Virtual Library

Abstract:
General considerations Early stage lung cancer - a term in transition Generally early stage lung cancer is understood as stage I and stage II non-small lung cancer. An alternative understanding of early stage lung cancer is resectable disease. However, both definitions are imprecise and subject to development and Expertise. 1. Defining early stage lung cancer as resectable disease depends on regional philosophies and local expertise and therefore is the most unreliable and variable definition. The term resectability focuses on the T factor of the tumour and describes the ability of the surgeon to achieve radical resection. In contrast operability includes any potential regional and systemic spread and focuses more on the N and M descriptors. 2. Defining early stage lung cancer based on mediastinal nodal involvement neglects the fact, that single station N2 (N2a) is associated with the same five-year survival as multistation N1 (N1b). This touches on the term locally advanced disease, which in fact also means different things for different people. For the oncologist locally advanced disease usually means N2 involvement with the consequent call for chemotherapy. For the surgeon locally advanced disease primarily addresses the T factor and is used for T3 or T4 tumours, indicating more extended resections in the absence of N2 disease. In summary, terms like early stage, locally advanced stage or advanced stage should be avoided since they do not properly describe a clinical situation nor are they guiding therapy. If the term early stage lung cancer should be maintained for any reason, there is need for revisions. The five-year survival of stage I and stage II non-small lung cancer is a range of less than 30 to more than 90% and the survival expectedly mainly depends on nodal involvement. The estimated median five-year survival of patients with Screening detected T1N0 NSCLC is a reported 92%. Even nodal negativeT3 tumours are associated with almost 60% five year survival following radical resection. On the other hand involvement of multiple N1 lymph nodes results in a much worse prognosis of about 35%. However, for this presentation the current definition of stage I and stage II non-small lung cancer was used. Preoperative staging Resectability of lung cancer for technical reasons in general, and in early stage lung cancer in particular, very rarely is an issue. Oncological operability has to be defined preoperatively along international guidelines. The European Society of Thoracic Surgeons (ESTS) recently has ublished revised guidelines for preoperative mediastinal lymph nodes staging for non-small cell lung cancer. Only one selected group of patients with tumours of less than 3 cm in diameter (cT1) in the outer third of the lung without signs of nodal involvement at CT scan, PET scan or PET CT (cN0) may directly undergo surgical resection. All other clinical situations require invasive preoperative staging by bronchoscopy plus EBUS/EUS. If the absence of nodal involvement is verified by EBUS/EUS this patient may also directly undergo surgery. In the presence of radiologically suspect mediastinal lymph nodes and negative EBUS/EUS further confirmation is recommended using mediastinoscopy or thoracoscopy. If mediastinal nodal involvement is histologically verified by any means the patient has to undergo multimodality treatment. All clinical findings are to be discussed in an interdisciplinary tumour board for proper therapy planning. [1] Surgical therapy of early stage NSCLC Surgery remains the cornerstone of treatment of early stage non-small lung cancer for patients willing to accept the procedure-related risks. Goal of any surgical intervention for early stage lung cancer is the complete resection of the primary tumour together with regional lymphatic nodes. The standard for any resection with curative intent is defined by anatomical lung resection. In early stage lung cancer the predominant type of resection is lobectomy or bilobectomy, sometimes along with bronchoplastic or angioplastic procedures or extended resections for locally invading T3 tumours. Pneumonectomy particularly in the treatment of early stage lung cancer is rarely used. Gold standard of surgical resection for lung cancer is lobectomy. This standard is based on a prospective multi-institutional randomized trial comparing limited resection with lobectomy for peripheral T1N0 non-small cell lung cancer published in 1995. [2 ]In the absence of more recent prospective randomised trials lobectomy still must be considered the surgical procedure of choice for patients with peripheral T1N0 non-small cell lung cancer. An extensive body of literature mainly composed of retrospective studies supports the use of radical anatomical segmentectomy for peripheral cT1N0M0 non-small lung cancer with less than 2 cm in diameter, certainly for older patients with limited cardiopulmonary function. However, caution should be taken to promote a widespread indication for intentional segmentectomy in young good surgical candidates until the results of the ongoing randomised controlled trials become available.[ 3,4] The role of minimally invasive surgery Minimally invasive anatomical resection for lung cancer carried out by means of video-assisted thoracic surgery (VATS) has been increasingly carried out during the past years. A systematic review and meta-analysis of randomized and nonrandomized trials published in 2009 reported an improved five-year survival and reduced systemic recurrences in patients who received VATS lobectomy. [5 ]A multicentric propensity-matched analysis of more than 1000 patients, of which 700 had undergone VATS lobectomy confirms, that thoracoscopic lobectomy is associated with lower morbidity as compared with thoracotomy. The positive impact of minimally invasive surgery in the treatment of lung cancer particularly applies to the elderly. [6] Regarding long-term survival after video-assisted thoracoscopic lobectomy a meta- showed a survival benefit in the favour of VATS with a difference in survival of 5% at five years. The reason for this observed survival benefit may be attributed to a less pronounced compromise of the immunocompetence after the surgical trauma. [7] The role of mediastinal lymph node dissection The rationale for a formal mediastinal lymph node dissection is multifold. The distribution pattern of mediastinal lymph node metastasis is not predictable and skip metastasis are seen in up to 30% of patients. Even small tumours may present with unexpected N2 disease with an incidence of 6-10%. The operative morbidity is not significantly influenced by a systematic mediastinal lymph node dissection. Recommended standard of mediastinal lymph node dissection is the removal of all mediastinal tissue containing lymph nodes in a systematic Approach within anatomical landmarks. The most recent randomized controlled trial published in 2011 did not find a survival benefit by complete mediastinal lymphadenectomy in patients with early stage lung cancer, but the results should not be generalized to patients staged only radiographically or those with higher stage tumours. The recommendation from this study is that a formal mediastinal en-bloc dissection may still affect survival and certainly optimally stages patients. In the subgroup analysis no difference between VATS and open lobectomy was observed for number of lymph nodes harvested and regarding long-term survival.