; 95% CI: 1.570-4.098; P < 0.001) compared with that of VPI in pN0 non-small-cell lung cancer and a tumor diameter of 3cm or smaller. When tumor size was between 3-4cm, patients with LVI and VPI were associated with inferior prognosis than those with only LVI or VPI (P < 0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The presence of LVI independently and significantly affects LCSS and RFS in patients with stage I NSCLC. Our results suggest that stage T1a-1c(IA) patients with LVI should be upstaged to T2a(IB), meanwhile, stage T2a(IB) patients coexist with LVI and VPI should be upstaged again in the TNM classification.

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      MA01.02 - Histologic Subtyping in Pathologic Stage I Lung Adenocarcinoma Provides Risk-Based Stratification for Surveillance (Now Available) (ID 13400)

      10:35 - 10:40  |  Presenting Author(s): Yusuke Takahashi  |  Author(s): Takashi Eguchi, Koji Kameda, Shaohua Lu, Raj G. Vaghjiani, Kay See Tan, David R. Jones, William D Travis, Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      Current national practice guidelines (NCCN, ACCP, ESMO) recommend a uniform follow-up protocol with intensive surveillance within the first two years following lung resection for stage I NSCLC. We hypothesize that the recurrence hazard following lung resection for stage I lung adenocarcinoma (ADC) varies according to histologic subtype.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 1572 patients with resected pathologic stage I lung ADC were investigated. Two thoracic pathologists reviewed all tumor H&E slides (range 1-8, median 3) for histologic subtyping and percentage of each subtype. Recurrence hazard was estimated using the Kernel-Epanechnikov smoothing procedure. Association between recurrence hazard and high-grade histologic subtypes (micropapillary [MIP] and solid [SOL]) was assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      Presence (≥5%) of these high-grade subtypes (MIP and/or SOL) was associated with significant increase of recurrence hazard compared to high-grade pattern negative (<5%) tumors (Figure): 1) patients with presence of either MIP or SOL had significant recurrence hazard peaks within two years after surgery; 2) SOL was associated with early hazard peak at the first year after surgery especially in distant recurrence hazard; 4) one-third of patients (515/1572, 33%) had no high-grade subtypes, in which the recurrence hazard was consistently very low (<2% risk each year) during the 10-year period after surgery without any hazard peak (red arrow).

      hazard fig 300.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data suggest the utility of histologic subtyping for identifying patients with very low recurrence hazard, and provide foundation for establishing risk-based follow-up protocols. A potential option for low-risk patients may be omission of intensive follow-up during the first two years after surgery.

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      MA01.03 - An Externally Validated Nomogram for Predicting Distant Metastasis After SBRT for Early Stage Non-Small Cell Lung Cancer (Now Available) (ID 11182)

      10:40 - 10:45  |  Presenting Author(s): Aditya Juloori  |  Author(s): Alexander Zajichek, Michael Kattan, Daniel J. Mullen, Pamela Samson, Neil M Woody, Mike Roach, Jeffrey Bradley, Gregory M.M. Videtic, Cliff Robinson, Kevin L Stephans

      • Abstract
      • Presentation
      • Slides

      Background

      SBRT is a standard option for patients with early stage NSCLC who are medically inoperable. While SBRT is associated with excellent local control, distant metastases (DM) represent the primary pattern of failure. Adjuvant systemic therapy has not traditionally been used in this patient population due to medical comorbidities. With the advent of immunotherapy that may be better tolerated, there has been a renewed interest in identifying patients that may derive benefit. We developed and internally validated a nomogram to predict the likelihood of DM after SBRT for early stage NSCLC which was then externally validated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our lung SBRT registry was queried for patients with early stage NSCLC treated with definitive intent from 2003-2017 and 1002 patients were identified for analysis to develop the model. A dataset from an external institution was used to similarly identify patients and 737 were used for the validation cohort. Random Survival Forest was used to assess importance, interactivity, and overall predictive ability with respect to DM for 14 variables. A Fine-Gray competing-risks regression model was formulated where apparent interactions were examined with likelihood-ratio tests. Backward variable selection was implemented to reduce to a parsimonious model. The concordance probability (C-index) of the model was internally validated with 10-fold cross validation.

      4c3880bb027f159e801041b1021e88e8 Result

      The median overall survival was 1.71 years internally and 1.92 years externally. Median follow-up was 18.3 months and 21.1 months. 1-year incidence of DM was 16% and 12.1% in the internal and external cohorts, respectively. Random Forest analysis suggested that tumor size and PET SUV are the most important predictors of distant failure. The 1-year cumulative incidence (CI) of DM was 18.5% for PET SUV ≥4.1 vs 8.4% for <4.1. 1-year CI for tumor size >3 cm was 26% vs 12.6% for ≤3 cm. The median time to DM was 0.86 years internally and 1.1 years externally. The final nomogram included tumor size, histology, PET SUV, age, KPS, and active smoking status, and had a cross-validated C-index of 0.62. The nomogram provides predictive value for probability of DM at 1-year between 10 and 70%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This novel nomogram with external validation can be used to predict the 1-yr DM risk after SBRT for patients with early-stage NSCLC, accounting for the competing risk of death. This nomogram may help define patient subsets for stratification in future clinical trials to help identify who may benefit from adjuvant systemic therapy after SBRT to reduce the incidence of DM and disease-related death.

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      MA01.04 - Discussant - MA01.01, MA01.02, MA01.03 (Now Available) (ID 14572)

      10:45 - 11:00  |  Presenting Author(s): Deepali Jain

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA01.05 - Opioids and Sleep Medication Use After Surgery for Early Stage Lung Cancer: A SEER-Medicare Analysis (Now Available) (ID 12961)

      11:00 - 11:05  |  Presenting Author(s): Stephanie Tuminello  |  Author(s): Juan Wisnivesky, Rebecca Schwartz, Bian Liu, Grace Mhango, Raja Flores, Emanuela Taioli

      • Abstract
      • Presentation
      • Slides

      Background

      More than 50% of patients undergoing surgery for early stage lung cancer experience persistent post-operative pain, which can prevent their returning to normal daily activities and cause disruptions in sleep. Whether Video-Assisted Thoracoscopic Surgery (VATS), a minimally invasive surgical technique, reduces long-term opioid and sleep medication use compared to traditional open surgery has not yet been established.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The Surveillance, Epidemiology and End Results data linked to Medicare data (SEER-Medicare) database was queried to identify patients with stage I primary non-small cell lung cancer (NSCLC) who had VATS or open resection between 2007 to 2013, and had no record of opioid medication in the 30 days before surgery. Long-term opioid and sleep medication use were defined as having fulfilled one or more prescriptions in the first 90 days after surgery as well another prescription in the 90-180 days post-surgery. Logistic regression was used to investigate the associations between surgical type and long-term opioid and sleep medication use. Models were adjusted for relevant clinical and socioeconomic covariates.

      4c3880bb027f159e801041b1021e88e8 Result

      There were 3,900 NSCLC patients included in this analysis; 1,987 (51.0%) VATS and 1,913 (49.0%) open surgery patients; 15.5% of patients had a record of opioid use and 9.7% of sleep medication use long-term postoperatively.

      In the adjusted model, patients were less likely to use opioids long-term if they had VATS (ORadj 0.69, 95% CI: 0.57-0.84), were older (ORadj 0.96, 95% CI: 0.94-0.98), diagnosed in a later year (ORadj 0.86, 95% CI: 0.82-0.90), and had higher income (ORadj 0.77, 95% CI: 0.60-0.99). Long-term opioid use was more likely in those with a higher comorbidity score (ORadj 1.10 , 95% CI: 1.05-1.16), large cell histology (ORadj 1.88, 95% CI: 1.17-3.00), using sleep medication before surgery (ORadj 1.72, 95% CI: 1.28-2.32) and with a previous psychiatric condition (ORadj 1.64, 95% CI: 1.28-2.09).

      After adjustment, only those with a previous psychiatric condition (ORadj 1.95, 95% CI: 1.40-2.71) and previous sleep medication use (ORadj 37.36, 95% CI: 27.92-50.00) were more likely to use sleep medications long-term; no significant difference were observed with type of surgery (ORadj 1.01, 95% CI: 0.76-1.33).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients who were not previous opioid users became long-term opioid users after surgery. VATS might offer NSCLC patients a better quality of life than open surgery, and therefore minimize the risk of longer-term opioid use.

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      MA01.06 - Evaluation of Safety and Efficacy in Surgical Treatment for Octogenarian Lung Cancer Patients by Multicenter Prospective Study: JACS1303 (Now Available) (ID 13117)

      11:05 - 11:10  |  Presenting Author(s): Tomohiro Haruki  |  Author(s): Hisashi Saji, Takahiko Ueno, Morihito Okada, Hiroshige Nakamura, Masayuki Chida

      • Abstract
      • Presentation
      • Slides

      Background

      The percentage of octogenarian lung cancer patients have increased on the background of the aging of Japan’s demographics. Although some retrospective studies reported clinicopathological scoring systems for predicting postoperative complications and survival outcomes for elderly lung cancer patients, optimized scoring systems remain controversial. This study (JACS1303) aims to evaluate the clinical factors to develop a comprehensive operative risk scoring (RS) system for octogenarian patients with lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      JACS conducted a nationwide multicenter prospective cohort and enrolled a total of 1,019 octogenarians with medically operable lung cancer. Details of the clinical factors, comorbidities, and comprehensive geriatric assessment were recorded for 895 patients to develop a comprehensive risk scoring (RS) system capable of predicting severe complications.

      4c3880bb027f159e801041b1021e88e8 Result

      Operative (30 days) and hospital mortality rates were 1.0% and 1.6%, respectively. Complications were observed in 308 (34%) patients, of whom 81 (8.4%) had grade 3–4 severe complications. Pneumonia was the most common severe complication, observed in 27 (3.0%) patients. The following five predictive factors: gender, comprehensive geriatric assessment (CGA)75: memory, Simplified Comorbidity Score (SCS): diabetes mellitus, Alb, and %VC were identified as independent predictive factors for severe postoperative complications (odds ratio = 2.73, 1.86, 1.54, 1.66, and 1.61, respectively) through univariate and multivariate analyses. A 5-fold cross validation was performed as an internal validation to reconfirm these five predictive factors (average AUC: 0.70). We developed a simplified RS system as follows: RS = 3 (Gender: male) + 2 (CGA75: memory: yes) + 2 (Alb: <3.8 ng/ml) + 1 (%VC: ≤90) + 1 (SCS: Diabetes mellitus: yes).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The current study shows that octogenarians can be successfully treated for lung cancer with surgical resection with an acceptable rate of severe complications and mortality. We propose a simplified RS system to predict severe complications in octogenarian patients with medically operative lung cancer.

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      MA01.07 - Validation of RTOG 0813 Normal Tissue Constraints for Pulmonary Toxicity in SBRT for Central Non-Small Cell Lung Cancer (Now Available) (ID 11318)

      11:10 - 11:15  |  Presenting Author(s): Kyle Verdecchia  |  Author(s): Bindu Manyam, Gregory M.M. Videtic, Tingliang Zhuang, Neil M Woody, Kevin L Stephans

      • Abstract
      • Presentation
      • Slides

      Background

      Stereotactic body radiation therapy (SBRT) yields excellent local control rates for medically inoperable early stage "central" non-small cell lung cancer. Normal tissue constraints provided in RTOG 0813, which tested safety and efficacy of lung SBRT for central tumors, were largely based on expert estimates, and clinical validation of constraints is limited. We sought to identify the sensitivity and specificity of the current RTOG constraints for predicting pulmonary toxicity in a large institutional data set.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified 136 lesions within 2 cm of the proximal bronchial tree (PBT), treated from 2005 to 2014 from a prospective registry of 1,462 patients. Dose was 50 or 60 Gy given in 5 fractions. Pulmonary toxicity was categorized as pneumonitis or non-pneumonitis (fistula, bronchial stenosis or necrosis, atelectasis, hemoptysis, or clinically significant pleural effusion). A series of dose endpoints for the PBT was generated based on dose volume histograms, where dose levels ranged from 0 Gy to 80 Gy in increments of 0.1 Gy, and volumes ranged from 0.03 cc to 50 cc in increments of 0.03cc. A total of 1,333,600 dosimetric endpoints were analyzed. The sensitivity and specificity of these endpoints in predicting pulmonary toxicity was calculated. The optimal dosimetric endpoint was chosen by identifying the highest F-score.

