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T. Mok

Moderator of

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    G01 - Progress in Lung Cancer: Celebrating 40 Years of IASLC and Research Progress (ID 14)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 4
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      G01.1 - Surgery and Staging (ID 436)

      17:30 - 18:30  |  Author(s): H. Asamura

      • Abstract
      • Slides

      Abstract
      Staging is an objective measurement of the extent of cancer to allow logical grouping of patients with similar prognosis and pathobiological characteristics. Actually, the stage is expressed as combination of three factors: the size and invasion of the primary tumor (T), metastasis to the locoregional lymph nodes (N), and distant disease (M). Nowadays, any planning of the treatment is not possible without accurate staging. Moutain, who took the great leadership in the revision of TNM staging system, described staging as “assigning a simple coded designation to be a patient in accordance with an established set of rules”. Traditionally, UICC and AJCC have taken an initiative for the revision of the classification rules of TNM system. Since 7[th] edition which was published in 2009, IASLC was principally involved in the creation of proposals for revision to UICC and AJCC based upon the world-wide database. This process was known as “IASLC Lung Cancer Staging Project” lead by Goldstraw, and it is still underway for 8[th] edition. Although TNM staging system covers the malignant tumors of most organs, such aggressive intervention of international academic societies has been rarely seen except IASLC. The advent of mediastinoscopy, PET, and EBUS technique contrubuted to better staging. The IASLC Staging Project is now extended to cover not only lung cancer but also mesothelioma, thymic tumors, and esophageal cancer. As of 2013, surgery is still playing a principal role in the treatment of lung cancer especially for the relatively early stages of the disease with curative intent. Surgery is respected as the integration of two different parts: "art (surgical skill)" and "science". Therefore, we should realize that the evolution of lung cancer surgery has been achieved by the refinement of surgeons’ skills and advent of new technique (technology) as well as the accumulation of novel scientific evidence given by the well planned clinical trials. Surgery for lung cancer began as pneumonectomy as early as in 1930. However, the present-day gold standard surgery for lung cancer is defined as at least lobectomy and lymph node sampling/dissection. Series of clinical trials in 1980’s, mainly focusing upon the prognostic evaluation of adjuvant chemotherapy, were performed by Lung Cancer Study Group. The technically challenging surgery, such as those for superior sulcus tumor, has been also improved greatly. Even tumors located at the difficult potion of the thoracic inlet could be resected by refined method as shown by Grunenwald. How to manage the metastasis to the locoregional lymph nodes is also an important issue. Owing to the lymph node map originally drawn by Naruke and colleagues in 1970’s, the precise location of the metastatic nodes could be documented, and further analyses and comparison of the resected lung cancer with node metastasis became possible. The prognostic impact of the lymph node dissection was evaluated by the recent ACOSG study. In 1990’s, the minimally invasive technique (video-assisted thoracic surgery) was introduced in the surgery for lung cancer, and the comparison between open and VATS procedures were being performed. The trend toward the minimally invasive surgery is now generalized in the thoracic surgical community. The future directions in lung cancer surgery include the development of less invasive technique such as robotics, the improvement of the adjuvant treatment with new active drugs, the definition of the role of surgery in the multimodality treatment for advanced lung cancer, and the comparison between surgery and other local modalities (SBRT, ablation) as the treatment for pathologically early lung cancer. References 1970’s Pearson FG et al. The role of mediastinoscopy in the selection of treatment for bronchial carcinoma with involvement of superior mediastinal lymph nodes. J Thorac Cardiovasc Surg 1972;64:382-90. Naruke T et al. Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 1978;76:832-9. 1980’s Holmes EC, et al. THE LUNG CANCER STUDY GROUP. A randomized comparison of the effects of adjuvant therapy on resected stages II and III non-small cell carcinoma of the lung. Ann Surg 1985;202:335-41 Mountain CF. A new international staging system for lung cancer. Chest 1986;89:225S-33S 1990-1995 Valk PE, et al. Staging of non-small-cell lung cancer by whole-body positron emission tomographic imaging. Ann Thorac Surg 1995;60:1573-82. Lung Cancer Study Group. Randomized trial of lobectomy versus limited resection for T12 N0 non-small cell lung cancer. Ann Thorac Surg 1995;60:615-23. 1995-2000 TNM Classification of Malignant Tumours. 5[th] Ed. Lung. International Union Against Cancer. Wiley-Liss, New York, pp93-97, 1997. Grunenwald D et al. Transmanubrial osteomuscular sparing approach for apical chest tumors. Ann Thorac Surg 1997;63:563-6. 2001-2005 Goya T et al. Prognosis of 6,644 resected non-small cell lung cancers in Japan: a Japanese lung cancer registry study. Lung Cancer 2005;50:227-34. Mateu-Navarro M et al. Remediastinoscopy after induction chemotherapy in non-small cell lung cancer. Ann Thorac Surg 2000;70:391-395. Van Schil PE et al. Remediastinoscopy after neoadjuvant therapy for non-small cell lung cancer. Lung Cancer 2002;37:281-285. Stamatis G et al. Repeat mediastinoscopy as a restaging procedure. Pneumologie 2005;59:862-866. De Leyn P et al. Prospective comparative study of integrated PET-CT scan versus re-mediastinoscopy in the assessment of residual mediastinal lymph node disease after induction chemotherapy for mediastinoscopy proven IIIA-N2 non-small cell lung cancer. A Leuven Lung Cancer Group study. J Clin Oncol 2006;24:3333-9. 2005-2010 The IASLC Staging Manual in Thoracic Oncology, Editorial Rx, Florida, 2009. Falcoz et al. The Thoracic Surgery Scoring System (Thoracoscore): Risk model for in-hospital death in 15,183 patients requiring thoracic surgery., J Thorac Cardiovasc Surg 2007;133:325-32. 2010- Yasufuku K et al. A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediatinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg 2011;142:1393-400. Darling GE et al. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: Results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 2011;141:662-70. Swanson SJ et al. Video-Assisted Thoracoscopic Lobectomy Is Less Costly and Morbid Than Open Lobectomy: A Retrospective Multiinstitutional Database Analysis., Ann Thorac Surg 2012;93:1027-32