[8] As minimally invasive surgery along with unilateral mediastinal lymphadenectomy generally prolongs operation times and the requirement of single lung ventilation the advantages for the elderly population has to be questioned and discussed individually. An alternative to thoracoscopic unilateral lymphadenectomy is offered by video-assisted mediastinal lymphadenectomy through the neck (VAMLA). The approach is similar to transcervical mediastinoscopy and allows for a radical bloc dissection of all mediastinal lymph node stations. Besides the benefit of bilateral lung ventilation during this phase of the operation a bilateral mediastinal lymphadenectomy offers improved surgical radicality. Alternatives to surgical resection and the role of primary radiotherapy In patients unfit for surgery SABR is the treatment of choice for peripherally located stage I non-small cell lung cancer. If SABR is not available a hypofractionated radiotherapy is advocated. A systematic Review comparing outcomes of SABR and surgery in patients with severe COPD revealed a higher 30 day mortality following surgery but similar overall survival at one and three years. [9] In a meta-analysis of 19 out of 318 papers with the best evidence addressing a comparison of SABR and surgical wedge resection both methods proved as reasonable alternatives to lobectomy in high risk surgical patients. In this analysis SABR was associated with reduced local recurrence compared to wedge resection and should be considered when wedge resection is planned due to anatomical location and size of the primary tumour in a patient who is high risk for surgery. [10] Although local tumour control may be comparable or even superior to extra-anatomic surgical resection a quite high rate of late radiological changes after stereotactic ablative radiotherapy for early stage lung cancer has to be considered. At one year follow-up the predicted probability of having expected or pronounced radiological changes after SABR were 65 and 22%. These changes included phenomena like mass-like appearance, radiation fibrosis, and rib fractures, which sometimes are difficult to differentiate from tumour recurrence. Summary The ACCP guidelines address the question, who had to be considered a high risk candidate for surgery. With the advent of minimally invasive resection, the criteria to classify a patient as too ill to undergo an anatomic lung resection are being redefined. Surgical resection remains the primary and preferred approach to the treatment of stage I and II NSCLC in patients with good or low surgical risk. Primary radiation therapy remains the primary curative intent approach for patients who refuse surgical resection or are determined by a multidisciplinary team to be inoperable. [11] References 1. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, Turna A, Van Schil P, Venuta F, Waller D, Weder W, Zielinski M. Eur J Cardiothorac Surg. 2014 May;45(5):787-98 2. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ginsberg RJ; Rubinstein LV. Ann Thorac Surg. 1995; 60(3):615-22; discussion 622-3 3. Tsutani Y, Miyata Y, Nakayama H, et al. Oncologic outcomes of segmentectomy compared with lobectomy for clinical stage IA lung adenocarcinoma: propensity score-matched analysis in a multicenter study. J Thorac Cardiovasc Surg 2013;146:358-64. 4. Zhao X, Qian L, Luo Q, et al. Segmentectomy as a safe and equally effective surgical option under complete video-assisted thoracic surgery for patients of stage I non-small cell lung cancer. J Cardiothorac Surg 2013;8:116, 5. Yan TD, Black D, Bannon PG, McCaughan BC. Systematic review and metaanalysis of randomized and non-randomized Trials on safety and efficacy of videoassisted thoracic surgery lobectomy for early-stage non-small cell lung cancer. J Clin Oncol 2009; 27: 2553–2562 6. Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy.Villamizar NR, Darrabie MD, Burfeind WR, Petersen RP, Onaitis MW, Toloza E, Harpole DH, D'Amico TA. J Thorac Cardiovasc Surg. 2009 Aug;138(2):419-25. 7. Long-term survival in video-assisted thoracoscopic lobectomy vs open lobectomy in lung-cancer patients: a meta-analysis. Taioli E, Lee DS, Lesser M, Flores R. Eur J Cardiothorac Surg. 2013 Feb 14. 8. Darling GE, et al. Randomized trial of m diastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 less than hilar) non-small cell carcinoma. J Thorac Cardiovasc Surg 011;141:662-70 9. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, Treatment and follow-up. J. Vansteenkiste, D. De Ruysscher, W. E. E. Eberhardt, E. Lim, S. Senan, E. Felip & S. Peters, on behalf of the ESMO Guidelines Working Group 10. Mahmood S, Bilal H, Faivre-Finn C, Shah R. Is stereotactic ablative radiotherapy equivalent to sublobar resection in high-risk surgical patients with stage I non-small-cell lung cancer? Interact Cardiovasc Thorac Surg. 2013 Nov;17(5):845-53. 11. Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC. Chest. 2013 May;143(5 Suppl)

Abstract:
Radiotherapy is a curative treatment for early-stage NSCLC. Following hypofractionated radiotherapy in 15 once-daily fractions of 4 Gy to biopsy-proven tumors, a prospective multicenter study reported a 3-year local control rate of 82.7% (95% CI = 69.7% to 90.5%) [Cheung PC, 2014]. In the past decade, stereotactic ablative radiotherapy (SABR or SBRT) has become established as the guideline-recommended standard of care for medically inoperable patients with a peripheral early-stage NSCLC, as 5-year local control rates of 90% have been reported [Louie AV, 2015]. SABR is usually delivered in 3-8 fractions, utilizes small margins for positional uncertainty, 4-dimensional computed tomography (4DCT) for treatment planning, multiple conformal beams or arcs for delivery, and cone-bean CT scans for daily setup. Where facilities for SABR are unavailable, hypofractionated radiotherapy delivered using 4DCT planning remains an acceptable curative treatment. Diagnosis Population studies reveal that a significant proportion of elderly patients, as well as those with severe co-morbidities, do not receive any treatment. Guidelines recommend that a tissue diagnosis be obtained before initiating treatment for early-stage NSCLC, but also permit the use of SABR following review by an expert tumor board, in tumors where the calculated probability of malignancy is high [Vansteenkiste J, 2014; Callister ME, 2015]. However, any decision to proceed to a FDG-PET directed SABR approach in less fit patients must take into account the likelihood of benign disease. Given a high incidence of pulmonary tuberculosis, guidelines for Asia have recommended performing early non-surgical biopsies in Asian patients [Bai C, 2016]. Toxicity Treatment-related grades 3-4 toxicity are uncommon following SABR to peripheral lung tumors, while local control rates are approximately 90% [Louie AV 2015]. Commonly reported toxicities are chest wall pain, rib fractures, and except in patients who have pre-existing interstitial lung disease (ILD), the incidence of high-grade radiation pneumonitis is low. A systematic literature review of SABR in patients with ILD reported a treatment-related mortality in 15% [Chen H, Proc ASTRO 2016]. Follow-up Guidelines recommend 6-monthly CT scans for up to 3 years following SABR, followed by annual scans thereafter. The assessment of radiological changes can be challenging in a sub-group of patients during long-term follow-op, and the so-called high-risk radiological features [HRF] can identify patients in whom a biopsy is warranted [Figure 1, Huang K, 2014]. The HRF’s identified in the literature are an enlarging opacity at primary site, a sequential enlarging opacity, enlarging opacity after 12-months, a bulging margin, loss of linear margin, loss of air bronchogram and cranio-caudal growth [Huang K, 2014]. Initial reports on surgery for local failures following SABR indicate that this salvage procedure can be performed safely [Allibhai Z, 2012; Hamaji M, 2015; Verstegen N, Proc ELCC 2015]. Figure 1 The observed rates for a second primary lung cancer following SABR appear similar to those following surgery [Verstegen N, 2015]. In this situation, a subsequent course of SABR can generally be performed safely. Operable patients The role of SABR in fit patients remains a topic of active debate. Indirect comparisons of outcomes following the two modalities have revealed conflicting results. The role of SABR in surgical patients is currrently being investigted in 3 prospective randomized studies (NCT02468024, NCT02629458, NCT01753414), with a fourth study (VALOR) scheduled to open shortly.