      4c3880bb027f159e801041b1021e88e8 Result

      We observed nine Grade 2 pneumonitis and 10 Grade ≥ 2 non-pneumonitis toxicities, of which three were Grade 5 (broncho-pleural fistula, left mainstem bronchus necrosis, and bronchial stenosis). The optimal dosimetric endpoint to avoid Grade 2-5 non-pneumonitis toxicity was D0.03cc<50 Gy to the PBT, with 90% sensitivity and 77% specificity. The optimal point dose to avoid Grade 3-5 non-pneumonitis toxicity was D0.3cc<46.5 Gy, with 100% sensitivity and 85% specificity. Applying PBT RTOG constraints to our dataset achieved 18% sensitivity and 91% specificity for D4cc<18 Gy and 29% sensitivity and 93% specificity for D0.03cc<52.5 Gy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Clinical results from this large institutional data set validate current RTOG constraints for PBT as predictive for pulmonary toxicity. The results also suggest that RTOG constraints D4cc<18 Gy and D0.03cc<52.5 Gy to PBT have moderate sensitivity but excellent specificity for pulmonary toxicity. We identified D0.03cc <50 Gy to PBT as having the largest sensitivity and specificity for toxicity prediction, and this value parallels current RTOG constraint of D0.03cc <52.5 Gy. This analysis suggests that an additional volume/dosimetric constraint of D0.3cc<46.5 Gy may be considered for avoidance of Grade 3-5 non-pneumonitis pulmonary toxicity.

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      MA01.08 - Discussant - MA01.05, MA01.06, MA01.07 (Now Available) (ID 14573)

      11:15 - 11:30  |  Presenting Author(s): Biniam Kidane

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA01.09 - Risk Factors of Radiation-Induced Lymphopenia (RIL) and Its Prognostic Significance in Small Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy (Now Available) (ID 14426)

      11:30 - 11:35  |  Presenting Author(s): Xiaomei Gong  |  Author(s): Qianqian Zhao, Jian He

      • Abstract
      • Presentation
      • Slides

      Background

      The decrease in peripheral blood lymphocytes induced by radiation lessens the antitumour effect of the immune response, which might cause immunosuppression. This reduction might be affected by fractionation scheme. The purpose of this study was to assess the effect of fractionation scheme (consecutive daily fractions or nonconsecutive fractions) of SBRT on clinical outcomes in early-stage peripheral non-small cell lung cancer (NSCLC). We also analyzed the different effect of these two fractionation schemes in reducing peripheral blood lymphocytes during SBRT treatment period.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data from a total of 61 early-stage peripheral NSCLC patients who had received SBRT were retrospectively analyzed. A total dose of 50 Gy in 5 fractions over 5-7 days was delivered for all patients. Peripheral blood lymphocytes were measured before and after SBRT. We used the Kaplan-Meier method, the log-rank test, and Cox proportional hazards regression to determine whether radiation treatment schedule associated with clinical outcomes.

      4c3880bb027f159e801041b1021e88e8 Result

      Figure 1 showed Kaplan–Meier estimates for progression free survival (PFS) (Figure A) and overall survival (OS) (Figure B) for entire cohort stratifying for fractionation regimen. Multivariate analysis showed that nonconsecutive fractionation was an independent predictor of a longer PFS (P = 0.002). OS trended toward improvement in the non-consecutive group, but this was not statistically significant (P = 0.181). Development of any grade 3 or higher toxicity was not significantly different between the two groups (P = 0.813). The average circulating lymphocyte counts of consecutive group patients significantly declined after RT (1977.27 versus 1368.18 cells/µl, P < 0.001) while the nonconsecutive group patients did not (1700.00 versus 1450.00 cells/µl, P = 0.155).
      figure 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Five-fraction SBRT delivered over non-consecutive days achieved superior clinical outcomes and similar toxicity compared to consecutive fractionation. Consecutive daily fractions of SBRT might cause worse immunosuppression by the more severe damage of peripheral lymphocytes.

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      MA01.10 - Toxicity and Local Control in “Ultra-Central” Lung Tumors Treated With SBRT or High-Dose Hypofractionated RT (Now Available) (ID 13969)

      11:35 - 11:40  |  Presenting Author(s): Chunyu Wang  |  Author(s): Baho Sidiqi, Ellen Yorke, Dominique McKnight, Rosalind Dick-Godfrey, Danielle Torres, Daphna Gelblum, Andreas Rimner, Abraham J. Wu

      • Abstract
      • Presentation
      • Slides

      Background

      Stereotactic body radiation therapy (SBRT) for central lung tumors has been associated with higher rates of severe toxicity. Data suggests that tumors with specific high-risk features, namely GTV abutting proximal bronchial tree (PBT), trachea or PTV intersecting esophagus (“ultra-central” tumors), are at risk of severe complications. We sought to evaluate toxicity and efficacy for high-risk lung tumors treated with SBRT in our institution.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients treated with SBRT for central lung tumors during 2008 to 2017 were reviewed to identify ultra-central tumors. Patients who received more than 4 Gy per fraction and BED10≥84 were included in the analysis. The primary endpoint was grade 3+ adverse events potentially attributable to RT, based on CTCAE 4.0. Secondary endpoints were local control (LC) and overall survival (OS) for primary lung cancer patients, Kaplan-Meier analysis was used to estimate LC and OS.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 88 patients who met the inclusion criteria (76 with abutment of PBT, 8 with abutment of trachea, 22 with overlap of esophagus, and 17 with multiple structures at risk). The median follow-up was 21.5 (95%CI, 12.5 to 30.5) months. Forty-six patients had primary NSCLC, 7 had locally recurrent NSCLC and 35 had lung metastases. The prescription doses were 400cGy x 15 (n=21), 750cGy x 8 (n=13), 1000cGy x 5 (n=29) and 900cGy x 5 (n=25). Eight patients (9.1%), all abutting the PBT, experienced fatal complications potentially related to RT. Four patients developed fatal pulmonary hemorrhage. Maximum point doses to PBT were 54.9Gy, 51.4Gy, 49.4Gy (in 5 fractions) and 63.8Gy (8 fractions) and 2 of them had received bevacizumab in close proximity to RT. Four patients developed fatal pneumonia/radiation pneumonitis (all had pre-existing COPD). No Grade 4 toxicity was identified. Grade 3 overall toxicity rate was 12.5%. Only 3 of 22 (13.6%) patients whose PTV overlapped with esophagus had Grade 3 toxicity. The 1-year and 2-year LC for the whole cohort were 87.5% and 79.1%, respectively. The 1, 2-year OS for primary NSCLC patients were 77.8% and 62.6%, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      To our knowledge, this is the largest reported series of patients who received SBRT for ultra-central tumors. RT achieves high rates of local control in these patients, but the rate of severe or fatal toxicity is substantial. Further studies are needed to establish the relationship between SBRT and toxicity in these patients.

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      MA01.11 - Salvage SBRT for Local Recurrence After Primary Surgical Resection of Early Stage Non-Small Cell Lung Cancer (Now Available) (ID 11284)

      11:40 - 11:45  |  Presenting Author(s): Sarah Sittenfeld  |  Author(s): Aditya Juloori, Chandana A. Reddy, Kevin L Stephans, Gregory M.M. Videtic

      • Abstract
      • Presentation
      • Slides

      Background

      To report on the patient, tumor and treatment characteristics of patients treated with salvage lung SBRT (sSBRT) for non-metastatic NSCLC that has relapsed after previous surgical resection, and the resulting clinical outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We surveyed our IRB-approved prospective lung SBRT registry for patients who received sSBRT for local recurrence after previous resection of an early stage NSCLC. Following sSBRT, outcomes of interest included local control (LC), overall survival (OS), and treatment-related toxicity graded per CTCAE version 4.0.

      4c3880bb027f159e801041b1021e88e8 Result

      For the interval 2004-2017, 50 (3.4%) pts, of a total of 1,461 lung SBRT cases, met criteria for analysis. Pre-sSBRT surgical approaches were: 23 (46%) wedge resection, 2 (4%) segmentectomy, 20 (40%) lobectomy, 2 (4%) bilobectomy, 1 (2%) pneumonectomy and 1 (2%) with unspecified surgery. At the time of resection, disease stage was: 34 (68%) stage I, 4 (8%) stage II, 5 (10%) stage III and for 3 (6%) pts, pre-operative stage was unknown. Median time to local recurrence after surgery was 27.45 months. At sSBRT, 38 (76%) pts had biopsy-proven recurrence while 12 (24%) had recurrence diagnosed only by radiographic findings. Forty seven (94%) pts could not have surgical salvage due to pulmonary (60%), cardiac (2%), technical unresectability (4%), poor KPS (2%), or multifactorial reasons (26%), with 3 (6%) refusing re-resection. Median age and KPS at salvage treatment was 74 years (range 50-89) and 80 (range 60-100) respectively. The most common sSBRT schedule was 50Gy in 5 fractions (68%), with all schedules having a BED of at least 100 Gy10. Median follow up after sSBRT was 22.2 months (3.8-108.8 months). Eight pts subsequently experienced local or lobar failure (16%), and 9 patients had nodal failure (18%). Median time to local failure after sSBRT was 12.5 months (2-66.1 months). At analysis, 11 (22%) pts remain alive and free from disease progression. At 24 months, LC and OS were 83.6% (95% CI 71.1-96) and 66.7% (95% CI 53.3-80.1). Median OS after sSBRT was 29.3 months. Twenty one (42%) pts failed distantly at a median time of 11.4 months and 12 (24%) pts received systemic therapy following distant failure. 74% of pts experienced no toxicity after sSBRT and three patients (6%) developed grade III toxicity (cough, atelectasis or soft tissue necrosis).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Similar to SBRT for primary early stage NSCLC, sSBRT for local relapse following initial surgical resection of NSCLC offers high rates of LC with limited toxicity. Distant failure remains the primary pattern of failure.

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      MA01.12 - Discussant - MA01.09, MA01.10, MA01.11 (Now Available) (ID 14574)

      11:45 - 12:00  |  Presenting Author(s): Drew Moghanaki

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      • Presentation
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      Abstract not provided

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    MA09 - Lung Cancer Surgical and Molecular Pathology (ID 908)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 202 BD
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      MA09.01 - Correlation of Pre-Operative Cancer Imaging Techniques with Post-Operative Macro and Microscopic Lung Pathology Images   (Now Available) (ID 13181)

      15:15 - 15:20  |  Presenting Author(s): Stephen James Harrow  |  Author(s): Gabriel Reines-March, Craig Dick, Xiangyang Ju, Stephen Marshall

      • Abstract
      • Presentation
      • Slides

      Background

      This research project aims to investigate the performance of several PET radiotracers in lung cancer by aligning PET-CT and pathology imagery acquired from the same patients at different points in time. The discrimination of tumour substructures is of great importance in therapy planning, as a given treatment may be better adapted depending on the local characteristics of the carcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Due to the high deformability of lung tissue, several intermediate steps must be used for merging pathology and pre-operative PET-CT in a coherent manner. Firstly, the tumour volume is reconstructed from the macroscopic images taken during dissection. For this purpose, an enhanced dissection protocol is used, where the lung specimen is placed in a bespoke slicing rig and embedded in agar to hold it in place. Using a threaded plunger, the specimen is pushed upwards in 5mm steps, sliced and photographed. This procedure allows us to obtain slices of uniform thickness. Secondly, microscopic digital slides of the cancerous tissue are merged with the macroscopic 3D model. Finally, the whole volume is fused with the pre-operative PET-CT scan, using a non-linear deformable model.

      4c3880bb027f159e801041b1021e88e8 Result

      Preliminary results obtained with a synthetic phantom allowed us to analyse the accuracy of the tumour 3D reconstruction algorithm from planar macroscopic slices. Using these findings, we could optimise the interpolation and segmentation routines for building an accurate 3D model of the tumour mass. During our first trial with lung tissue (on-going work), each cross-sectional slice was photographed, the tumour boundary was delineated in each image by a pathologist (CD), and from these contours a high-resolution 3D tumour model was built. Next, the corresponding microscopic digitised slices were merged. To date, ten patients have been identified and consented, therefore allowing us to test our algorithm on different cases and assess its performance.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We demonstrate a novel set of methods for co-registration of pre-operative PET-CT to macro and microscopically defined lung tumours. This proof of principle now allows interrogation of the raw data from PET-CTs using a range of tracers and the development of algorithms that identify substructure detail within a tumour mass, which could lead to tailored radiotherapy for individual tumours based on tracer patterns and uptake.

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      MA09.02 - Tumor Size and Frozen Section Should Be Considered Jointly to Predict the Final Pathology for Lung Adenocarcinoma (ID 13365)

      15:20 - 15:25  |  Presenting Author(s): Erjia Zhu  |  Author(s): Chang Chen

      • Abstract
      • Slides

      Background

      Invasive adenocarcinoma intraoperatively misdiagnosed as adenocarcinoma in situ or minimally invasive adenocarcinoma is more likely to undergo potentially insufficient resection. The purpose of our study was to evaluate the diagnostic accuracy of frozen section.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed 1,111 lung adenocarcinomas to evaluate the diagnostic performance of frozen section. A derivation cohort consisting of 436 cases of AIS or MIA diagnosed by frozen section in the same period were analyzed to find predictive factors for invasive adenocarcinoma as the final diagnosis. Validation cohorts were included to confirm the results.

      4c3880bb027f159e801041b1021e88e8 Result

      Intraoperatively measured tumor size was the only independent factor for invasive adenocarcinoma as the final diagnosis (P = 0.001) in the derivation cohort, and was confirmed by validation cohorts. Fifty-nine misdiagnosed invasive adenocarcinomas in the three cohorts consisted of 54 lepidic predominant type, 1 papillary and 4 acinar predominant type. There were no positive N1, N2 node, pleural, lymphatic and vascular invasion cases found. Thirty-seven (37/59, 63%) cases of misdiagnosis were attributed to sampling error, which was the main reason.figure1.jpgfigure3.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Adenocarcinoma in situ or minimally invasive adenocarcinoma ≥ 1 cm by frozen section were more likely to be invasive adenocarcinoma because of sampling error.