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      G01.2 - Early Detection, Etiology, Epidemiology, Pulmonology and Radiology (ID 437)

      17:30 - 18:30  |  Author(s): P.E. Postmus

      • Abstract
      • Slides

      Abstract
      Etiology and epidemiology Awareness that lung cancer is for many patients a self-inflicted disease has become common knowledge and its incidence can only be reduced by an active fight against smoking . The IASLC has always considered this as very important (1). The last decade much attention was given the non-smokers who developed lung cancer. These patients have specific characteristics, of which EGFR mutation is one (2). What is responsible for this class of lung cancer is unknown. With an estimated number of 300,000/year, it is far from an orphan disease (3). Early detection Lung cancer cure rates are far from impressive (4). For those diagnosed with symptoms the outcome is grim, cure is extremely rare, palliative needs are common (5). The 5 year survival rates in patients with resectable tumors is decreasing with increasing stage (6). Finding early stage lung cancer with state-of -the-art CT technology resulted in an impressive 10 yr survival rate of 88% (7). This modern CT technologywas evaluated in the largest lung cancer screening study ever performed (8). For the first time it was demonstrated that screening is effective and results in a relative reduction in mortality from lung cancer of 20.0%, and death from any cause by 6.7% (95% CI, 1.2 to 13.6; P = 0.02). Still many questions remain unanswered and confirmation is needed (9)? How to treat these lesions with minimal invasive surgery (10) or stereotactic radiotherapy (11). Pulmonology Autofluorescence bronchoscopy improves the detection of mucosal abnormalities (12) such as pre-invasive lesions (13), carcinoma in situ (14) and radiologically occult lung cancer (15). Through the EBUS (endobronchialultrasound) scope virtually every lymph node adjacent to the bronchial tree can be reached (16). In combination with the ultrasound from inside the oesophagus (17) this results in a sensitivity of > 90% (18). In a RCT it was demonstrated that combining these techniques should be done before thinking of a mediastinoscopy as their yield is comparable to mediastinoscopy (19). Bronchoscopy became important for treatment as well, ranging from palliative to really curative. Stenting the airway but should be used with great caution as migration is common, it seriously affects mucus clearance and narrowing of the airways through granulation tissue might develop (20). A desobstruction technique such as Nd-YAG laser, electrocautery or argon plasma coagulation can be used if intraluminal tumor gives obstruction (20). In specific situations with very limited cancer within the bronchial wall endobronchial treatment might even lead to cure, an example of this is photodynamic therapy (21). Radiology Within the last 40 years imaging techniques have improved considerably. With the introduction of computed tomography, it became possible to visualize the primary tumor as well as mediastinal lymphnodes in a much better way. A further technical improvement, the Positron Emission Tomography (PET) and the use of 18-fluorodeoxyglucose (18-FDG) improved this (22). Further developments of imaging may lead to decision making on treatment (23). References 1 Tobacco policy recommendations of the International Association for the Study of Lung Cancer (IASLC): a ten point program. Lung Cancer 1994; 11: 405-407 2 Ren JH, et al. EGFR mutations in non-small-cell lung cancer among smokers and non-smokers: a meta-analysis. Environ Mol Mutagen. 