Abstract:
Adjuvant Chemotherapy of Completely Resected NSCLC Glenwood D. Goss Lung cancer remains the leading cause of cancer death world-wide and accounts for approximately 28% of all cancer deaths(1,2). Surgical resection is the cornerstone of therapy for early stage disease, but relapse is high with 30-60% of patients with resected NSCLC still dying of their disease. Despite the results of a 1995 meta-analysis demonstrating a non-significant 5% survival advantage at five years with the addition of adjuvant cisplatin-based chemotherapy, no large randomized studies conclusively demonstrated a benefit following resection until 2003(3). Five large randomized trials were undertaken to determine if adjuvant platinum-based chemotherapy after curative surgery for NSCLC conferred a survival advantage: ALPI; IALT; JBR10; CALGB 9633; and ANITA (4,5,6,7,8). Three of these five trials showed statistically significant improvements in overall survival, ranging from 4% [IALT] to 15% [JBR10] at 5 years, corresponding to an absolute improvement in relapse-free survival from 49% to 61%. Of the two trials that did not demonstrate improved survival, one [ALPI] suffered from poor compliance to the treatment regimen (69%), and the second was a smaller trial (n=344) limited to patients with stage IB disease [CALGB 9633], which was likely underpowered to detect a statistically significant improvement in overall survival. Interestingly, despite being limited to patients with stage IB disease, CALGB 9633 did demonstrate an overall survival hazard ratio comparable to the other adjuvant trials (HR=0.8) that included patients with more advanced disease, despite not achieving statistical significance. Since the publication of original adjuvant chemotherapy trials, a number of meta-analyses have confirmed the benefit of adjuvant platinum-based chemotherapy after surgical resection for NSCLC(9,10). In these meta-analyses, all-stage (IB-IIIA) hazard ratios were in the range of HR=0.86, corresponding to an absolute benefit for chemotherapy on overall survival of 4-5% at 5 years. The benefit, however, was demonstrated to be stage dependent (albeit using older staging criteria versions), with the benefit only reaching statistical significance for stages II and III. While the role of adjuvant chemotherapy in stage I disease is controversial (11), subgroup analyses in a number of trials in high-risk patients with stage IB disease (tumours≥4cm) suggests that there may be an overall survival advantage with adjuvant chemotherapy in this subgroup of patients, comparable to those observed in stage II and III disease [Strauss 2008]. In 2009 the long term follow up of the IALT study (with a median follow up of 7.5 years) was reported. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06) suggesting that those patients receiving adjuvant chemotherapy had a higher death rate from non- lung causes after 5 years(12). However these conclusions were not support by the findings of Butts and colleagues reporting on JBR10 with a median follow-up was 9.3 years (range, 5.8 to 13.8). Adjuvant chemotherapy continued to show a benefit (hazard ratio [HR], 0.78; 95% CI, 0.61 to 0.99; P = .04). There was a trend for interaction with disease stage (P = .09; HR for stage II, 0.68; 95% CI, 0.5 to 0.92; P = .01; stage IB, HR, 1.03; 95% CI, 0.7 to 1.52; P = .87). Adjuvant chemotherapy resulted in significantly prolonged disease specific survival (HR, 0.73; 95% CI, 0.55 to 0.97;P = .03). Observation was associated with significantly higher risk of death from lung cancer (P = .02), with no difference in rates of death from other causes or second primary malignancies between the arms. They concluded that prolonged follow-up of patients from the JBR.10 trial continues to show a survival benefit for adjuvant chemotherapy(13). Recently in a post hoc analysis of ECOG 1505, a trial of adjuvant chemotherapy +/- bevacizumab for early stage NSCLC, Wakelee and colleagues had the opportunity to compare four different cisplatin doublet regimens namely, cisplatin with one of vinorelbine, docetaxel, gemcitabine or pemetrexed. Median follow-up time for each chemotherapy doublet was: vinorelbine 54.3 months; docetaxel 60.3 months; gemcitabine 57.0 months; and pemetrexed 40.6 months respectively. The arms were well balanced for the major prognostic factors apart from smoking where the rate was slightly lower in the pemetrexed arm. There was no difference in the median number of cycles between arms. Both in the nonsquamous and squamous subgroups there was no difference in overall survival (nonsquamous logrank p=0.18 and squamous p=0.99) and disease free survival (nonsquamous p=0.54 and p=0.83). The authors concluded that there did not appear to be a difference in outcome between cisplatin doublet regimens(14). Despite the established benefit of adjuvant chemotherapy after curative surgery for NSCLC there is still much to be done with approximately 50 % of patients still dying from disease. Furthermore, not all patients with early stage disease are eligible or willing to undergo chemotherapy following complete surgical resection [Booth 2010]. As such, the long-term prognosis of patients with NSCLC, even among those with early stage disease, remains poor. Therefore it is imperative that we find new and better therapies to improve upon the results of surgical resection and adjuvant chemotherapy. . References: 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society; 2012. 2. Jemal A, Siegel R, Ward E et al. Cancer Statistics 2007. CA Cancer J Clin 2007; 57: 43-66. 3. L. A. Stewart, S. Burdett, J. F. Tierney, J. Pignon on behalf of the NSCLC Collaborative GroupSurgery and adjuvant chemotherapy (CT) compared to surgery alone in non-small cell lung cancer (NSCLC): A meta-analysis using individual patient data (IPD) from randomized clinical trials (RCT). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 25, No 18S (June 20 Supplement), 2007: 7552 4. Scagliotti GV, Fossati R, Torri V et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003; 95: 1453–61. 5. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Eng J Med 2004; 350: 351-60. 6. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Eng J Med 2005; 352: 2589-97. 7. Strauss GM, Herdone JE, Maddaus et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26: 5043-51. 8. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomized controlled trial [published erratum appears in Lancet Oncol 2006; 7: 797]. Lancet Oncol 2006; 7: 719-27. 9. Pignon JP, Tribodet GV, Scagliotti G et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26: 3552-9. 10. NSCLC Meta-analyses Collaborative Group. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010; 375: 1267-77. 11. Wakelee H, Dubey S, Gandara D et al. Optimal adjuvant therapy for non-small cell lung cancer – how to handle stage I disease. Oncologist 2007; 12: 331-7. 12. Arriagada R, Dunant A, Pignon JP, et al. Long-Term Results of the International Adjuvant Lung Cancer Trial Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected Lung Cancer JCO January 1, 2010 vol. 28no. 1 35-42 13. Butts C, Ding K, Seymour L,et al. Randomized Phase III Trial of Vinorelbine Plus Cisplatin Compared With Observation in Completely Resected Stage IB and II Non–Small-Cell Lung Cancer: Updated Survival Analysis of JBR-10. Journal of Clinical Oncology, January 1, 2010 vol. (28) 1 29-34. 14. H.A. Wakelee[1], S.E. Dahlberg[2], S.M. Keller te al. E1505: Adjuvant chemotherapy +/bevacizumab for early stage NSCLC: Outcomes based on chemotherapy subsets. ASCO Annual Meeting, 2016 Abstr 8507: E1505 Chemotherapy subsets. 15. Booth CM, Shepherd FA, Peng Y et al. Adoption of adjuvant chemotherapy for NSCLC: a population-based outcome study. J Clin Oncol 2010; 28: 3472-8.