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      MA09.03 - Multiple Pathological Variables Predict Efficacy of Adjuvant Chemotherapy in Primary Lung Adenocarcinoma (Now Available) (ID 13761)

      15:25 - 15:30  |  Presenting Author(s): John Le Quesne  |  Author(s): Marco Sereno, Claire Smith, Madhumita Das, Robert Hastings, Grace Rake, David Moore

      • Abstract
      • Presentation
      • Slides

      Background

      Adjuvant chemotherapy has become established as a vital complement to surgery over the last decade, and improves survival by targeting micrometastatic disease which is clinically inaparrent at the time of surgery. However, in comparison to other common malignancies, the guidelines for the administration of adjuvant chemotherapy in lung cancer are rudimentary, being based solely upon clinical stage II and above at the time of surgery. We set out to discover pathological factors with the potential to better identify patients who are likely to benefit from this vital therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      662 cases of primary lung adenocarcinoma treated with surgery with curative intent were identified from 2005-2014; 109 received adjuvant chemotherapy. Comprehensive survival/recurrence data, pathological data, and treatment history data were collected. Detailed histopathological data (growth pattern, vascular invasion, pleural stage) were collected by review of scanned histopathological images.

      Multivariate Cox regression survival models were used to identify interactions between clinicopathological variables and adjuvant chemotherapy. A propensity score matching approasch was used to reduce selection biases in the data.

      4c3880bb027f159e801041b1021e88e8 Result

      The existing stage criteria for the recommendation of adjuvant chemotherapy are stage pN1/2 and size>40mm; only nodal invasion interacts with chemotherapy in an OS model (interaction term HR=0.67 P=0.017). However, signficant interactions are seen with predominant growth pattern (HR=0.47 P=0.001 ), pleural stage (HR=0.62 P=0.002 ), and vascular invasion (HR=0.56 P=0.033).

      We reduced selection bias by balancing treated and untreated groups by propensity matching for all prognostic variables. In the matched dataset, patients with predominantly in situ tumours experience no benefit of chemotherapy (HR=1.81 P=0.18), while higher-grade cases show substantial benefit (HR=0.53 P=0.01). Similar benefits were seen for patients with increasing pleural stage and vascular invasion.

      In a multivariate model designed to identify which variable(s) had the most ability to predict treatment efficacy, only tumour growth pattern showed a significant interaction with chemotherapy treatment (HR=0.51 P=0.01 ).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We find that the existing stage-based criteria for adjuvant chemotherapy can be much improved. Low-grade cases experienced only negative effects of chemotherapy, while higher-grade cases showed a benefit. Pleural stage and vascular invasion were also significantly predictive. We suggest that the current criteria may be leading to substantial over- and under-treatment. A nuanced algorithm for the identification of patients likely to benefit from chemotherapy, which includes these additional pathoogical measures, may significantly improve patient outcomes. This would be especially impactful to the majority of surgical patients for whom no personalised therapy is as yet available.

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      MA09.04 - Discussant - MA 09.01, MA 09.02, MA 09.03 (Now Available) (ID 14605)

      15:30 - 15:45  |  Presenting Author(s): Natasha Rekhtman

      • Abstract
      • Presentation
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      Abstract not provided

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      MA09.05 - Can We Predict Radiosensitivity in Non-Small Cell Lung Cancer? (Now Available) (ID 13835)

      15:45 - 15:50  |  Presenting Author(s): Juvenal Baena  |  Author(s): Christopher Talbot, John Le Quesne

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with lung cancer receive different treatments depending on their detailed clinical-pathological context. However, over 70% of patients are treated with radiotherapy, which is of varying efficacy. Rather surprisingly, no biomarkers are currently used to predict tumour response and to aid with radiotherapy dosing or regimen. The aim of this study is to identify histopathological features which may predict tumour radiosensitivity in patients with NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We have identified a set of 67 NSCLC cases with a history of radiotherapy for which pre-treatment archival tissue and CT imaging follow-up is available from the period 2009 to 2014. Digital images of archival diagnostic tissue sections were examined to derive morphological measures with the potential to predict radiosensitivity. Quantitative radiological measures of response up to 6 months after radiotherapy were derived. Since radiographic measurements were taken at variable time-points, we standardised by inferring the fractional maximum diameter of the tumour 100 days after radiotherapy (FRT100)

      4c3880bb027f159e801041b1021e88e8 Result

      The density of multipolar mitoses seen microscopically is related to radiosensitivity (regression against FRT100: R2 = 0.14, p=0.005*) and a trend toward a negative relationship with neuroendocrine differentiation (R2 =0.06, p=0.058). The presence of multipolar mitoses was further associated with poor overall survival ( Univariate Cox p= 0.02*). Patients with radiological evidence of good response (ie low FRT100) showed a time-dependent survival benefit (p=0.02*), while after 2 years tendency of both groups was similar. Patients showing squamous differentiation had a poor prognosis, with no overall survival after 4 years, while 21.8% of the ACA were still alive after 4 years (p= 0.04*)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Multipolar mitoses and neuroendocrine differentiation may be predictive histological markers of radiosensitivity in NSCLC. More samples are being gathered, and immhunohistochemical and DNA sequence biomarkers of radiosensitvity are currently being assessed.

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      MA09.06 - The Newly Recognized Filigree Pattern of Micropapillary (MIP) Lung Adenocarcinoma (LADC) is as Clinically Important as the Classical Pattern (Now Available) (ID 11874)

      15:50 - 15:55  |  Presenting Author(s): Katsura Emoto  |  Author(s): Takashi Eguchi, Raj G. Vaghjiani, Yusuke Takahashi, Natasha Rekhtman, Prasad S. Adusumilli, William D Travis

      • Abstract
      • Presentation
      • Slides

      Background

      Filigree pattern is a newly recognized addition to the morphological spectrum of the poor prognostic category of micropapillary (MIP) LADC. However, its morphologic features and clinical importance are not well understood. The aim of this study was to investigate the morphologic spectrum and clinical significance of filigree MIP pattern.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Filigree pattern was defined as tumor cells growing in delicate lace-like narrow stacks of cells (at least 3 piled-up nuclei) without fibrovascular cores, with frequently visible attachments to alveolar walls. This differs from the 2015 WHO description of classical MIP pattern as tumor cells growing in papillary tufts forming florets that lack fibrovascular cores. In order to assess for filigree vs classical MIP, we documented the frequency and extent of both patterns in 1325 Stage I LADC. These were correlated with recurrence free probability (RFP) and lung cancer-specific survival (LCSS) using Kaplan-Meier analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      In addition to 87 MIP predominant ADC previously diagnosed, we identified 57 more cases of MIP predominant LADC due to the new criteria of MIP filigree pattern. Of these 57 cases, 37, 16, and 4 cases were reclassified from papillary, acinar, and solid predominant LADCs, respectively. Survival curves of previously diagnosed MIP and newly diagnosed MIP for RFP showed a similar worse prognosis compared to other LADC histologic subtypes (previously diagnosed MIP vs newly diagnosed MIP, 5-year RFP 66% vs 68% [Figure]) as well as LCSS (previously diagnosed MIP vs newly diagnosed MIP, 5-year LCSS 82% vs 85%). When the MIP cases were divided into filigree or classical predominant MIP, no significant prognostic differences were observed between the two groups.

      figure filigree.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The lack of significant prognostic difference between filigree vs classical predominant MIP LADC supports our proposal that the filigree pattern is an important addition to the morphologic spectrum of the MIP subtype.

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      MA09.07 - Developing a Pathological Grading System in Predicting Prognosis for Invasive Mucinous Adenocarcinomas (Now Available) (ID 12124)

      15:55 - 16:00  |  Presenting Author(s): Wei-Chin Chang  |  Author(s): Yu Zhi Zhang, Eric Lim, Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      Invasive mucinous adenocarcinoma (IMA) is a variant of lung adenocarcinoma with a predominance of mucinous type neoplastic epithelial cells, often showing aerogenous spreading and multifocality. The correlation between histopathological features and prognosis has not been well studied due to its relatively rare incidence compared to non-mucinous adenocarcinoma. Our study aims to evaluate the significance of histopathological features in relation to clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed a series of 101 cases of IMAs resected between 2000 to 2012, comprised of stage I~IV tumours. Five pathological features were scored for each tumour: predominant histological pattern (lepidic: 1, acinar/papillary: 2, solid/micropapillary/cribriform: 3), nuclear atypia (mild:1, moderate: 2, severe: 3), mitotic activity per 2mm2 (<4: 0, ≥4: 1), necrosis (absent: 0, present: 1), lymphovascular invasion (absent: 0, present: 1), and pleural invasion (PL0: 0, PL1: 1, PL2: 2, PL3: 3). Each pathological feature was correlated with disease-free (DFS) and overall survival (OS). Cases were then divided into three grades based on the total pathological score (grade I: 2-4, grade II: 5-7, grade III: 8-11) and correlated with outcome.

      4c3880bb027f159e801041b1021e88e8 Result

      Nuclear atypia, mitotic activity, lymphovascular invasion, and pleural invasion showed significant correlation with OS (p < 0.05). Histological pattern and necrosis showed no significant correlation in relation to OS (p = 0.09). Pleural invasion and lymphovascular invasion were significantly correlated with DFS (p < 0.05), while a trend was noted for nuclear atypia (p = 0.086). No correlation with DFS was seen for histological pattern (p = 0.499), necrosis (p = 0.464), and mitotic activity (p = 0.931). There was an inverse correlation between OS and grade, with grade III tumours showing a significantly worse prognosis (p = 0.001). There was no significant difference in DFS between the three groups (p = 0.201).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our pathological scoring system was able to stratify IMAs into three separate groups with statistically significant differences in overall survival between grade III and grades I/II tumours.

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      MA09.08 - Discussant - MA 09.05, MA 09.06, MA 09.07 (Now Available) (ID 14607)

      16:00 - 16:15  |  Presenting Author(s): Lucian R Chirieac

      • Abstract
      • Presentation
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      Abstract not provided

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      MA09.09 - EBUS-TBNA in Assessing PD-L1 Expression in NSCLC (Now Available) (ID 13471)

      16:15 - 16:20  |  Presenting Author(s): Jason S Agulnik  |  Author(s): Goulnar Kasymjanova, Hangjun Wang, Lama Sakr, David Small, Victor Cohen, Alan Spatz

      • Abstract
      • Presentation
      • Slides

      Background


      Pembrolizumab is the only immunotherapy approved as a first line agent for metastatic NSCLC in patients with high programmed death‐ligand 1 (PD‐L1) expression. The standard samples for PD-L1 testing are considered surgical or core biopsies. In this study, our primary objective is to identify the adequacy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) tumor samples in detecting PD-L1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between July 2016 and April 2017 a total of 1352 consecutive cases of non-small cell lung cancer (NSCLC) were identified. 29 specimens were deemed inadequate (less than 100 viable tumor cells) and were excluded. 1323 specimens analyzed included surgical samples (N=238), small biopsy (N=744) and cytology cell blocks (N=341). Cytology cell blocks were from EBUS-TBNA (N=190), fine needle aspiration (FNA) (N=61) and pleural/pericardial fluid (N=90). PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as <1%, 1-49% and ≥ 50% tumor cells.

      4c3880bb027f159e801041b1021e88e8 Result

      Most of the 1323 specimens (84%) were non-squamous carcinomas. Overall yield for TPS > 50% was 36%. Rate of PD-L1 positivity was no different in non-squamous (37%) compared to squamous (32%). Diagnostic yield of PD-L1 for different sample types varied substantially (Table 1). The EBUS-TBNA samples had the highest yield for TPS ≥ 50% (p=0.025).

      TPS Surgical resection Small biopsy EBUS-TBNA FNA Fluid cytology Total
      Adequacy 100% 99% 98% 96% 92% 98%
      ≥ 50% 69 (29) 269 (36) 84 (44) 21 (34) 38 (42) 481
      1-49% 87 (37) 274 (37) 57 (30) 22 (36) 22 (24) 462
      <1% 82 (35) 201 (27) 49 (26) 18 (30) 30 (33) 380
      Total 238 744 190 61 90 1323
      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results show that cytology cell blocks could be considered as a valuable resource for PD-L1 testing in advanced NSCLC. Future studies are warranted to explore clinical correlation of PD-L1 on EBUS-TBNA samples and immunotherapy outcome.