2012 Jan;53(1):78-82 3 Sun S, et al. Lung cancer in never smokers—a different disease. Nat Rev Cancer. 2007;7(10):778-790. 4 Goldstraw P, et al. The International Association for the study of lung cancer. The International staging project on lung cancer. J ThoracOncol 2006; 1: 281-286. 5 Ferrell B, et al. Palliative care in lung cancer. SurgClin North Am 2011; 91: 403-418. 6 Goldstraw P, et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification for Lung Cancer. J Thor Oncol 2007; 2: 706-714. 7 The International Early Lung Cancer Action Program Investigators. Survival of Patients with Stage I Lung Cancer Detected on CT Screening. N Engl J Med 2006; 355:1763-1771. 8 National lung screening trial research team, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: 395-409. 9 Field JK, et al. Prospects for population screening and diagnosis of lung cancer. Lancet 2013; 382: 732-741. 10 Nakamura K, et al. A phase III randomized trial of lobectomy versus limited resection for small sized peripheral non-small cell lung cancer. Jpn J ClinOncol 2010; 40: 271-274. 11 Senan S, et al. Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy? Lancet Oncol 2013; 14: 270-274. 12 Venmans BJW, et al. Clinically relevant information obtained by performing autofluorescence bronchoscopy. J Bronchol 2000; 7: 118-121. 13 Breuer RHJ, et al. The natural course of preneoplastic lesions in bronchial epithelium - A longitudinal study. Clin Cancer Res 2005; 11: 537-543. 14 Venmans BJW, et al. Outcome of bronchial carcinoma in situ. Chest 2000; 117: 1572-1576. 15 Vonk-Noordegraaf A, et al.Bronchoscopic treatment of patients with intraluminal microinvasiveradiographically occult lung cancer not eligible for surgical resection: a follow-up study. Lung Cancer 2003; 39: 49-53. 16 Herth FJ, et al. Transbronchial and transoesophageal (ultrasound-guided) needle aspiration for the analysis of mediastinal lesions. EurRespir J 2006; 28: 1264-1275. 17 Silvestri GA, et al. Endoscopic ultrasound with fine-needle aspiration in the diagnosis and staging of lung cancer. Ann ThoracSurg 1996; 61: 1441-1445. 18 Wallace MB, et al. Minimally invasive endoscopic staging of suspected lung cancer. JAMA 2008; 299: 540-546. 19 Annema JT, et al. Mediastinoscopyvsendosongraphy for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 2010; 304: 2245-2252. 20 Bolliger CT, et al. Therapeutic bronchoscopy with immediate effect: laser electrocautery, argon plasma coalgulation and stents. EurRespir J 2006; 27: 1258-1271. 21 Cortese DA, et al. Photodynamic therapy for early stage squamous cel carcinoma of the lung. Mayo ClinProc 1997; 72: 595-602. 22 Silvestri GA, et al Methods for staging lung cancer. Chest 2013; 143: 211S-250S. 23 Bahce I, et al. Development of [(11)C]erlotinib positron emission tomography for in vivo evaluation of EGF receptor mutational status. Clin Cancer Res. 2013; 19: 183-193.