Abstract:
Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC - Heather Wakelee, USA The use of four cycles of cisplatin-based adjuvant chemotherapy is now the standard of care for patients with resected stage II and IIIA NSCLC and is commonly used for patients with larger (at least 4 cm in size) stage IB tumors. The survival benefit with adjuvant chemotherapy though is limited with meta-analyses revealing a 4-5% absolute survival benefit at 5 years for patients receiving adjuvant cisplatin-based chemotherapy.[1,2]Some recent attempts to improve outcomes with the addition of other agents to cisplatin doublets (or as longer term therapy) have been disappointing. The addition of bevacizumab to chemotherapy in the ECOG-ACRIN E1505 adjuvant trial failed to show a benefit in disease free survival (DFS) or overall survival (OS).[3] The use of the MAGE-A3 vaccine in the MAGRIT trial was similarly negative.[4] With knowledge about molecular drivers of NSCLC and targeted treatment options in advanced disease, multiple studies are either completed or underway to study molecularly targeted agents in earlier stages of lung cancer, particularly with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In metastatic NSCLC the EGFR TKIs produce superior response and progression free survival (PFS) compared with platinum doublet chemotherapy in treatment naïve patients with tumors with activating EGFR mutations (EGFRmut).[5,6]Similar outcomes with significant response and PFS improvements with the anaplastic lymphoma kinase (ALK) inhibitor crizotinib compared to chemotherapy have been reported in patients with tumors harboring translocations of ALK.[7] Encouraging data from retrospective and non-randomized trials looking at adjuvant EGFR TKI use led to randomized trials. Earlier trials that did not select based on EGFRmut status were negative, but more recent trials have been more encouraging. The phase III RADIANT trial selected patients with resected early stage NSCLC for EGFR expression by IHC/FISH, but not by EGFR mutation status, and randomized them to adjuvant erlotinib or placebo. [8] The primary end point was DFS in the full data set, with secondary analyses focused on patients with tumors harboring del19 or L858R EGFR mutations. No differences were found in DFS or OS based on treatment arm for the nearly 1000 patients who were enrolled. In the EGFRmut subset (N=161) DFS did favor erlotinib (HR 0.61, 95% CI = 0.384-0.981, p = 0.0391), but this was not considered statistically significant, as the primary endpoint of the trial was negative. The overall survival results, while still immature, were not in favor of the erlotinib arm, even in the EGFRmut subset. The conclusion from this study is that adjuvant EGFR TKI therapy requires further investigation and should not be considered a standard treatment option at this time. Multiple ongoing trials are exploring adjuvant EGFR TKI (and adjuvant ALK TKI) therapy for resected early stage NSCLC patients with tumors harboring the appropriate molecular marker.(Table 1) The ongoing trials are looking not only at whether or not an OS benefit can be obtained with adjuvant molecularly targeted therapy but also duration of therapy and the potential to use EGFR TKIs instead of chemotherapy in selected patients. The largest United States study is the NCI National Clinical Trials Network (NCTN) ALCHEMIST trial. The study is open to patients with resected early stage (IB-IIIA) NSCLC who are screened for EGFR activating mutations and ALK translocations. Patients with tumors harboring EGFR mutations or ALK translocations enter the appropriate sub-study and, after completion of all planned adjuvant chemotherapy or radiation therapy, are randomized to targeted TKI therapy or placebo for 2 years. Both sub-studies will enroll approximately 400 patients (410 EGFR; 378 ALK) and are powered for an OS endpoint. Patients without actionable mutations can enroll on the ANVIL sub-study looking at adjuvant nivolumab, a PD-1 targeted agent.(Table 1) Globally most targeted therapy adjuvant trials are being conducted in Asia, particularly China and Japan. ADJUVANT (C-TONG 1104) trial in China and IMPACT WJOG6410L in Japan are phase III trials for patients with resected stage II-IIIA EGFRmut NSCLC comparing gefitinib to cisplatin/vinorelbine using DFS as the primary endpoint.(Table 1) Other trials outlined in Table 1 are exploring variations on this theme using gefitinib or icotinib and either after or instead of adjuvant chemotherapy. The PD-1 inhibitors nivolumab and pembrolizumab are approved for the second line treatment of advanced stage NSCLC and will likely be utilized in first-line in the near future.[9-11] Based on their promise in advanced stage NSCLC, multiple trials with PD-1 and PD-L1 agents are ongoing. Most studies are for patients who have completed adjuvant chemotherapy (though some allow chemotherapy naïve patients) and they predominantly randomize patients to approximately 1 year of PD-1 or PD-L1 inhibitor therapy. Most include testing for PD-L1 expression, but do not exclude patients with low tumor levels of PD-L1. Many are placebo controlled.(Table 1) Chemotherapy has helped improve outcomes but continued investigations with novel approaches will be necessary to continue to improve cure rates for patients with resected early stage NSCLC. The use of molecularly targeted agents for patients with tumors containing EGFRmut or ALK translocations are promising with validation studies ongoing and the hope of immunotherapy is being investigated as well in multiple global trials. Table 1. Ongoing Phase III Targeted and Immunotherapy Adjuvant Trials

Trial	Description	Primary Endpoint(s)
C-TONG 1104 NCT01405079	*gefitinib vs. cisplatin/vinorelbine	3-year DFS
GASTO1002 NCT01996098	*Chemo then icotinib vs obs	5-year DFS
BD-IC-IV-59 NCT02125240	*Chemo then icotinib vs. placebo	2-year DFS
WJOG6401L IMPACT	*Gefitinib vs. cisplatin/vinorelbine	5-year DFS
ALCHEMIST A081105/E4512	*Erlotinib vs. placebo: ALK^ crizotinib vs placebo	OS
ALCHEMIST/ANVIL	&EGFR/ALK wildtype; US NCI NCTN, Nivolumab vs obs	OS/DFS
Impower010	Restricted to PD-L1+ Global, Atezolizumab vs. placebo	DFS
MEDI4736	&Global, MEDI4736 vs placebo	DFS
Keynote-091	&ETOP/EORTC, Pembrolizumab vs placebo	DFS

All EGFR studies include stage II-IIIA All PD-1/PD-L1 studies open to IB (4cm) – IIIA after adjuvant chemotherapy N: Number of estimated enrollment DFS: disease-free survival; OS: overall survival *EGFR deletion 19 or exon 21 L858R mutation only ALK^ : Positive for ALK translocation by FISH &- regardless of PD-L1 status US NCI NCTN: United States National Cancer Institute, National Clinical Trials Network References: 1. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol, 2008 2. Group NM-aC, Arriagada R, Auperin A, et al: Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 375:1267-77, 2010 3. Wakelee HA, Dahlberg SE, Keller SM, et al: Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non-small cell lung cancer (NSCLC): Results of E1505. Journal of Thoracic Oncology Proceedings WCLC 2015:Abstr: Plen04.03, 2015 4. Vansteenkiste JF, Cho BC, Vanakesa T, et al: Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:822-835, 2016 5. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med, 2009 6. Sequist LV, Yang JC, Yamamoto N, et al: Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol, 2013 7. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-77, 2014 8. Kelly K, Altorki NK, Eberhardt WE, et al: Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 33:4007-14, 2015 9. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373:123-35, 2015 10. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373:1627-39, 2015 11. Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540-50, 2016