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      MA09.10 - Molecular Profiling and PD-L1 Status in 900 Cases of Surgically Resected Non-Small Cell Lung Cancer with Clinical and Pathological Correlation (Now Available) (ID 11188)

      16:20 - 16:25  |  Presenting Author(s): Zhaolin Xu  |  Author(s): Mathieu Castonguay, Wenda Greer, Akram Alwithenani, Drew Bethune, Arik Drucker, Gordon Flowerdew, Marika Forsythe, Daniel French, Harry Henteleff, Michael Johnston, Mary Macneil, Wojciech Morzycki, Madelaine Plourde, Stephanie Snow, Alexi Surette

      • Abstract
      • Presentation
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      Background

      Precision medicine provides efficient treatment options for lung cancer patients as it targets the individual tumor’s genetic makeup. Recent development of immune therapy based on immune checkpoint inhibitor also provides hope for patients. Currently lung cancer mutational data available in the literature are mainly from advanced stage non-small cell lung cancer. There is insufficient information from early stage lung cancer patients. PD-L1 status in relation to clinical and pathological characteristics is also unclear. This study tried to address these issues from 900 cases of surgically resected lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Multiplexed molecular profiling in 900 surgically resected lung cancer specimens. A panel of gene including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK was tested. PD-L1 was also evaluated by immunohistochemistry using pharmDx22C3. Tumor proportional score (TPS) in a 10% increment was measured. Mutational status and PD-L1 TPS in each cancer subtype in relation to cancer pathological characteristics were investigated. Correlations between gene mutation, PD-L1 status and cancer staging were performed. Gene mutation and PD-L1 status with patients’ demographic information such as gender, age, smoking history, as well as survival data after surgery were also analysed.

      4c3880bb027f159e801041b1021e88e8 Result

      This cohort includes adenocarcinoma (65%), squamous cell carcinoma (24%), large cell carcinoma (6%), other subtypes (5%). Stage I accounts for 56%, stage II, 26%, stage III, 16%, stage IV, <2% with a mean age of 66 years. In adenocarcinoma, KRAS accounts for 36%, EGFR 10%, BRAF 1%, PIK3CA 1%, ALK 0.2%, no mutations 52%. Only 5% squamous cells carcinoma showed mutations.

      PD-L1 TPS <1% accounts for (37%), TPS 1-9% (18%), TPS 10-19% (7%), TPS 20-29% (5%), TPS 30-39% (5%), TPS 40-49% (1%), TPS 50-59% (5%), TPS 60-69% (4%), TPS 70-79% (4%), TPS 80-89% (5%), TPS 90-99% (7%) and unsuccessful (2%). EGFR mutations were significantly associated with female (p<0.001) and never smokers (p<0.001), with well differentiated adenocarcinoma (p<0.001), and with absence of vascular invasion (p<0.01). KRAS mutations were more prevalent in younger age group (p=0.003). Poorly differentiated cancer histology was associated with absence of KRAS or EGFR mutations. There was no significant association between PD-L1 expression and age, sex, pathological stage and smoking status. PD-L1 expression was significantly associated with vascular invasion (p=0.035). EGFR mutations were significant associated with absence of PD-L1 expression (p=0.02), but no association between KRAS mutations and PD-L1 expression (p=0.10).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study provides comprehensive information enhancing our knowledge in depth about driver gene mutations and immune checkpoint PD-L1 status in non-small cell lung cancer patients.

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      MA09.11 - Genomic Landscape and its Correlation with TMB, CD8 TILs and PD-L1 Expression in Chinese Lung Squamous Cell Carcinoma (Now Available) (ID 12370)

      16:25 - 16:30  |  Presenting Author(s): Tao Jiang  |  Author(s): Jinpeng Shi, Chunyan Wu, Henghui Zhang, Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      The current study aimed to comprehensively depict the genomic landscape of Chinese lung squamous cell carcinoma (LSCC) and investigate its correlation with tumor mutation burden (TMB), CD8 tumor infiltrating lymphocytes (TILs) density and PD-L1 expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Whole-exome sequencing (WES) were performed on tumor tissue collected from 189 patients with surgically resected LSCC. TMB was defined as total number of nonsynonymous single nucleotide and indel variants. High TMB was defined as greater than 75th percentile. CD8+ TILs and PD-L1 expression were assessed by immunohistochemistry. We determined the 5% of CD8+ TIL or PD-L1 expression as the cut-off point for high/low CD8+ TIL or PD-L1 positive/negative expression.

      4c3880bb027f159e801041b1021e88e8 Result

      We found recurrent mutations (>5%) in 8 genes, including TP53, KMT2C, NFE2L2, KEAP1, CDKN2A, PTEN and FBXW7. FGFR1 and PIK3CA amplifications were found in 19% and 11% of samples. 24.9% of patients had high TMB. Except for expected differences by smoking status, baseline clinical variables were similar between those with high and low TMB. Interestingly, FGFR1, PIK3CA or SOX2 amplification was independently associated with higher TMB (P=0.020, P=0.017, P=0.029; respectively). Patients with copy number variations had significantly higher TMB than those without (P=0.009). Positive PD-L1 and CD8+ TILs expression were identified in 24.3% and 78.8% of all cases. Baseline features were comparable between those with positive and negative CD8+ TIL or PD-L1 expression. NFE2L2 mutation and PIK3CA amplification were independently associated with significantly higher PD-L1 expression (P=0.003, P=0.014; respectively). TP53 mutations were associated with higher CD8+ TILs expression (P=0.008), but FGFR1 amplification was correlated with lower CD8+ TILs expression (P=0.042). Of note, there is no association between TMB and PD-L1 expression (r=0.052, P=0.476), or CD8+ TILs expression (r=0.026, P=0.718). None of TMB, PD-L1 and CD8+ TIL expression could individually predict overall survival (OS). However, combination of TMB and PD-L1 could stratify total populations into two groups with distinct prognosis. Patients with negative PD-L1 expression and high TMB had the worst prognosis (P=0.008). Additionally, combination of TMB and CD8+ TIL expression could also divide total populations into two groups with different prognosis (worst prognosis in negative CD8+ TIL expression and high TMB, P=0.022).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This was the first and most large-scale study to comprehensively portray genomic landscape of Chinese LSCC. The current study provides several meaningful and referential findings for the future design of clinical trials in LSCC, especially immunotherapy based on immune checkpoint inhibitors.

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      MA09.12 - Discussant - MA 09.09, MA 09.10, MA 09.11 (Now Available) (ID 14610)

      16:30 - 16:45  |  Presenting Author(s): Philippe Joubert

      • Abstract
      • Presentation
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      Abstract not provided

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    MA12 - Mesothelioma Surgery and Novel Targets for Prognosis and Therapy (ID 913)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 202 BD
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      MA12.01 - The Information Pathway to Randomisation: Patients Experience of the Mesothelioma and Radical Surgery (MARS2) Feasibility Trial (Now Available) (ID 11200)

      10:30 - 10:35  |  Presenting Author(s): Angela Mary Tod  |  Author(s): Clare Warnock, Karen Lord, Liz Darlison

      • Abstract
      • Presentation
      • Slides

      Background

      The Mesothelioma and Radical Surgery 2 (MARS 2) trial was established in the UK to evaluate the role of radical surgery, (Pleurectomy decortication), for the treatment of malignant pleural mesothelioma (MPM). It compares chemotherapy and surgery to chemotherapy alone. The feasibility trial included a nested qualitative sub-study. The sub study aimed to 1) understand the patient experience of MARS2 trial process and interventions and 2) Identify any information and support needs required by patients. We present here the results related to MARS2 participant’s information experiences and needs at the point of randomisation. Implications for information provision to enhance patient experience and overcome recruitment barriers1 within MPM trials are considered.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      41 in-depth longitudinal qualitative methods were used with 15 participants following randomisation. 9 participants received chemotherapy and surgery and 6 received chemotherapy alone. Interviews were conducted following randomisation, and at 6 and 12 months after the initial interviews. Participants randomised to surgery also had an interview after post-operative discharge. Data was collected between August 2015 and March 2017 and analysed using Framework analysis2

      4c3880bb027f159e801041b1021e88e8 Result

      The findings provide insight into the challenging context within which potential participants have to assimilate knowledge about a trial such as MARS2. Prior to hearing about the trial participants had encountered a diverse range of new and concerning experiences. These included worrying symptoms, diagnostic tests, investigations and the drainage of litres of fluid from the lung. They had to absorb an array of life-changing facts in a short time including that they had a rare incurable cancer with a poor prognosis; their illness was an occupational disease with legal and financial implications due to asbestos exposure. Participants attended their trial consultation soon after this challenging diagnostic information provision. The study reveals variations in understanding of the trial procedures, specifically decision-making regarding treatments, equipoise and the process of randomisation. Motivations for participating in the trial were identified along with preferences for information formats.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study provides unique insight into the information pathway of MPM trail participants, from diagnosis to randomisation. Results suggest that improvements in presentation of trial information and the development of formats that can be tailored to individual needs and preferred ways of learning, many enhance experience of and recruitment to MPM trials. Working with patients to co-produce information that communicates challenging concepts effectively, (such as randomisation and equipoise), may be a useful approach to meeting this challenge.

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      MA12.02 - Quality of Life Following Pleurectomy Decortication and Extrapleural Pneumonectomy for Pleural Malignant Mesothelioma (Now Available) (ID 12983)

      10:35 - 10:40  |  Presenting Author(s): Wil Lieberman-Cribbin  |  Author(s): Andrea Wolf, Rebecca Schwartz, Raja Flores, Emanuela Taioli

      • Abstract
      • Presentation
      • Slides

      Background

      Few studies have focused on quality of life (QoL) after treatment of malignant pleural mesothelioma (MPM). Questions remain as to which surgical procedure, extrapleural pneumonectomy (EPP) or pleurectomy (P/D), is most effective and results in better outcomes for survival and involves fewer complications. A comprehensive review was conducted on MPM patients to assess differences in QoL following P/D and EPP.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Original research studies on QoL after mesothelioma surgery were identified through May 2018: 17 articles, 14 datasets encompassing 659 patients, were retrieved. Measures of lung function (FEV, FVC) and EORTC QLQ-C30 were compared 6 months following surgery with preoperative values.

      4c3880bb027f159e801041b1021e88e8 Result

      QoL data was available for 102 EPP patients and 432 P/D patients. Two studies directly compared QoL between the two techniques. While QoL was still compromised 6 months following surgery, P/D patients fared better than EPP patients across all QoL measures. Physical function, social function, global health and dyspnea were higher at follow-up for PD than for EPP, while other indicators such as pain and cough were similar. FEV and FVC were higher at follow-up for P/D compared to EPP, although only one study reported FEV and FVC following EPP.

      8eea62084ca7e541d918e823422bd82e Conclusion

      QoL is better for patients undergoing P/D compared to EPP for an extended period following surgery. Given the need for multimodality therapy and the aggressive nature of MPM, QoL outcomes should be strongly considered when choosing type of surgery for MPM.

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      MA12.03 - The Impact of Malignant Pleural Mesothelioma Histology on the Use of Surgery and Survival in a Population-Based Analysis (Now Available) (ID 14406)

      10:40 - 10:45  |  Presenting Author(s): Chi-Fu Jeffrey Yang  |  Author(s): Nicholas Mayne, John Z Deng, Sarah J Commander, Thomas A. D'Amico, Mark Berry

      • Abstract
      • Presentation
      • Slides

      Background

      Histologic subtype for malignant pleural mesothelioma (MPM) is known to be an important determinant of both treatment and survival. This study aimed to quantify the impact of MPM histology on the use of surgery and survival in a population-based analysis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Overall survival (OS) of patients with stage I-III epithelioid, sarcomatoid, and biphasic MPM in the National Cancer Database from 2004 to 2015 was evaluated using Kaplan-Meier survival analysis and multivariable Cox proportional hazard models.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 3,346 patients who met inclusion criteria, the histologic subtype was epithelioid in 2,326 patients (70%), biphasic in 482 patients (14%), and sarcomatoid in 538 patients (16%). Median survival was 16.2 [95% CI: 15.3 – 17.2] months in the epithelioid group, 10.9 [95% CI: 9.8 – 11.9] months in the biphasic group, and 5.3 [95% CI: 4.7 – 6.0] months in the sarcomatoid group (p<0.001). Cancer-directed surgery was utilized more often in epithelioid (31%, n=718) and biphasic patients (38%, n=181) compared to sarcomatoid patients (17%, n=91) (p<0.001). Among patients who underwent surgery, median survival was significantly better for epithelioid (22.6 [95% CI: 21.2 – 24.8] months) and biphasic (14.7 [95% CI: 12.6 – 17.3] months) histologies compared to sarcomatoid histology (7.7 [95% CI: 6.4 – 8.6] months) (p<0.001). Surgery was associated with better survival in multivariable analysis for epithelioid (HR 0.81; [95% CI: 0.72 – 0.93], p=0.002) and biphasic histologies (HR 0.69; [95% CI: 0.53 – 0.89], p=0.004), but not for sarcomatoid type mesothelioma (HR 0.87; [95% CI: 0.65 – 1.16, p=0.34). Further, the absolute difference in median survival between surgical and non-surgical therapy was more clinically significant for the epithelioid (22.6 vs 15.8 months; p <0.001 and biphasic (14.7 vs 10.4 months; p=0.001) patients compared to the sarcomatoid (7.7 vs 7.2 months; p=0.13).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this U.S. national analysis of patients with malignant pleural mesothelioma, surgery was most commonly used for epithelioid and biphasic histologies and was associated with a median survival of nearly 2 years and over 1 year, respectively. However, surgery was also used in almost 1 in 5 patients with sarcomatoid mesothelioma but was associated with a median survival of less than 8 months. These results suggest that the specific mesothelioma histology should be firmly established before surgery, and it is reasonable to aggressively treat select patients with epitheloid and biphasic mesothelioma with surgery, but that surgery should not be performed for most patients with sarcomatoid mesothelioma.