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      G01.3 - Biology and Pathology (ID 3858)

      17:30 - 18:30  |  Author(s): F. Hirsch

      • Abstract
      • Slides

      Abstract not provided

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      G01.4 - Non-Surgical Therapy (ID 3859)

      17:30 - 18:30  |  Author(s): P.A. Bunn, Jr.

      • Abstract
      • Slides

      Abstract
      Systemic Therapy of Early Stage NSCLC The addition of chemotherapy to surgery before or after surgery was studied because trials in the 1970’s demonstrated that cure rates were lower than in other cancers and because the majority of relapses were in distant sites (1). Initial adjuvant studies showed no survival advantage for single agent chemotherapy. Subsequent trials in the 1980’s and 1990’s established that cisplatin based 2-drug combinations produced a modest (4-5%) improvement in 5 year survival rates but only in stages II and IIIa (2). Adjuvant therapy has not been shown to improve outcomes in Stage I with the possible exception of Stage IB tumors larger than 4 cm (3). Neoadjuvant chemotherapy produces similar improvement compared to adjuvant therapy as demonstrated by randomized trials and metaanalyses (4,5). Post-operative radiotherapy has not shown benefits in stage I and II where it may be harmful and it role in stage IIIa after surgery is under evaluation as there are conflicting data on its role in this setting (6,7).Systemic Therapy of Stage III NSCLC Combinations of radiotherapy with chemotherapy were shown to produce superior survival compared to either alone based on randomized trials conducted in the 1990’s (8). Subsequent studies indicated that concurrent chemo-radiotherapy was superior to sequential therapy (9,10). There are conflicting data on whether two or four cycles of chemotherapy is best (11). There are also conflicting data on whether triple modality therapy is superior to two modalities for Stage IIIA N2 disease (12).Systemic Therapy of Stage IV NSCLC Chemotherapeutic agents and chemotherapy combinations were tested in the 1970’s and early 1980’s but failed to show any survival advantage. Two drug combinations combining cisplatin with vindesine or vinorelbine were shown to prolong survival compared to best supportive care in the 1980’s and 1990’s (13,14). Subsequent studies showed that 2-drug platinum based combinations were superior to a single active drugs (13,15,16). The survival advantage increased median survival times from 4-5 months to 8-12 months. Two-drug combinations with a platinum combined with gemcitabine, paclitaxel, docetaxel or pemetrexed were shown to produce equivalent survival in randomized trials conducted in the 1990’s and in the 2000’s (17,18). An exception to the equivalence was the finding that the pemetrexed/cisplatin combination was superior to gemcitabine/cisplatin in non-squamous cancer but inferior in squamous cancers (19). Three and 4 drug combinations were not superior to 2 drug combinations. These 2 drug combinations were superior in patients with PS 0-1 but benefitted elderly as well as younger patients (20). There is evidence that the paclitaxel/carboplatin combination may benefit PS2 patients (21). Thus, histology and performance status are key factors in therapy selection. Since the 1990’s, docetaxel, erlotinib, and pemetrexed have been shown to prolong survival when used in the 2[nd] line setting (22-24). For pemetrexed this improvement was limited to non-squamous histology (24). Since 2000 the use of targeted therapy began with the studies of inhibitors of VEGFR and EGFR signaling. Angiogenesis inhibitors were widely studied. Bevacizumab, a monoclonal antibody to VEGF, was shown to produce promising results in a randomized phase II trial (25). However, patients with squamous cell carcinoma had excess bleeding on this study and were excluded from all further trials. An ECOG randomized trial (4599) showed that bevacizumab improved survival in non-squamous histologies when combined with platinum doublets (26). However, the survival advantage is small and is less striking in elderly patients. The survival advantage was not observed in a randomized trial from Europe using gemcitabine/cisplatin as the chemotherapy backbone (27). As noted above, the EGFR TKI erlotinib was shown to prolong survival in unselected patients failing 1 or 2 chemotherapy regimens (23). In 2004 an association between mutations in the EGFR and response to EGFR TKIs was established (28,29). Subsequent randomized trials showed that EGFR TKIs were superior to chemotherapy in 1[st] line therapy of EGFR mutant patients but chemotherapy was preferred for those without mutations (30-35). In 2007, it was shown that EML4/ALK fusions could serve as driver molecular changes in up to 5% of NSCLC’s (36). Crizotinib, an ALK TKI was shown to produce high response rates and long PFS and was superior to chemotherapy in the second