Abstract:
Small cell lung cancer, which accounts for 10-15% of all lung cancers, is a biologically and clinically virulent malignancy that has a propensity to disseminate systemically and therefore is often initially diagnosed at an advanced incurable stage. Although typically associated with heavy tobacco use, there have been recent clinical observations of histologic evolution from adenocarcinoma to a SCLC phenotype, particularly in tumors harboring activating mutations in the epidermal growth factor receptor (EGFR) gene that had been treated with EGFR inhibitors. Due to its high proliferative rate, SCLC is known to be highly responsive – at least initially - to cytotoxic chemotherapy. Tumor response rates of 50-70% following platinum-based chemotherapy are usually expected. Intracranial metastases, a common feature of ES-SCLC, have been also shown to respond at a similar rate to cytotoxic therapy as that of metastases to other visceral organs. The standard frontline chemotherapy for ES-SCLC, unchanged for the past three decades, has been platinum (either cisplatin or carboplatin) plus etoposide. No other regimen has convincingly been demonstrated to be superior to platinum-etoposide in the frontline setting. Neither dose intensification approaches nor the incorporation of other cytotoxic agents into the platinum backbone have yielded any palpable or tangible survival benefits. In recent years, only prophylactic cranial irradiation and (in highly selected patients) consolidative thoracic irradiation have been shown to marginally improve survival outcomes. Furthermore, despite the high initial response rates to chemotherapy, drug resistance and subsequent tumor progression are universal events. Following failure of frontline platinum-based therapy, therapeutic options are limited and generally are of very modest clinical benefit. Current investigations into optimizing cytotoxic therapy include the development of novel cytotoxics (e.g., alisertib), sequential/combination strategies that involve novel “targeted” therapies and immunotherapeutics such as checkpoint inhibitors, or conjugating a cytotoxic payload onto a monoclonal antibody directed against an antigen expressed on SCLC, among others. A critical appraisal of the current status and future directions of cytotoxic therapy in ES-SCLC will be presented.

Abstract:
Limited stage Small cell lung cancer (SCLC) comprises 10-15% of all lung tumors and is associated with an aggressive clinical behavior. Two out of three patients presents with hematogenous metastases at diagnosis (extensive stage (ES)). For patients without hematogenous metastases (limited stage (LS)), chemoradiotherapy is the standard treatment. Although radiotherapy after chemotherapy has the theoretical benefit of treating smaller target volumes with less toxicity, concurrent chemoradiotherapy has shown to be superior. Moreover, earlier use of radiotherapy during chemotherapy leads to better results. The absolute benefit of early versus late radiotherapy was about 10% for patients who had received cisplatinum-based chemotherapy [1]. Turrisi et al. [2] demonstrated that twice daily radiotherapy starting with a first course of chemotherapy resulted in improved survival rates. Median survival was 23 months for patients who received twice-daily radiotherapy (45Gy/30fractions/3weeks) versus 19 months for once daily treated patients (45Gy/25fractions/5weeks). The corresponding 5 years survival rates were 26% and 16%. However, more Grade 3-4 oesophagitis was seen during twice-daily treatment (32% versus 16%). Only a minority of patients in the US and Europe receive twice daily radiotherapy. Recently the results of the CONVERT trial, in which once-daily radiotherapy (70Gy) was compared with twice daily radiotherapy (45 Gy) were presented [3]. Radiotherapy was initiated at the 2nd course of 4-6 cycles of cisplatin/etoposide. There was no statistically significant difference in overall survival between the two arms. Overall survival at 2 years was 56% for patients treated twice-daily versus 51% for patients treated once-daily (p= 0.15) [3]. There was also no significant difference in time to progression. There were no differences in a acute toxicity, except for Grade 3-4 neutropenia, which occurred more often in the twice-daily treatment arm (74% versus 65%). There were no differences in Grade 3-5 oesophagitis (19%) and pneumonitis (2%). The authors concluded that survival in both study arms was higher than reported previously and that radiation related toxicities were lower than expected, probably related to the use of modern radiotherapy techniques. The results of the study support the use of either twice daily or once daily as standard of care for patients with limited stage disease and in good performance score. In RTOG0538 study, which also compares 70 Gy once-daily and 45 Gy twice-daily radiotherapy, radiotherapy commences with the first or second course of chemotherapy. The results of this study are eagerly awaited [4]. Extensive stage In the EORTC study on prophylactic cranial irradiation (PCI) for ES-SCLC, it was noted that the vast majority of patients still had intrathoracic disease after completion of chemotherapy. After on the positive effects of PCI which not only reduced the risk of symptomatic brain metastases (40 versus 15%) but also improved overall survival (1 year: 27 versus 13% (P= 0,003)) [5], the next logical step was to investigate the use of thoracic radiotherapy in ES-SCLC as well. Evidence for a possible role of thoracic radiotherapy (TRT) in ES-SCLC also comes from the results of a trial published by Jeremic et al. in 1999 [6] in which patients with ES-SCLC and good prognosis with a complete response outside the thorax were randomized between TRT plus PCI during chemotherapy versus chemotherapy and PCI only. Overall survival was 17 months for the patients who received thoracic radiotherapy versus 11 months for those who did not. In the CREST trial, patients with ES-SCLC and any response after 4-6 cycles of platinum based chemotherapy were randomized between PCI plus TRT (30Gy/10 fractions) or PCI only. Overall survival at one year, the primary endpoint of the study, was not statistically significant between the groups (p=0.066) but with longer follow up the survival curves diverged and at 2 years, survival was 13% in patients who received TRT versus 3% in the controls (p=0,004). There was also significant difference in progression free survival. In an additional analysis of patients with and without residual intrathoracic disease, which was one of the stratification factors of the study, it was demonstrated that there was no significant benefit of TRT in patients with a CR in the thorax. However, in patients with residual intrathoracic disease after chemotherapy, TRT led to a significant improvement in overall survival [7]. In patients who received thoracic radiotherapy the risk of intrathoracic recurrence was reduced from 80% to 44%. In patients who received thoracic radiotherapy the most recurrences occurred outside the brain and the thorax and at a later stage. The next logical step after demonstration of a beneficial effect of PCI and TRT would be the use of higher doses for TRT and possibly also treatment of extrathoracic metastatic sites. This topic was addressed in the NRG-RTOG0937 study and was presented at ASTRO 2015 [8]. patients with ES-SCLC and a CR or PR after chemotherapy and 1-4 metastatic lesions were randomized between PCI or PCI plus TRT plus radiotherapy of metastatic sites. The study which accrued very slowly was closed early due to observed toxicities. The study did not show a survival difference between the two groups, but included only 86 patients over a five years period and had imbalance groups with worse prognostic factors in the experimental arm. There were many, partly unrelated, Grade 4-5 toxicities in the experimental arm. To define which patients are most likely to benefit from a more aggressive approach we have performed an additional analysis for patients from the top accruing centers from the CREST trial. An evaluation of 260 patients showed significantly better outcome in patients with 0 to 2 metastases versus and without liver metastases [10]. These patients are believed to be best candidates for future studies. References 1. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 2004. 22, 4837-45. 2. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 340, 265-71. 3. Faivre-Finn C, Snee M, Ashcroft L. CONVERT: An international randomised trial of concurrent chemo-radiotherapy (cCTRT) comparing twice-daily (BD) and once-daily (OD) radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good performance status (PS). ASCO Meeting abstracts J Clin Oncol 2016, 8504. 4. Slotman BJ, Senan S; Radiotherapy in small-cell lung cancer: Lessons learned and future directions. Int J Radiat Oncol Biol Phys 2011, 79, 998-1003. 5. Slotman BJ, Faivre-Finn C, Kramer G. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007, 357, 664-72. 6. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined- modality treatment of patients with extensive disease small-cell lung cancer; A randomized study. J Clin Oncol 1999,17, 2092-9. 7. Slotman BJ, van Tinteren H, Praag JO, et al., Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015, 385, 239-44. 8. Slotman BJ, van Tinteren H. Which patients with extensive stage small-cell lung cancer should and should not receive thoracic radiotherapy? Transl Lung Cancer Res. 2015, 4, 292-4. 9. Gore EM, Hu C, Sun A, et al. NRG Oncology/RTOG 0937: Randomized phase II study comparing prophylactic cranial irradiation (PCI) alone to PCI and consolidative extra-cranial irradiation for extensive disease small cell lung cancer (ED-SCLC). Proc ASTRO, Int J Radiat Oncol Biol Phys 2016, 94, 5.

Abstract:
Background: A previous study has shown that prophylactic cranial irradiation (PCI) reduced the risk of brain metastases (BM) and prolonged the overall survival (OS) of patients (pts) with extended disease small cell lung cancer (ED-SCLC). However Japanese trial to reconfirm these results was stopped at first interim analysis (n=163 pts) because of futurity. According to this study protocol, final follow up was done. Materials and methods: From March 2009 pts with ED-SCLC who had any response to first-line chemotherapy (platinum agent plus irinotecan or etoposide) were randomized to either PCI (25Gy/10 fractions) or observation (Obs) alone. The patients were required to prove the absence of BM by MRI prior to enrollment. The primary endpoint was OS and a planned sample size of 330 was determined to detect the hazard ratio (HR) of 0.75 at a significance level of 0.05 and a power of 80%. Secondary endpoints included time to BM (evaluated every 3 months by imaging), progression-free survival (PFS), and adverse effects (AEs) and mini mental status examination (MMSE). Results: In Apr 2014, follow up analysis was conducted for the survival data of 224 all enrolled pts. One hundred fourth-five deaths were observed. The median OS was 11.6 and 14.1 months for PCI (n=112) and Obs (n=111), respectively (HR=1.28, 95%CI= 0.95-1.72; stratified log-rank test, P=0.107). PCI significantly reduced the risk of BM as compared to Obs (33.6% vs 59.7% at 12 months; Gray’s test, P<0.001), whereas PFS was comparable between the two arms (median, 2.3 vs. 2.4 months; HR=0.98, 95%CI=0.75-1.28). No significant difference in AEs greater than Grade 2 was observed between the two arms. At the MMSE there was no statistical difference between two arms, however in pts age 70 and older pts in PCI tended to be worse over time. Conclusion: PCI after response to chemotherapy could not show the OS impact in pts with ED-SCLC even in this follow up data.

Abstract:
The role of surgical treatment in the management of patients with small-cell lung cancer (SCLC) remains controversial. Although in the past, two randomized studies have failed to show any survival benefit by adding surgery to chemotherapy, different retrospective and prospective reports including the recently published studies using the database of Cancer Institute Surveillance Epidemiology and End Results (SEER), showed, that surgery offers a reasonable overall survival in a subset of patients with SCLC stage I and II disease. Two important recommendations have been introduced regarding the histology of SCLC as a high grade aggressive neuroendocrine tumor and the use of TNM classification in staging of SCLC and in clinical trials. Patient’s selection is important including extensive radiologic staging and biopsy of the mediastinal nodes. The use of PET scanning is likely to improve the accuracy of staging. Surgery can be performed with a curative intent in patients with SCLC and stage I or II disease or significant nodal response after chemotherapy. Weksler has used the SEER database and analyzed the outcomes of 3566 patients with SCLC stage I and II from 1988 to 2007. The surgical treatment was performed in 895 patients (25.1%); the median survival was 34 months in the surgical group versus 16 months in the nonsurgical group. In a similar report by Yu and colleagues, 21 the 5-year overall survival was 21.1%, but it was 50.3% for those patients who received a resection (45.7% after pneumonectomy and 33.7% after sublobar one). This analysis confirmed the acceptable survival rates in a subset of patients with stage I SCLC. By primary surgery or after induction chemotherapy complete tumor resection and systematic mediastinal lymphadenectomy should be undertaken. Adjuvant chemotherapy is recommended also for stage I patients; prophylactic cranial irradiation prolongs survival in those patients who achieve a complete or partial response to initial treatment. Until now, the standard systemic treatment of patients with LD-SCLC remains the combination of platinum and etoposide. The following groups of patients could potentially benefit from surgical resection: a. Patients with small lesion unexpectedly identified as SCLC at the time of thoracotomy. Complete resection and systematic lymph node dissection should be undertaken. Chemotherapy is recommended postoperatively and PCI should be considered. b. For stage I and II disease after chemotherapy and tumor response, surgery can improve local control and increase cure rates and long term survival. Complete resection and mediastinal lymph node resection should be performed. If possible, rather than pneumonectomy sleeve lobectomy should be preferred. c. In patients with mixed histology initial treatment should be chemotherapy to control the small cell component and after that surgery to control the non-small cell part of the tumor. d. For patients with initial failure to