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      MA12.04 - Discussant - MA 12.01, MA 12.02, MA 12.03 (Now Available) (ID 14623)

      10:45 - 11:00  |  Presenting Author(s): Marc De Perrot

      • Abstract
      • Presentation
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      Abstract not provided

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      MA12.05 - Phase 1 Study of HSP90 Inhibitor Ganetespib with Pemetrexed and Cisplatin/Carboplatin Chemotherapy for Pleural Mesothelioma (Now Available) (ID 11921)

      11:00 - 11:05  |  Presenting Author(s): Dean A Fennell  |  Author(s): Sarah Danson, Martin Forster, Denis Talbot, Penella Woll, Jennifer Child, Yenting Ngai, Laura Farrelly, Allan Hackshaw, Annabel Sharkey, Sara Busacca, Robert Hastings, Dan Barnes, Marianne Nicolson, Paul Taylor, Samreen Ahmed, Graham Mark Wheeler

      • Abstract
      • Presentation
      • Slides

      Background

      There have been no new licenced therapies for mesothelioma in over a decade. Ganetespib is a small-molecule heat-shock protein 90 (Hsp90) inhibitor, with significant activity for down-regulating Hsp90 client protein levels. Prior evidence indicates efficacy for ganetespib in mesothelioma through critical survival pathways and synergies with antifolates and platinum chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a dose-escalation study of ganetespib in patients with pleural malignant mesothelioma and ECOG 0-1. Ganetespib was combined with standard pemetrexed/platinum therapy, using either cisplatin (GCisP), or carboplatin (GCarbP). Three ganetespib cohorts were: 100, 150 & 200mg/m2 given days 1 and 15, every 21 days. GCisP was evaluated using a 3+3 design. GCarbP followed an accelerated titration run-in using single patients, switching to a 3+3 design after one dose limiting toxicity (DLT). DLT was assessed during cycles 1-2 for GCisP and cycle 1 for GCarbP. Genomic instability was inferred by array-based analysis of somatic copy number.

      4c3880bb027f159e801041b1021e88e8 Result

      27 patients were treated (GCisP, n=16; GCarbP, n=11). Median age 66 (range 37-76), 6 PS-0/21 PS-1, and 25 male. Only 3 patients experienced DLTs, all at 200mg/m2: grade 3 nausea (GCisP, n=1; GCarbP, n=1); grade 2 infusion-related reaction (GCarbP, n=1). This dose was the maximum tolerated dose. Partial tumour response rate was 61% (14/23 evaluable patients); 7 patients had tumour burden reduction of >50% (Figure). PFS was better using 200mg/m2 versus 100mg/m2 (hazard ratio 0.32, 95%CI 0.11-0.95, p=0.04). One patient remains progression-free even after 37 months. Total loss of heterozygosity (LOH) was correlated with increased tumour burden (n=7, correlation=0.7, p=0.078).

      meso02abstract_bestresponse.png

      Figure. Best tumour response (% change in tumour burden from baseline)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Ganetespib plus pemetrexed and platinum chemotherapy was well-tolerated in patients with pleural mesothelioma, with evidence of activity, particularly at the recommended dose of 200mg/m2. LOH correlated with poorer response to this triplet combination.

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      MA12.06 - STELLAR – Final Results of a Phase 2 Trial of TTFields with Chemotherapy for First-Line Treatment of Malignant Pleural Mesothelioma (Now Available) (ID 13806)

      11:05 - 11:10  |  Presenting Author(s): Giovanni L Ceresoli  |  Author(s): Joachim G.J.V. Aerts, Jaroslaw Madrzak, Rafal Dziadziuszko, Rodryg Ramlau, Susana Cedres, Birgitta Hiddinga, Jan P Van Meerbeeck, Manlio Mencoboni, David Planchard, Antonio Chella, Lucio Crinò, Maciej Krzakowski, Federica Grosso

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable, medical device. In-vitro, human mesothelioma cells were highly susceptible to TTFields. TTFields have been shown to significantly extend survival of patients with glioblastoma when added to chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The trial accrued 80 patients with unresectable, previously untreated mesothelioma. Patients were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin (at standard dosing). Inclusion criteria included ECOG PS of 0-1, pathologically proven mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients were followed q3w (CT scan q6w) until disease progression. The primary endpoint was overall survival (OS) and secondary endpoints were response rate, progression free survival (PFS) and toxicity. This prospective, single arm study assumed an historical control with a median survival of 12.1 months (Vogelzang et al. 2003). The sample size provides 80% power with a two-sided alpha of 0.05 to detect an increase in median OS of 5.5 months.

      4c3880bb027f159e801041b1021e88e8 Result

      All 80 patients were enrolled between 2016 and 2017, with a minimum follow up of 12 months. Median age was 67 (range 27-78), 84% were male and 56% smokers. 16% (13 patients) had metastatic disease and 44% (35 patients) had an ECOG PS of 1. 66% (53 patients) had epithelioid histology. Compliance with TTFields was 68% (16.3 hours/day) during the first 3 months of therapy and 63% (50 patients) received carboplatin.

      Median OS was 18.2 months (95% CI 12.1-25.8) compared to 12.1 months in the historical control. Median PFS was 7.6 months (95% CI 6.7-8.6) compared to 5.7 months in the historical control. Partial responses were seen in 40.3% of patients and clinical benefit (PR+SD) was seen in 97.2% of patients. No device-related serious adverse events (AEs) were reported. Expected TTFields-related dermatitis was reported in 46% (37 patients). Only 4 patients (5%) had grade 3 dermatitis. The following grade 3-4 systemic AEs were reported in >3% of patients: hematological AEs (15%) and fatigue (4%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The study met its primary endpoint of significant extension of survival for previously untreated mesothelioma patients. Secondary efficacy endpoints were also improved compared to historical control. The study demonstrated no safety concerns for the combination of TTFields to the thorax together with standard chemotherapy. These results support the addition of TTFields to standard chemotherapy in the treatment of first-line malignant pleural mesothelioma.

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      MA12.07 - gC1qR Expression is Independently Prognostic for Survival Benefit Following Chemotherapy in Mesothelioma (Now Available) (ID 13284)

      11:10 - 11:15  |  Presenting Author(s): Xiaoyu Li  |  Author(s): Takashi Eguchi, Rania G Aly, Navin Chintala, Kay See Tan, John Messinger, Marjorie G. Zauderer, Berhane Ghebrehiwet, Prasad S. Adusumilli, Ellinor I.B. Peerschke

      • Abstract
      • Presentation
      • Slides

      Background

      Overexpression of gC1qR, a multicompartmental and multifunctional cellular protein, has been shown to promote chemotherapy-induced apoptosis in cancer cells, but compromise CD4 T-cell proliferation in viral infections. The goal of this study was to investigate the overexpression of gC1qR, and its prognostic association with chemotherapy and CD4 T-cell infiltration in malignant pleural mesothelioma (MPM).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue microarrays comprising 6 tumoral and 3 stromal cores from 265 patients with MPM (216 epitheloid, 26 biphasic, and 23sarcomatoid, 1989-2010) were investigated by immunohistochemistry for gC1qR expression (intensity and distribution by H-score, range 0-300), and CD4 T-cell infiltration. Overall survival (OS) was analyzed by the Kaplan-Meier method (high versus low gC1qR expression delineated by median score). Multi-variable analysis included clinical, pathological factors and stage (T, N).

      4c3880bb027f159e801041b1021e88e8 Result

      In comparison to benign and reactive mesothelial cells (median H-score 30), gC1qR is overexpressed (median H-score 155) in all histological types of MPMs (263/265, 99.2%). In epithelioid MPM patients – 1) among patients who received neoadjuvant chemotherapy (NAC), high gC1qR was associated with better median OS (25 vs.11 months, Fig1A), 2) among patients without NAC, high gC1qR was associated with better survival, survival benefit is pronounced in patients who received postoperative chemotherapy (median OS 38 vs.19 months, Fig1B), and 3) in multivariate analysis, high gC1qR was an independent factor for better OS. gC1qR expression did not correlate with CD4 T cell infiltration. However, among patients without NAC, high CD4+ T cell infiltration-high gC1qR expression was associated with better OS (26 vs 18,12, and11 months, Fig1C).

      gc1qr.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      gC1qR is overexpressed on MPM cells. MPM patients with high gC1qR expression have a significant survival benefit particularly following chemotherapy; or in the presence of high CD4 T-cell infiltration.

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      MA12.08 - Discussant - MA 12.05, MA 12.06, MA 12.07 (Now Available) (ID 14625)

      11:15 - 11:30  |  Presenting Author(s): Quincy Chu

      • Abstract
      • Presentation
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      Abstract not provided

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      MA12.09 - Preclinical Investigations of Folate Receptor Targeted Nanoparticles for Photodynamic Therapy of Malignant Pleural Mesothelioma (Now Available) (ID 11277)

      11:30 - 11:35  |  Presenting Author(s): Tatsuya Kato  |  Author(s): Cheng S Jin, Hideki Ujiie, Kosuke Fujino, Daiyoon Lee, Hironobu Wada, Hsin-pei Hu, Licun Wu, Rober A Weersink, Juan Chen, Hiromi Kanno, Yutaka Hatanaka, Kanako C Hatanaka, Yoshihiro Matsuno, Marc De Perrot, Brian C Wilson, Gang Zheng, Kazuhiro Yasufuku

      • Abstract
      • Presentation
      • Slides

      Background

      Photodynamic therapy (PDT) following lung-sparing extended pleurectomy (EPD) for malignant pleural mesothelioma (MPM) has been investigated as a potential means to kill residual microscopic cells. High expression of folate receptor 1 (FOLR1) has been reported in MPM, and targeting the FOLR1 has been considered as a new potential strategy. We have developed FOLR1-targeting porphyrin-lipid nanoparticles (folate-porphysomes; FP) for PDT. The inhibition of survival pathways of activated epidermal growth factor (EGFR) also enhance the PDT efficacy. Here, we have combined these approaches by using FP based PDT together with an EGFR-tyrosine kinase inhibitor (EGFR-TKI).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The frequency of FOLR1 and EGFR expression in MPM was analyzed using tissue microarrays. Confocal microscopy and a cell viability assay were performed to confirm the specificity of FOLR1-targeting cellular uptake and photocytotoxicity in vitro. In vivo fluorescence activation and the therapeutic efficacy were then examined. The effect of EGFR-TKI was assessed in vitro. The in vivo combined anti-tumor effect of EGFR-TKI and FP-PDT was then evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      FOLR1 and EGFR were expressed in 79 % and 89 % of the MPM samples, respectively. The intracellular uptake of FP corresponded well with FOLR1 expression. When MPM cells were incubated in FP and then irradiated at 671 nm, there was significant in vitro cell kill, which was inhibited in the presence of free folic acid, suggesting the specificity of FPs. FOLR1 targeting resulted in disassembly of the porphysomes and subsequent fluorescence activation in intrathoracic disseminated MPM tumors, as demonstrated by ex vivo tissue imaging. FP-PDT resulted in significant cellular damage and apoptosis in vivo. Furthermore, the combination of pre-treatment with EGFR-TKI plus FP-PDT showed further marked improvement of treatment responses.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Folate-porphysome based PDT shows selective destruction of MPM cells based on FOLR1 targeting, and pre-treatment with EGFR-TKI further enhances the therapeutic response.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA12.10 - Long-Term Impact of Radiotherapy Before Surgery for Mesothelioma on the Distribution of Memory T Cell Subsets (Now Available) (ID 12728)

      11:35 - 11:40  |  Presenting Author(s): Junichi Murakami  |  Author(s): Licun Wu, Mikihiro Kohno, Mei-Lin Chan, Yidan Zhao, Zhihong Yun, Marc De Perrot

      • Abstract
      • Presentation
      • Slides

      Background

      Postoperative recurrence remains one of the critical issues in treatments for mesothelioma. We previously reported that non-ablative, hypo-fractionated radiation before surgery generated an antigen-specific activation of the immune system and could provide an in situ vaccination with long-term protection against mesothelioma in our murine model. An effective immunological protection depends on memory T cell subset diversification. However, limited work has been done to address the distribution of memory T cell subsets and its effects on the immune system after radiotherapy followed by surgery for mesothelioma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      C57BL/6 mice bearing AE17-OVA tumor were treated with local radiotherapy (LRT). LRT 5Gy was delivered on days 10, 11 and 12. We performed radical tumor resection 7 days after LRT. The mice were re-challenged under the skin or into thoracic cavity with AE17-OVA 28 days after surgery and defined as immunological protective memory model if the tumors were completely rejected. Memory model received subcutaneous tumor inoculation once again (second rechallenge), samples were harvested on day 0, 3, 10. We investigated memory T cell subsets using flow cytometry. In addition, the harvested total splenocytes (effector) were co-cultured with CFSE-labeled AE17-OVA (target) for three days. Each of their cytotoxic potential was analyzed by evaluating a number of AE17-OVA and its early or late apoptosis.