line setting (37-39). Patients with ALK fusions nearly always have adenocarcinoma histology, more often are younger and female sex and are light or never smokers (40) but clinical features should not be used to determine who should be tested (41). These and other molecular drivers may be present in more than 50% of lung adenocarcinomas (42). Molecular analyses of squamous and small cell cancers have recently been described (43-46). Checkpoint inhibitors such as PD1 and PDL1 were shown to be therapeutic targets since 2010. Antibodies to PD1 and PDL1 have produced responses in about 20% of patients who had failed multiple lines of chemotherapy and many of these were durable (46,47). PDL1 expression is being evaluated as a biomarker and many trials are in progress. Maintenance therapy with continuation of the original platinum doublet was shown in many trials to be associated with an increase in the PFS, an increase in toxicity but no increase in survival and therefore this approach was not adopted (48) . In 2009, Fidias et al reported that maintenance docetaxel could increase survival as well as PFS (49). This trial was followed by a trial showing that erlotinib could improve PFS and survival as maintenance after a platinum doublet (50). PFS and survival were improved in all histologies but the improvement in PFS and OS was most striking in patients with EGFR mutations. Pemetrexed was shown to improve PFS and survival as switch maintenance after a platinum doublet that did not contain pemetrexed (51). A subsequent trial showed that pemetrexed continuation maintenance also improved PFS and OS after induction therapy with a pemetrexed/platinum doublet induction (52). An unpublished trial, (POINTBREAK), comparing pemetrexed/carboplatin/bevacizumab with pemetrexed/bevacizumab maintenance compared to paclitaxel/carboplatin/bevacizumab followed by bevacizumab, showed no difference in survival. Thus, there is no evidence at presence that maintenance should contain two drugs although the ECOG is comparing pemetrexed with bevacizumab or the combination after induction therapy with paclitaxel/carboplatin/bevacizumab.Systemic Therapy of Early Stage SCLC Patients with Stage I and IIA SCLC, although infrequent, benefit from resection and adjuvant chemotherapy and the IASLC TNM classification is more accurate than the old VA classification (53). SCLC patients with stage IIB and III (limited stage SCLC) were shown to have prolonged survival when treated with chemotherapy and radiotherapy compared to either alone (54,55). An ECOG randomized trial showed that chest RT with BID radiation to 45 Gy was superior to once daily chest RT to the same dose when combined with etoposide/cisplatin (56). However, similar results were obtained with higher total doses of once daily RT and both once daily and twice daily are in routine practice. Concurrent chemoradiotherapy is superior to sequential therapy but results with radiotherapy starting at either cycle 1 or cycle 3 are similar. The combination of etoposide/cisplatin is the most frequent chemotherapy regimen because of reduced toxicities compared to Adriamycin or other combinations. Prophylactic cranial irradiation in good responders reduces brain relapse and prolongs survival (57). 25 Gy is the preferred dose (58).Systemic Therapy for Stage IV SCLC Both cisplatin and etoposide were first tested and shown to be active in the 1970’s. Studies in the 1980’s showed that the combination of etoposide and cisplatin produced high response rates (80%) with some complete responses (10-15% (59, 60). These results lead to randomized trials comparing etoposide/cisplatin to CAV, CAE or alternating combinations. Etoposide/cisplatin (EP) produced equivalent efficacy with less toxicity (60,61) and thus became the standard combination in the 1990’s. Pemetrexed/carboplatin was compared to etoposide/carboplatin and was inferior (62). Several trials have shown that irinotecan combined with cisplatin or carboplatin is equivalent to etoposide with cisplatin or carboplatin (63, 64). Thus EP remains the standard today. Topotecan is approved for used in the second line setting albeit at a dose and schedule rarely used due to toxicity (65,66). Both oral and intravenous topotecan produce similar results. Topotecan improved PFS as maintenance but did not improve survival and increased toxicity (67). Thus, use in the maintenance setting was not widely adopted. Retreatment with EP for those with late relapse has been the most successful retreatment approach and is standard in this setting (68). After 2000, randomized trials showed that PCI after induction response could prolong survival in extensive stage as well as limited stage SCLC and as now used routinely in this setting (69). There has been little change in chemotherapy options for SCLC over the past 20 years but there is some hope that the immune checkpoint inhibitors could improve outcomes (70).