chemotherapy or patients with localized late relapse after treatment for pure small cell tumors salvage operations may be considered on individual basis. e. In patients with second primary small cell or non-small cell lung cancer who achieved cure from primary SCLC, surgery should be considered in the course of an multidisciplinary approach f. Patients with synchronous ispilateral or bilateral small and non small cell tumors could be potential candidates for surgery in a diagnostic or therapeutic intention g. In selected patients with IIIA N2 disease and complete histological regression of tumor tissue in the mediastinal lymph nodes after induction chemotherapy or chemoradiortherapy, surgery can improve local control and survival. Taking into account the TNM use in SCLC and the encouraging SEER results for patients submitted to surgery, a reconsideration of the role of surgery seems to be mandatory. Finally, to improve current management strategies for SCLC, surgeons should participate in the evaluation of SCLC patients together with oncologists and radiotherapists and common guidelines for indications and therapy concepts should be adopted. Interdisciplinary approaches should be employed in the context of controlled clinical trials. Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of the bronchus. Ten-year follow-up. Lancet 1973;2(7820):63-65 Lad T, Piantadosi S, Thomas P, et al. A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 1994;106:320-323 Waddell TK, Shepherd FA. Should aggressive surgery ever be part of the management of small cell lung cancer? Thorac Surg Clin 2004;14:271-281 Eberhardt W, Stamatis G. Stuschke M, et al. Prognostically orientated multimodality treatment including surgery for selected patients of small-cell lung cancer patients stage Ib to IIIB: long-term results ofc a phase II trial. Br J Cancer 1999;81:1206-12 Shepherd FA, Crowley J, Van Houte P, Postmus PE, Carney D, Chansky K, Shaokh Z, Goldstraw P. International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2007;2:1067-77 Valliéres E, Shepherd FA, Crowley J, Van Houte P, Postmus PE, Carney D, Chansky K, Shaokh Z, Goldstraw P. International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathological staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4:1049-59 Yu JB, Decker RH, Detterbeck FC, et al. Surveillance Epidemiology and End Results Evaluation on the Role of Surgery for Stage I Small Cell Lung Cancer. J Thorac Oncol 2010; 5:215–9. Weksler B, Nason KS, Shende M, et al. Surgical resection should be considered for stage I and II small cell carcinoma of the lung. Ann Thorac Surg 2012; 94:889–93. Stamatis G. Neuroendocrine tumors of the lung: the role of surgery in small cell lung cancer Thorac Surg Clin. 2014 Aug; 24(3):313-26.

Abstract:
Immunotherapy of Small Cell Lung Cancer Nevin Murray MD, British Columbia Cancer Agency, Vancouver, Canada The general principles of cytotoxic chemotherapy for advanced SCLC and NSCLC have many similarities and have advanced minimally over the past two decades.(1) The success of cancer genomics research in changing the care of patients with NSCLC with a driver mutation suitable for targeted treatment has been a powerful incentive to discover such molecular targets in SCLC. Although comparative genomic profiling shows some similarities between SCLC and NSCLC, for SCLC, the abnormalities identified to date are mainly tumor suppressor genes.(2) These loss-of-function alterations do not provide the clear opportunity for rapid clinical translation offered by an activating mutation in a known receptor tyrosine kinase. A considerable number of targeted agents have already been tried in SCLC clinical trials without notable success.(3) In contrast, there is a growing body of evidence for immunotherapy as a promising new treatment for both SCLC and NSCLC. Immunotherapy investigated for SCLC includes interferon, vaccines, antibody-drug conjugates and immune checkpoint inhibitors. Interferon and vaccines have been studied in phase II and III trials without sufficient activity to change practice. Although preliminary, the data emerging from trials of antibody-drug conjugates and immune checkpoint inhibitors has generated more excitement and are the focus for this abstract. Antibody-Drug Conjugates The components of an antibody-drug conjugate include an antibody directed at a defined antigen on cancer cells, a linker, and a cytotoxic agent. This package represents an effective mechanism of targeted drug delivery potentially resulting in decreased toxicity and an improved therapeutic index. Rovalpituzumab teserine targets the Notch pathway with a monoclonal antibody portion directed against the cell surface available Notch ligand delta-like protein 3 (DLL3), which is over-expressed in SCLC tumor-initiating cells but not in normal tissue. Rudin et al.(4) have reported a phase I study including 74 patients with previously treated SCLC. The confirmed response rate in 56 evaluable patients was 16%, but in 26 that showed high DLL3 expression, the response rate was 31%. Response rate was 13% in second-line and 25% in the third-line setting with some durable responses observed. A phase II trial for third-line treatment of patients with DLL3 expressing tumors has begun and if positive will be the first approved agent in this setting. Sacituzumab govitecan is another antibody-drug conjugate of a topoisomerase I inhibitor linked to an antibody to the Trop-2 epithelial antigen.(5) In a phase I/II clinical trial enrolling 33 evaluable SCLC patients with a median of 2.5 previous chemotherapies, the response rate was 24% and the median overall survival was 8.1 months. Dose limiting neutropenia was 34% and grade 3+ diarrhea was seen in 9%. Immune Checkpoint Inhibitors Since immune checkpoint blockade is more active in hyper-mutated tumors, SCLC should be a good candidate disease for this treatment because of a strong association with tobacco carcinogenesis and a high frequency of somatic mutations.(2) The most advanced trial evidence is available for a cytotoxic T-cell antibody (CTLA4) and data for two programmed death (PD-1) immune checkpoint inhibitors is emerging. After a randomized phase II trial of ipilimumab and phased chemotherapy showed a modest improvement in progression-free survival as first-line treatment of advanced SCLC,(6) a large phase III placebo controlled trial was performed in which 1,132 previously untreated patients were randomly assigned to receive either etoposide and platinum for four cycles alone or together with the CTLA-4 antibody ipilimumab.(7) The trial was negative with similar response rates and no difference in the primary end point of overall survival (hazard ratio 0.94; 95% CI 0.81-1.09). Immune checkpoint blockade with PD-1 or dual CTLA-4 and PD-1 inhibition may be a more effective strategy. In a large phase I/II trial including 180 previously treated SCLC patients, Antonia et al.(8) reported a response rate of 13% (7/80) with nivolumab 3 mg/kg and 31% (14/45) in a cohort of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg. The activity of nivolumab alone or combined with ipilimumab was seen regardless of PD-L1 expression and not related to platinum sensitivity or line of therapy. The responses were durable with one-year overall survival of 27% for nivolumab alone and 48% for the combination arm. These results have led to two phase III studies among patients with SCLC evaluating nivolumab, nivolumab/ipilimumab versus placebo in the maintenance setting after first-line therapy and nivolumab versus placebo in the second-line setting. As part of a phase IB multi-cohort study (KEYNOTE-028), pembrolizumab was evaluated among patients with relapsed SCLC with PD-L1 positive tumors.