      4c3880bb027f159e801041b1021e88e8 Result

      8 out of 10 mice completely rejected the subcutaneous tumor in mice treated with LRT and surgery after re-challenged. We observed significantly better survival in the memory model re-challenged into the thoracic cavity compared with no treatment mice. After subcutaneous tumor inoculation, central memory T cells (CD44[+]CD62L[+]KLRG1[-]) on day 0, effector memory T cells (CD44[+]CD62L[-]KLRG1[-]) and terminal effector T cells (CD44[+]CD62L[-]KLRG1[+]) on day 0, 3, 10 increased significantly in CD8[+] splenocytes of memory model compared with no treatment mice. This observation was also seen in draining and non-draining lymph nodes. The MFI of CFSE reflecting a number of AE17-OVA cells decreased, whereas the proportion of early (Annexin V[+]FVD[low]) or late (Annexin V[+]FVD[high]) apoptotic cells in CFSE[+] cells increased, depending on time passage and effector/target ratio after tumor inoculation in both memory model and naïve mice. However, during time passage, memory model always had a stronger cytotoxicity (even at Day 0) as compared to naïve mice.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data raise an important possibility that non-ablative, hypo-fractionated radiotherapy followed by surgery for mesothelioma contributes to the development and long-term maintenance of memory T cell subsets, which could remain poised to rapidly recall effector functions upon antigen re-exposure.

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      MA12.11 - Analysis of Angiogenic and Stromal Biomarkers in a Large Malignant Mesothelioma Cohort (Now Available) (ID 12234)

      11:40 - 11:45  |  Presenting Author(s): Puey Ling Chia  |  Author(s): Prudence Russell, Khashayar Asadi, Carmel Murone, Marzena Walkiewicz, Ulf Eriksson, Andrew Scott, Thomas John

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant mesothelioma (MM) is an aggressive malignancy of the pleura and other mesothelium membranes. Agents targeting vascular endothelial growth factor (VEGF) receptor such as bevacizumab; and multi-kinase inhibitors like nintedanib [angiokinase inhibitor of VEGF, platelet-derived growth factor (PDGF) receptor and fibroblast growth factor receptor (FGFR)] have recently demonstrated efficacy in MM. In the setting of these new therapies, it is important to evaluate angiogenic and stromal markers in MM to assess their associated prognostic implications.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue microarrays (TMAs) were created from formalin-fixed, paraffin-embedded tissue samples obtained from 326 patients who underwent surgical resection or biopsy for MM between 1988 and 2014. PDGF-CC, FGFR-1, VEGF and CD31 expression were analysed by immunohistochemical (IHC) staining. The H-score method assigned a score of 0–300 to each sample, based on the percentage of cells stained at different intensities. The discriminatory threshold was set for each IHC stain (usually the median score) and samples were classified as low (below median) or high expression (above median). CD31 was evaluated via Chalkley’s method to evaluate microvessel density. We evaluated the association between expression of the biomarkers, clinicopathological factors and outcomes, in patients with MM.

      4c3880bb027f159e801041b1021e88e8 Result

      The histological subtypes comprised of 203/325 (62.5%) epithelioid; 72/325 (22.2%) biphasic; 42/325 (12.9%) sarcomatoid, or indeterminate. The median age was 67 (range 24-88) with Male: Female ratio of 266: 53.

      CD31 high (≥5) was seen in only 31/302 (10.3%) irrespective of histology (13/31 (42%) epithelioid; 10/31 (32%) sarcomatoid; 7/31 (23%) biphasic; 1/31 indeterminate).

      PDGF-CC high (≥150) was seen in 203/310 (65%) of all samples but was higher in epithelioid subtype [129/203 (64%)]. VEGF high (≥80) was seen in 219/322 (68%) of all MM with 143/209 (68%) of epithelioid histology.

      FGFR-1 high (≥40) was seen in 127/310 (41%) of all MM and 73/127 (57.5%) are of epithelioid histology.

      There was no association of VEGF and FGFR-1 IHC with survival nor differences between histological subtypes.

      There was a non-significant trend towards poorer survival in epithelioid tumours with increased PDGF-CC expression (OS 18.5 vs 13.2 months; HR 0.7928; 95%CI 0.5958 to 1.055, P=0.1110).

      High CD31 score was associated with significantly poorer survival (OS 12 vs 8.6 months; HR 0.48; 95%CI 0.2873 to 0.7941, P=0.0044). Of the 31 patients with high CD31 scores; 23/31 (74%) were also high for PDGF-CC and 20/31 (64%) with high VEGF scores.

      8eea62084ca7e541d918e823422bd82e Conclusion

      High PDGF-CC expression and CD31 scores are associated with poor survival in MM. Abrogating these pathways may have prognostic implications.

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      MA12.12 - Discussant - MA 12.09, MA 12.10, MA 12.11 (Now Available) (ID 14627)

      11:45 - 12:00  |  Presenting Author(s): Masaki Anraku

      • Abstract
      • Presentation
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      Abstract not provided

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    MS20 - Innovative and Evolving Strategies in Diagnosis and Management of Stage I NSCLC (ID 799)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 6
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 202 BD
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      MS20.01 - Robotic and Innovative Surgery (Now Available) (ID 11484)

      15:15 - 15:30  |  Presenting Author(s): Waël C. Hanna

      • Abstract
      • Presentation
      • Slides

      Abstract

      In the era of personalized lung cancer treatment, surgery is follwoing the trend of targeted therapy. As lung cancer becomes easier to detect at early stages with low dose computed tomography, innovations in surgery have been developed to make targeted surgery easier and more prevalent.

      This talk will focus on novel innovations in surgery for small pulmonary nodules. We will discuss targeted robotic surgery, mapping with near-infrared techology, electromagnetic navigation, 3D preoperative mapping and simulation, hybrid operating rooms, and minimally invasive staging. We will also touch on the role of Artificial Intelligence in the future of surgery for lung cancer.

      The goal of this talk would be to introduce the audience to the future of surgical treatment of early stage lung cancer.

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      MS20.02 - The Future of Stereotactic Ablative Radiotherapy (SABR) (Now Available) (ID 11485)

      15:30 - 15:45  |  Presenting Author(s): Billy W Loo

      • Abstract
      • Presentation
      • Slides

      Abstract

      Stereotactic ablative radiotherapy (SABR) has produced a paradigm shift in the curative treatment of lung cancer over the past two decades. Particularly in stage I lung cancer, systematic clinical investigation through prospective trials has established SABR as the current standard of care for definitive treatment in patients who are medically inoperable or have contraindications to surgery. Optimization of treatment protocols, better understanding of normal tissue tolerance to accelerated radiation, and technological advances have led to progressive improvements in efficacy, safety, and clinical efficiency, and are concomitantly expanding both the clinical adoption and indications for SABR of lung tumors to new and larger patient populations.

      With recent advances in systemic therapies, including genetically targeted agents and immunotherapies, successful eradication of micrometastatic disease is finally a prospect for a growing proportion of patients. As such, radical radiotherapy approaches including SABR will be increasingly crucial to achieve combined modality cures for many patients with all stages of lung cancer from early to metastatic.

      This lecture will review the major clinical data underlying the current practice of SABR and the emerging evidence and investigations pointing the way to its future.

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      MS20.03 - Immunotherapy and Surgery: Neoadjuvant or Adjuvant? Is It Safe? (Now Available) (ID 11486)

      15:45 - 16:00  |  Presenting Author(s): Jamie E Chaft

      • Abstract
      • Presentation
      • Slides

      Abstract

      Background: Immune checkpoint blockade (ICB) has become a standard of care for many patients with non-small cell lung cancer, either alone or in combinations with standard chemotherapy. There is also an emerging role of combinations after progression on targeted therapies. The role of ICB in the perioperative setting is yet to be defined. Many large trials have launched to evaluate either neoadjuvant or adjuvant ICB drugs alone or in combination with chemotherapy.

      Preclinical data:

      Preclinical data demonstrate a greater efficacy of neoadjuvant versus adjuvant ICB in eliminating distant metastases after resection of the primary triple negative breast cancer tumor in mouse models.1 This preclinical data has fostered enthusiasm for neoadjuvant studies of ICB in resectable lung cancers, though none of these presently designed studies directly compare neoadjuvant to adjuvant ICB therapy.

      Clinical data:

      The TOP1201 study was the first to evaluate ICB with ipilimumab in addition to carboplatin + paclitaxel in early-stage NSCLC. Of 24 patients treated, only 13 were ultimately resected 2 with delays due to diarrhea, 11 were deemed not appropriate for surgery after treatment, 1 because of toxicity.2 There was no obvious safety concern posteropatively when compared to non-randomized controls treated with preoperative chemotherapy. There was also no signal of added benefit from addition of ipilimumab in this study in an unselected population, comparable to studies in metastatic disease.

      The recently published study of neoadjuvant nivolumab was different by design. In this two-institution study resectability was defined pretreatment, and 20 of 21 patients were completely resected without delay. A high rate of major pathologic response was seen after only 2 doses of nivoluamb in this study. There were no safety signals.3

      Preliminary presentations of data from the lung cancer mutation consortium study of neoadjuvant atezolizumab and the single institution study of carboplatin + nab-palictaxel + atezolizumab have met their pre-defined safety and efficacy boundaries for expansion, respectively.4,5

      Ongoing studies:

      By nature of design, the presenting data is from neoadjuvant studies where efficacy and safety signals are available faster than those in a standard adjuvant study design. This should not negative the huge international efforts ongoing to evaluate the efficacy of adjuvant ICB after resection and standard adjuvant therapy for resected NSCLC. There are 4 ongoing randomized phase 3 studies comparing single agent anti-PD-(L)1 agents versus observation or placebo.

      In the neoadjuvant space, the phase 2 studies listed above will expand to provide larger datasets anticipated to result in the next year. Other small phase 1 and 2 efforts are ongoing. Additional large phase 3 efforts comparing neoadjuvant chemotherapy to chemotherapy + ICB and some ICB combinations are actively recruiting internationally. These studies will answer important directly comparative questions and investigate the role of potential surrogates of survival, such as pathologic response.

      Conclusions:

      The field has embraced the importance of investigating immunotherapy in this potentially curative space, but we are years from being able to draw definitive conclusions from the randomized Phase 3 studies of perioperative ICB. Preclinical data suggest the neoadjuvant approach may be superior to adjuvant ICB and the single small reported study of neoadjuvant nivolumab showed a tremendous efficacy signal that ongoing studies hope to replicate.3 While the rapidly enrolling adjuvant studies remain extremely important given the high rate of pathologic upstaging at the time of surgical resection, emphasis on appropriate patient identification for neoadjuvant study enrollment will lead to earlier trial readouts, important correlative science, and essential study of potential surrogate efficacy endpoints such as pathologic response.

      References:

      1. Liu J, et al. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Cancer discovery 2016;6:1382-99.

      2. Yang CJ, et al. Surgical Outcomes After Neoadjuvant Chemotherapy and Ipilimumab for Non-Small Cell Lung Cancer. Ann Thorac Surg 2018;105:924-9.

      3. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018;378:1976-86.

      4. Rusch, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer: Initial results from a multicenter study (LCMC3). J Clin Oncol 36, 2018: supple; abstr 8541.

      5. Shu C, et al. Neoadjuvant atezolizumab + chemothearpy in resectable non-small cell lung cancer. J Clin Oncol 36, 2018: supple; abstr 8532

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      MS20.04 - Prediction of Clinical Outcome in NSCLC Using Integrative Genomics: Implications for Adjuvant Chemotherapy (Now Available) (ID 11487)

      16:00 - 16:15  |  Presenting Author(s): Phillippe Broet

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS20.05 - Beyond Surgery - Support of the Surgical Patient (Now Available) (ID 11488)

      16:15 - 16:30  |  Presenting Author(s): Kate Kuhns

      • Abstract
      • Presentation
      • Slides

      Abstract

      Purpose:

      Discuss how to optimize patient support and education to achieve improved patient satisfaction, decrease patient anxiety, decrease readmission rates associated with post-operative complications and improve overall outcomes of the thoracic surgical patient.

      Introduction:

      Lung cancer is the most common cancer worldwide contributing 13% of the total number of new cases diagnosed in 2012. SEERS data shows that the five-year survival for lung cancer patients is only 18.6%. Surgery remains the gold standard of care for Stage I and II non-small cell lung cancer (NSCLC) and for selected patients with locally advanced Stage IIIA disease.

      Support and education of the thoracic patient is imperative to achieve the best outcomes in terms of physical, emotional, social and spiritual well-being. The support and education not only focus on the surgery but must also embrace the whole patient journey which includes lifestyle modifications, secondary prevention, knowledge and acceptance of their disease and self-empowerment.

      Thoracic patients undergoing surgery for a known or suspected lung cancer usually have little knowledge of what to expect during the preoperative, postoperative and recovery period. A dedicated multidisciplinary support system which includes physicians, advanced practice providers, nurses, radiologists, oncologists, therapists and nutritionists is needed to help patients navigate through this process to achieve optimal outcomes with minimal complications, decreased hospital stays, high patient satisfaction, low anxiety and lifestyle modifications that last long after recovery.