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    PL05 - Genomics: From Research Tool to the Lung Cancer Clinic (ID 76)

    • Event: WCLC 2013
    • Type: Plenary Session
    • Track: Pathology
    • Presentations: 3
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      PL05.1 - Implications of the Lung Cancer Genome Sequencing (ID 796)

      16:15 - 17:45  |  Author(s): R. Govindan

      • Abstract
      • Slides

      Abstract not provided

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      PL05.2 - Challenges in Bioinformatics (ID 797)

      16:15 - 17:45  |  Author(s): Y. Shyr

      • Abstract
      • Slides

      Abstract not provided

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      PL05.3 - Challenges for the Clinician (ID 798)

      16:15 - 17:45  |  Author(s): S. Devarakonda, D. Morgensztern, C. Belani, R. Govindan

      • Abstract
      • Slides

      Abstract
      . Although EGFR mutations and fusions involving ALK and ROS1 are targetable by currently approved agents, these alterations are present in less than a fifth of patients with non-squamous NSCLC. Treatment options for the majority of patients remain largely empirical. The urgent need to develop therapies capable of targeting cancers without these alterations can only occur with a better understanding of the molecular biology and cytogenetic alterations. Recently, the lung cancer mutation consortium reported longer survival in patients with adenocarcinoma who underwent multiplexed genomic testing for the detection of alterations in 10 genes, and subsequently received matched targeted treatments. [Johnson et al J Clin Oncol 31, 2013 (suppl; abstr 8019)]. A total of 1,007 patients were screened for at-least one genetic alteration, and an actionable alteration that led to the use of targeted therapies was detected in 28% of these patients. The median survival in these patients was 3.5 years, while patients whose tumors did not harbor actionable alterations had a median survival of 2.1 years. It would be reasonable to assume that adapting NGS technologies, which allow comprehensive screening of the entire genome at a higher resolution, will result in improved outcomes in patients whose tumors do not harbor targetable mutations identifiable by commercially available assays. NGS has allowed a better characterization of lung cancer, with the identification of novel mutations and copy number alterations. Preliminary results from TCGA demonstrated that a significant percentage of patients with lung cancer harbor a targetable abnormality. It is still possible that additional less common mutations or alterations will be discovered once the sequencing of 1000 lung cancer samples is completed by TCGA. The next challenge is the development of novel drugs based on specific targetable abnormalities. Although this strategy may require extensive evaluation and multiple trials targeting distinct molecular subtypes of tumors, this departure from the empirical treatment of lung cancer, probably represents the best hope towards achieving meaningful progress.

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Author of

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    CALC - Chinese Alliance Against Lung Cancer Session (ID 79)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 1
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      CALC.09 - Targeted Therapies for SCC, Now and Future (ID 3876)

      07:30 - 12:00  |  Author(s): T. Mok

      • Abstract
      • Slides

      Abstract not provided

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    PL02 - Will Personalised Therapies Ever “Cure” Metastatic NSCLC? (ID 73)

    • Event: WCLC 2013
    • Type: Plenary Session
    • Track: Medical Oncology
    • Presentations: 1
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      PL02.4 - What is Cure and How Can We Achieve This With Targeted Therapies? (ID 636)

      08:15 - 09:45  |  Author(s): T. Mok

      • Abstract
      • Slides

      Abstract not provided

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