      Supporting the thoracic surgical patient begins at the first encounter and continues through the entire process which encompasses the pre-operative work up, surgery, recovery and beyond. During the initial encounter, the patient’s support system, level of education, social and economic needs and lifestyle choices need to be identified. Most patients and their families are overwhelmed by the diagnosis of cancer or potential cancer and are not only frightened by the diagnosis, but also of the impact an illness will have on them emotionally and financially.

      Multiple studies have shown that good quality preoperative teaching increases patient satisfaction, improves patient outcomes, and decreases patient readmission rates following surgery. Although the benefit of preoperative education is widely recognized in the literature, finding the resources available to provide efficient and effective teaching is a challenge.

      Using multi-format education including written material, video, internet access, support groups and access to health care providers has been found to improve patient outcomes, decrease anxiety and improve patient satisfaction. Furthermore, supporting patients by use of existing programs within a health care system can also help achieve optimal outcomes in patient’s undergoing thoracic surgery and reduce the cost. The use of nurse navigators, smoking cessation programs, nutritionists, outpatient rehabilitation, support groups and volunteers is critical.

      Hospital re-admission rates after major thoracic surgery can run as high as 10-17 percent. Improving the transition from hospital to post-discharge care can be effective in decreasing emergency room visits and re-hospitalizations. Moreover; use of concierge pharmacy services for management of discharge mediations, day after discharge phone calls and easy patient access to a hospital provider all help to support patients and their families during the transition from hospital to home.

      More studies need to be done to identify which programs and interventions achieve the best outcomes for patient’s undergoing thoracic surgery. The utilization of existing programs in combination with newer technologies needs to be reviewed and studied to determine what works best in helping patients to change behaviors and promote optimal outcomes following thoracic surgery.

      e353dbe42c8654f33588d4da0b517469

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      MS20.06 - Less Is More: Segmentectomy in the Management of Early Stage NSCLC (Now Available) (ID 11489)

      16:30 - 16:45  |  Presenting Author(s): Shun-ichi Watanabe

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS30 - Modern Day RT in LA NSCLC: Where Is the Evidence? (ID 808)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 6
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 202 BD
    • +

      MS30.01 - Introduction with Poll Questions (Now Available) (ID 14934)

      13:30 - 13:35  |  Presenting Author(s): Fiona Hegi-Johnson, Yuko Nakayama

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS30.01 - Overview of RT Technology in LA NSCLC (IMRT, VMAT, IGRT) (Now Available) (ID 11530)

      13:35 - 13:50  |  Presenting Author(s): Gerard G Hanna

      • Abstract
      • Presentation
      • Slides

      Abstract

      External bean radiotherapy remains the key treatment modality for the radical treatment of inoperable locally advanced non-small cell lung cancer (LA-NSCLC). Outcomes remain poor with a median overall survival of approximately 25–29 months in those patients who have received combined modality therapy [1,2]. In radiotherapy treatment the aim of radical treatment is to achieve an optimal therapeutic benefit with the highest probability of tumour control but with minimal associated toxicity. The Radiation Therapy Oncology Group (RTOG) randomised phase III 0617 study comparing standard dose (60 Gy) to dose escalated radiotherapy (74 Gy) given with concomitant systemic therapy has highlighted in the modern era the importance of the dose received by normal tissues and toxicity in relation to overall survival. In this study the maximum grade of oesophageal toxicity and the proportion of heart receiving radiation dose were both factors associated with poorer survival [2].

      The last two decades have seen many technical advances in radiotherapy delivery techniques. For treatment planning, the objective is to attain conformity of the planned dose to the target volume within minimal dose to adjacent normal tissues. There have been significant advances in radiotherapy treatment planning with improved accuracy of modelling how radiotherapy treatment beams interact with inhomogeneous structures such as the lung. This coupled with improved computing power, permits the accurate and fast generation of intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans. Both IMRT and VMAT delivery improves of the sparing of normal tissues but may increase low dose radiotherapy exposures to the lung. The impact of this low dose exposure remains uncertain.

      There have been important advances in assessment and management of target and organ motion within the thorax and use of techniques to individualise treatment based on the motion to improve the treatment accuracy [3,4]. For radiotherapy delivery over the course of treatment, the objective is consistency between the planned and delivered dose distributions. With recent widespread availability of cone-beam computerised tomography (CBCT) it is now possible to use these images to assess of the shape and position of the radiotherapy target in relation to the planned dose delivery prior to treatment, image guided radiotherapy (IGRT), to improve accuracy of treatment delivery and where necessary to use this information to adapt treatment based, image guided adaptive radiotherapy (IGART) [5]. It is hoped that emerging technologies such MR-Linac, which combines a magnetic reasonance imaging unit with linear accelerator, will further develop IGRT and IGART delivery.

      Establishing the clinical benefit and cost-effectiveness of these technological advances is challenging. The improved median survival in the standard arm of recent randomised trials [1,2] compared to historical trials suggests that technical advances may improve survival outcomes. Additionally, there are retrospective data from a large series that suggest IMRT in particular may be associated with improved outcome in stage III NSCLC with T3 and T4 tumours [6] and a recent secondary analysis of the RTOG 0617 trial suggests use of IMRT compared to 3D conformal techniques is associated with lower severe lung toxicity and lower cardiac doses [7]. Finally, it is hoped that the use of these advanced techniques will permit radiotherapy treatment intensification either through alter radiotherapy dose delivery or the combination with systemic therapy.

      References:

      [1] S. Senan, A. Brade, L.H. Wang, J. et al., PROCLAIM: randomized Phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 2016;34(9):953–962.

      [2] J.D. Bradley, R. Paulus, R. Komaki, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): A randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187–199.

      [3] J. Cole, G.G. Hanna, S. Jain, et al. Motion management for radical radiotherapy in non-small cell lung cancer, Clin. Oncol. (R. Coll. Radiol.) 2013;26(2):67–80.

      [4] J.W.H. Wolthaus, J.-J. Sonke, M. van Herk, et al. Comparison of different strategies to use four-dimensional computed tomography in treatment planning for lung cancer patients. Int. J. Radiat. Oncol. Biol. Phys. 2008;70 (4):1138–1229.

      [5] M. Kwint, S. Conijn, E. Schaake, et al. Intra thoracic anatomical changes in lung cancer patients during the course of radiotherapy, Radiother. Oncol. 2014; 113(3): 392–397.

      [6] N. Jegadeesh, Y. Liu, T. Gillespie, F. et al. Evaluating intensity-Modulated radiation therapy in locally advanced non-small-cell lung cancer: results from the national cancer data base. Clin. Lung Cancer 2016;17(5):398-405.

      [7] S.G. Chun, C. Hu, H. Choy, et al. Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial, J. Clin. Oncol. 2017 Jan;35(1):56-62.

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      MS30.02 - What Evidence Is Available to Support RT Technology in LA NSCLC (including Protons)? (Now Available) (ID 11531)

      13:50 - 14:05  |  Presenting Author(s): Yong Chan Ahn

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS30.03 - What Evidence Is Available to Support RT Treatment Intensification in LA NSCLC? (Now Available) (ID 11532)

      14:05 - 14:20  |  Presenting Author(s): Jeffrey Bradley

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS30.04 - Perspective (Now Available) (ID 11533)

      14:20 - 14:35  |  Presenting Author(s): Maria Werner-Wasik

      • Abstract
      • Presentation
      • Slides

      Abstract

      Radiation therapy (RT) in locally advanced non-small cell lung cancer (LA-NSCLC) has not changed in its essence over many decades. The refinements in “standard-of-care” RT followed the general advancements applicable to many other malignancies, such as introduction of IMRT (including VMAT) and IGRT. Tumor motion appears more relevant in lung tumors than in other disease sites, and lung-tumor interface allows for a measurable and intuitively observable movement, therefore enabling motion management in the lung to be more advanced, such as 4D CT for planning and tumor tracking (CyberKnife) or gating in daily practice.

      Nevertheless, the median survival time (MST) for good performance unresectable Stage II/III patients with NSCLC, treated with concurrent chemoradiotherapy (chemo-RT) has improved significantly over last quarter century, from MST of 17.1 mo (RTOG 9410) to MST of 28.7 mo (RTOG 0617). Since the agents used in concurrent chemotherapy are not significantly different, other causes, mostly widespread use of PET scans for staging, as well as improved RT techniques, likely play a role. Use of CT simulation is associated with improved MST, even when adjusted for other variables, such as chemotherapy use, comorbidities or urban location. Volumetric (rather than 2D) dose prescription; use of lower energy photons and heterogeneity correction; accounting for tumor motion with a 4D CT simulation and IGRT; better understanding of normal tissue tolerance (lung V20) and of the need to limit RT course breaks, all add incremental benefits for a more favorable outcome.

      In addition, factors such as RT center’s experience and volume of treated patients, as well as any protocol deviations in clinical trials, have been found to have a major impact in clinical practice, raising the possibility that strict adherence to RT planning guidelines might benefit all cancer patients treated with RT. Those factors have not yet been accounted for as eligibility/stratification factors in studies.

      Some much touted newer technologies, as particle RT (protons) have not so far demonstrated a verifiable superiority over photons. The Phase II randomized MDACC trial of photon vs. proton-based chemoradiotherapy for patients with Stage III or oligometastatic NSCLC did not show a difference in radiation pneumonitis rates between the arms and no improvement in local control in the proton arm. However, a steep learning curve in using proton RT was discovered, with lower pneumonitis rates in those patients in the proton group who were treated in the latter half of the study vs. those treated in its early phase.

      The ongoing NRG Oncology/RTOG 1308 Phase III randomized trial of photon vs. proton chemo-RT (70 Gy, but not lower than 60 Gy) has had a slow accrual, partially due to the paucity of participating centers, since proton technology is not widespread yet; also, a high percentage of patients not being able to enroll due to medical insurance coverage denial for protons, as well as possible perceptions of the superiority of protons. That study’s design has been modified recently to allow for a faster study’s completion. The original primary endpoint was overall survival, in contrast to the MDACC trial, where pneumonitis and local failure rate were co-endpoints. In order to complete the RTOG 1308 trial sooner by lowering its target accrual, the current primary hypothesis is that the MST in the proton arm is non-inferior to the photon arm (i.e. 28 mo), and major cardiac toxicity and grade 4 or higher lymphopenia is better in the proton vs. photon arm. Additionally, the Quality of Life hypothesis is that, compared with patients receiving photon therapy, patients on the proton arm will have less severe shortness of breath 6 months after the end of concurrent chemor-RT (representing late adverse response to therapy), and that the differences in symptom ratings (based on MDASI shortness of breath item) between arms will be clinically meaningful.

      The recent availability of Magnetic Resonance (MR)-Guided RT may open a new era in lung cancer RT, allowing for the real-time intrafractional tumor tracking and “on the fly” adaptive RT, both likely to allow smaller tumor target volumes and a rigorous evaluation of doses delivered to the normal structures, therefore lowering toxicity and potentially opening the door to reassessment of RT dose intensification.

      Finally, with the explosion of evidence-based applications of immunotherapy in metastatic lung cancer and the demonstration of an impressive survival prolongation in the Phase III randomized PACIFIC trial with the addition of maintenance durvalumab following chemo-RT, the role of chemotherapy may be eventually challenged and reevaluated in Stage III NSCLC, to be possibly replaced by concurrent immunotherapy or a chemo-immunotherapy combination.

      References:

      Curran WJ, Paulus R, Langer C et al, JNCI 2011

      Bradley J, Paulus R, Komaki R et al, Lancet Oncology 2015

      Chee KG, Nguyen DW, Brown M et al, Arch Internal Medicine 2008

      Ohri N, Shen X, Dicker AP et al, JNCI 2013

      Chen AB, Neville BA, Sher DJ et al, JCO 2011

      Eaton BR, Pugh SL, Bradley JD et al, JNCI 2016

      Liao Z, Lee JJ, Komaki R et al, JCO 2018

      Antonia SJ, Villegas A, Daniel D et al, NEJM 2017

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      MS30.05 - Nutritional Management During Radical Radiotherapy (Now Available) (ID 11534)

      14:35 - 14:50  |  Presenting Author(s): Rhys White

      • Abstract
      • Presentation
      • Slides

      Abstract

      Curative intent fractionated external beam radiotherapy (RT) with or without chemotherapy is used to treat locally advanced non-small cell cancer (NSCLC) and common side effects include anorexia, oesophagitis and fatigue, all of which can all impact on nutritional status. Previous research has shown that up to one third of lung cancer patients treated with RT experience clinically significant weight loss1 while one third of lung cancer patients present with malnutrition prior to even commencing RT 2. The negative impact of weight loss and malnutrition on patient and clinical outcomes is well established across all modes of cancer treatment including chemoradiotherpy3.

      There is limited evidence available relating to effective nutritional support strategies to prevent or treat weight loss and malnutrition in lung cancer4. There may be a role for enteral feeding where severe oesophagitis occurs in order to support patients through radical radiotherapy and its recovery1. The nutrition intervention demonstrated to be most effective in other tumours undergoing radiotherapy treatment is intensive individualised dietary counselling5 and the presence of dedicated dietetic services to head and neck and oesophageal cancer patients is well established in the U.K with dietitians identified as core members of the multi-disciplinary team.

      This session will explore the impact of a worsening nutritional status on clinical and patient outcomes and discuss the nutritional interventions that may be of benefit. It will also consider the role of a dedicated lung cancer dietitian and the impact this can have on patients with lung cancer.

      References:

      1. Kiss, N., Isenring, E., Gough, K. et al (2014) The prevalence of weight loss during (chemo)radiotherapy treatment for lung cancer associated patient- and treatment-related factors. Clin Nutr, 33: 1074-1080

      2. Unsal, D., Bulent, M., Akmansu, M. et al (2006) Evaluation of nutritional status in cancer patients receiving radiotherapy. Am J Clin Oncol 29: 183-188

      3. Sanders, K., Hendricks, L., Troost. et al. (2016) Early weight loss during chemoradiotherapy has a detrimental impact on outcome in NSCLC. J Thor Oncol, 11: 873-879

      4. Kiss, N., Krishnasamy, M. and Iserning, E. (2013) The effects of nutrition intervention in lung cancer patients undergoing chemotherapy and/or radiotherapy: a systematic review. Nutr Cancer, 66: 47-56

      5. Lee, J., Leong L. and Lim, S. (2016) Nutrition intervention approaches to reduce malnutrition in oncology patients: a systematic review. Support Care Cancer, 24: 469-480

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    MTE05 - Role of Pneumonectomy in N2 Disease (Ticketed Session) (ID 815)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 07:00 - 08:00, Room 202 BD
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      MTE05.01 - Role of Pneumonectomy in N2 Disease (Now Available) (ID 11554)

      07:00 - 07:30  |  Presenting Author(s): Jessica Donington

      • Abstract
      • Presentation
      • Slides

      Abstract

      Stage III non-small cell lung cancer (NSCLC) presents a significant treatment challenge. Patients are treated with curative intent, but only 20-30% achieve that goal, and acceptable treatment plans vary dramatically. Chemotherapy-based multimodality is the standard of care, but the ideal local therapy is unclear. Definitive concurrent chemo-radiotherapy without surgery is accepted by many as the treatment of choice, but local relapse is the first site of failure in up to >30%. Therefore, adding surgery to improve outcomes is attractive.

      Lung resection following induction chemo-radiotherapy to 45 Gy has been prospectively shown to be safe in numerous clinical trials. The use of pneumonectomy after induction therapy has been far more controversial. Multiple single institution series report on the safety of pneumonectomy following induction chemo-radiotherapy, even to doses of 60Gy, but results from multi-institutional prospective trials have not been as good, with reported peri-operative mortality up to 20-25%.

      The Intergroup trial 0139 was designed to evaluate the utility of adding surgery to chemo-radiotherapy for the treatment for N2+ IIIA NSCLC. The primary endpoint was improved overall survival, but was not met despite a significant improvement in progression-free survival. Some of this discrepancy was due to a high number of patients undergoing pneumonectomy and excessive mortality following pneumonectomy. Some of this was felt to be attributed to lack of surgical expertise both for pre-operative and intra-operative decisions.

      A recent evaluation of two prospective RTOG trials (0229 and 0839) which evaluated full-dose induction chemo-radiotherapy to 60 Gy followed by resection, reported increased peri-operative mortality (19%) with extended resections (pneumonectomy or bilobectomy). Results were complicated by the use of an EGFR antibody in the induction therapy, since 60% of grade 5 Adverse Events occurred in those who received both the EGFR antibody in addition to an extended resection.

      It is important to note that two large European prospective trials concentrated at experience surgical centers, reported excellent peri-operative outcomes with no increase in surgical mortality with use of pneumonectomy after induction chemo-radiotherapy.

      Stage IIIA NSCLC is a heterogeneous cohort of patients and treatment decisions need to be tailored to the individual patient and tumor. A pneumonectomy required for a large or central tumor with small volume nodal disease is distinct from tumors with bulky or infiltrative mediastinal nodes that require a pneumonectomy both in terms of short and long-term outcomes. Similarly outcomes vary by laterality, with mortality nearly twice as high for those on the right. While pneumonectomy needs to be used judiciously in this setting, eliminating it from all treatment decisions reduces the ability to achieve local control and long-term cure in a significant population.

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      MTE05.02 - Role of Pneumonectomy in N2 Disease (ID 11555)

      07:30 - 08:00  |  Presenting Author(s): Paula Ugalde

      • Abstract

      Abstract

      The therapeutic management of stage IIIA-N2 non-small cell lung cancer (NSCLC), which represents a locally advanced disease with ipsilateral mediastinal lymph node involvement, remains controversial despite the results of several randomized controlled trials [1-2]. By definition, stage IIIA-N2 represents a very heterogeneous population ranging from incidental discovery of N2 disease during surgery, through single mediastinal nodal involvement to bulky N2 disease where individual lymph nodes are difficult to identify and resect. Thus, treatment algorithms are controversial and guidelines are ambiguous.

      Patients with proven or suspected clinical stage IIIA-N2 NSCLC, are staged with contrast chest computed tomography (CT), integrated positron emission tomography – computed tomography (PET-CT) and brain magnetic resonance imaging (MRI) or CT. Additionally, before any treatment, histological proof of nodal involvement should be obtained either by a minimally invasive (EBUS) or invasive technique (mediastinoscopy). This is justified by the relatively high rate of false positive nodes [3] and also for complete mediastinal staging which includes the number of positive stations and the type of nodal infiltration. Proper lung cancer staging allows precise oncological treatment.

      When N2 disease is detected during surgery, in an entirely staged patient, this is referred as incidental, unsuspected or “surprise” N2 [4]. Here, if complete oncological resection can be achieved through lobectomy or pneumonectomy, the surgeon should proceed with the procedure. Adjuvant chemotherapy prolongs survival and is currently recommended in this setting. Major controversy occurs when N2 disease is confirmed either by staging EBUS or mediastinoscopy. A properly staged mediastinum has biopsies of stations 4R, 7 and 4L. Due to the absence of internationally accepted definition, the term “potentially resectable N2” is usually applied when mediastinal involvement is limited and surgery can potentially offer R0 resection.

      According to guidelines, patients in this sub-group should be treated by definitive concurrent chemo-radiotherapy or neoadjuvant therapy followed by surgery or definitive radiotherapy. In the recently published Swiss Cancer League trial, no significant difference was found when comparing those two strategies [5]. Specific controversy exists regarding the role of surgery versus radiotherapy and the acceptable extent of resection post-induction therapy.

      The Intergroup trial [6], a randomized study published in 2009 and comparing neoadjuvant chemoradiotherapy plus surgery to chemoradiotherapy alone, issued caution regarding pneumonectomy in the context of multimodality therapy. This was largely due to inexplicable surgical results in this series, which demonstrated morbidity and mortality higher than published averages (26%). Yet pneumonectomy continues to be advocated in this setting by high volume centers that achieve superior surgical morbidity and mortality [7-10]. A systematic review of pneumonectomy followed by neoadjuvant therapy was published in 2012 [11]. The report included 27 studies from 1990–2010, and included 4 randomized controlled studies, including the Intergroup trial. Mortality at 30 days was 7% and at 90 days was 12%, suggesting traditional reporting of 30-day mortality may not be the ideal marker of perioperative mortality for pneumonectomy patients. The ideal treatment for patients with locally advanced NSCLC, who require pneumonectomy for resection, remains controversial.

      Reference:

      1. Eberhardt WE, De Ruysscher D, Weder W, Le Péchoux C, De Leyn P, Hoffmann H et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol 2015; 26:1573-88.

      2. Eberhardt WE, Pöttgen C, Gauler TC, Friedel G, Veit S, Heinrich V et al. Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA-N2 and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J Clin Oncol 2015; 33:4194-201.

      3. De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 2014; 45:787-98.

      4. Van Schil P. Stage IIIA-N2 non-small-cell lung cancer: from “surprise” involvement to surgical nightmare. Eur J Cardiothorac Surg 2016; 49:1613-4.

      5. Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S et al. Induction chemo-radiotherapy in stage IIIA/N2 non-small cell lung cancer: a phase 3 randomised trial. Lancet 2015; 386(9998):1049-56.

      6. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86.

      7. Kim AW, Faber LP, Warren WH, et al. Pneumonectomy after chemoradiation therapy for non-small cell lung cancer: does "side" really matter? Ann Thorac Surg 2009;88:937-43; discussion 944.

      8. Weder W, Collaud S, Eberhardt WE, et al. Pneumonectomy is a valuable treatment option after neoadjuvant therapy for stage III non-small-cell lung cancer. J Thorac Cardiovasc Surg 2010;139:1424-30.

      9. Krasna MJ, Gamliel Z, Burrows WM, et al. Pneumonectomy for lung cancer after preoperative concurrent chemotherapy and high-dose radiation. Ann Thorac Surg 2010;89:200-6; discussion 206.

      10. Cerfolio RJ, Bryant AS, Jones VL, et al. Pulmonary resection after concurrent chemotherapy and high dose (60Gy) radiation for non-small cell lung cancer is safe and may provide increased survival. Eur J Cardiothorac Surg 2009;35:718-23; discussion 723.

      11. Kim AW, Boffa DJ, Wang Z, et al. An analysis, systematic review, and meta-analysis of the perioperative mortality after neoadjuvant therapy and pneumonectomy for non-small cell lung cancer. J Thorac Cardiovasc Surg 2012;143:55-63.

      e353dbe42c8654f33588d4da0b517469

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    MTE20 - Molecular Testing in Small Samples (Ticketed Session) (ID 830)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Pathology
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 07:00 - 08:00, Room 202 BD
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      MTE20.01 - Molecular Testing in Small Samples (Now Available) (ID 11581)

      07:00 - 07:30  |  Presenting Author(s): John W Longshore

      • Abstract
      • Presentation
      • Slides

      Abstract

      Recent advances over the past decade in canger genomics allows the rapid identification of patients with driver mutations or immune phenotypes that are eligible for targeted, rather than systemic, therapy. In many centers worldwide, biopsy material obtained from lung cancer patients is limited to core needle biopsy or fine needle aspirate samples. After a histologic diagnosis is rendered on these samples, often a limited amount of tissue remains for biomarker testing. To further complicate matters, the number of biomarkers required to profile patients is increasing with the number of new therapeutics available for treatment. During this educational session, techniques for proper tissue stewardship when working with small biopsy samples as well as utilizing tissue sparing biomarker testing methods will be presented.

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      MTE20.02 - Molecular Testing in Small Samples (Now Available) (ID 11582)

      07:30 - 08:00  |  Presenting Author(s): Jin-Haeng Chung

      • Abstract
      • Presentation
      • Slides

      Abstract

      Molecular targeted therapies have become a standard treatment for patients with lung cancer. Driver genetic alterations such as EGFR mutations, ALK rearrangements and ROS1 rearrangements are currently used as predictive biomarkers for EGFR tyrosine kinase inhibitors (TKIs), ALK inhibitors, and ROS1 inhibitors, respectively. In addition, antibodies blocking the PD-1 ligand PD-L1 have shown prominent antitumor activities and durable clinical response.

      Molecular analyses of these predictive biomarkers in tumor tissue or cytology specimens are the first prerequisite laboratory tests for the clinical management of lung cancers.

      Despite the increasing number of targets to be tested, most patients harboring non-small cell lung carcinoma (NSCLC) presents with advanced stage at the time of diagnosis, so the amount of tissue that can be acquired is very small.

      Small biopsy and cytology samples obtained from a variety of methods are acceptable for molecular testing, including transbronchial lung biopsy, endobronchial ultrasound– guided transbronchial needle aspiration, bronchial brushing or washing, computed tomography–guided gun biopsy or needle aspiration, and pleural fluid sampling.

      The molecular testing results using cytology samples are highly concordant with those of the corresponding tissue samples, especially with more sensitive methods. Routinely prepared cytology samples such as alcohol-fixed smears or cell block samples are also suitable for mutation testing.

      As targetable genetic alterations are increasingly identified, individual genotyping or molecular test seemed to be relatively inefficient and expensive. Thus, next-generation sequencing (NGS) technology with DNA or RNA is reported to be useful method for multiplexed and deep targeted sequencing.

      In this situation, each pathology laboratory needs to make a strategic approach to use these small samples in considerations of the important priorities for the management of the patients.

      In this MET session, I will introduce our experience of strategic approach to obtain the most useful information while reducing the loss of tissue using a small amount of samples.

      References

      1. Li T, Kung HJ, Mack PC, Gandara DR. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol 2013; 31: 1039-49.

      2. 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; 366: 2455-2465.

      3. Shim HS, Choi YL, Kim L, et al. Molecular testing of lung cancers J Pathol Trans Med 2017; 51: 242-254..

      4. Sun PL, Jin Y, Kim H, Lee CT, Jheon S, Chung JH. High concordance of EGFR mutation status between histologic and corresponding cytologic specimens of lung adenocarcinomas. Cancer Cytopathol 2013; 121: 311-9.

      .

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