(9) Of the 135 SCLC patients screened, 37 (27%) had PD-L1 positive tumors. The response rate was 29% in 24 evaluable patients. The median duration of response was 29 weeks and durable responses were observed. There is an ongoing phase II study of this agent as maintenance therapy after the completion of standard first-line therapy in extensive stage disease. A phase I trial is evaluating pembrolizumab with conconcurrent chemoradiation. Adverse events associated with checkpoint inhibitors is greater with CTLA-4 combined with the PD-1 antibody combination but were generally manageable. The proportion discontinuing therapy for toxicity was usually less than 10%. The literature contains anecdotes of autoimmune syndromes such as limbic encephalitis.(8) Immune para-neoplastic syndromes are expected in a small proportion of patients with SCLC and an increase in their occurrence with immunotherapy requires close monitoring. However, this concern is currently insufficient to impede further trials with these promising agents. Conclusion Over the past 20 years, almost all phase III trials of systemic therapy for SCLC have failed to improve outcome and advances have been restricted to improved application of radiotherapy. Like squamous carcinomas, the SCLC molecular battlefield is complex and bleak with little opportunity of even temporary respite by identification of mutually exclusive oncogenic drivers that can be treated for patient benefit. Ironically, this hyper-mutated genome and greater neo-antigen expression may enhance the probability of success with immunotherapy. One senses that the likelihood is high for approval of antibody-drug conjugates and immune checkpoint inhibitors for SCLC after the current roster of clinical trials are reported. References 1. Murray N, Lam S. Contrasting Management of Small Cell Lung Cancer and Non-Small Cell Lung Cancer: Emerging Data for Low-Dose Computed Tomography Screening. J Thorac Oncol. 2016 Feb;11(2):139-41. 2. Pietanza MC, Ladanyi M. Bringing the genomic landscape of small-cell lung cancer into focus. Nat Genet. 2012 Oct;44(10):1074-5. 3. Murray N, Noonan K. Can we expect progress of targeted therapy of small cell lung cancer? In: Dingemans A, Reck M, Westeel V, editors. Lung cancer. Sheffield: European Respiratory Society; 2015. p. 234. 4. Rudin CM, Pietanza MC, Bauer TM, Spigel DR, Ready N, Morgensztern D, et al. Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC). ASCO Meeting Abstracts. 2016 June 21;34(18_suppl):LBA8505. 5. Starodub A, Camidge DR, Scheff RJ, Thomas SS, Guarino MJ, Masters GA, et al. Trop-2 as a therapeutic target for the antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132), in patients (pts) with previously treated metastatic small-cell lung cancer (mSCLC). ASCO Meeting Abstracts. 2016 May 31;34(15_suppl):8559. 6. Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013 Jan;24(1):75-83. 7. Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016 Jul 25. 8. Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016 Jul;17(7):883-95. 9. Ott PA, Callahan MK, Odunsi K, Park AJ, Pan LS, Venhaus RR, et al. A phase I study to evaluate the safety and tolerability of MEDI4736, an anti- programmed cell death-ligand-1 (PD-L1) antibody, in combination with tremelimumab in patients with advanced solid tumors. ASCO Meeting Abstracts. 2015 May 18;33(15_suppl):TPS3099.

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Abstract:
The aim of mediastinal staging is to exclude with the highest certainty and the lowest morbidity patients with mediastinal nodal disease. The concepts of decision analysis and Bayes’ theorem form the basis for a mediastinal staging strategy. The goal of the clinical staging strategy is to lower the post-test probability sufficiently so that it falls below a testing threshold, which ascertains the clinician that the result is accurate. The ESTS working group considers a rate of unforeseen mediastinal nodal disease at the time of anatomic resection with lymph node dissection less than 10% as acceptable.[1] Contrast-enhanced multi-detector CT (computed tomography) scanning has an excellent spatial resolution but is an imperfect means of staging the mediastinum. A Cochrane review evaluated integrated positron emission tomography (PET) - CT for assessing mediastinal lymph node involvement in NSCLC.[2] The review showed that the accuracy of PET-CT is insufficient to allow management on PET-CT alone, but PET-CT can be used to guide clinicians in the next step (either a biopsy or direct to surgery). The suboptimal specificity of mediastinal lymph nodes positive on PET-CT requires a tissue confirmation. There are conditions where invasive staging is also mandatory despite a normal mediastinum on PET-CT as the prevalence of N2/N3 disease remains significant. These conditions include a primary tumour >3 cm, any central primary tumour, PET/CT hilar N1 disease, or low FDG uptake in the primary tumour.[1] Cervical Mediastinoscopy. A conventional cervical mediastinoscopy through a pretracheal suprasternal incision was introduced in 1959 and for decades considered the gold standard for invasive mediastinal nodal staging. Recently, a very large (N=721 patients; prevalence of mediastinal nodal disease 47 %) retrospective single center study reported on safety and efficacy of cervical mediastinoscopy performed by general thoracic surgeons.[3] There was no mortality, a low perioperative complication rate at 1.3 %, and an unexpected hospital (re)admission rate of 0.46 %. The sensitivity, negative predictive value and post-test probability were 0.90 (95% CI 0.87-0.92), 0.92 (95% CI 0.90-0.94), and 0.09 (95% CI 0.07-0.11), respectively. It is performed under general anesthesia and allows a full mapping of the ipsilateral and contralateral superior mediastinal lymph nodes. Since 1995, the use of video techniques has been introduced leading to video-assisted mediastinoscopy (VAM) clearly improving visualization and teaching. In addition, VAM allows bimanual dissection with possibilities to perform nodal dissection and removal rather than sampling or biopsy. The ESTS working group recommends performing VAM.[1] Endoscopic ultrasonography (EUS) en endobronchial ultrasonography (EBUS). In the last decade, the predominant role of cervical mediastinoscopy has been challenged by EUS and EBUS using a convex probe. When mediastinal nodal staging is required, systematic nodal sampling seems feasible but some primary choices have to be made. At least mediastinal nodal stations 4R, 4L and 7 should be sought. To avoid contamination, the order of sampling should begin at the level of N3 stations followed by N2 stations before N1. There is no evidence to suggest that sampling of all visible nodes in each nodal station is superior to a systematic nodal sampling of the largest measuring ≥5 mm or PET-positive node in each station. It must be stressed that EBUS cannot access the prevascular nodes (station 3a), the subaortic and para-aortic nodes (stations 5 and 6) as well as the paraesophageal and pulmonary ligament nodes (stations 8 and 9). Some of these nodes (stations 8 and 9) can however be reached from the esophagus. Therefore the use of the EBUS scope is extended to an esophageal exploration with EUS-B sampling of stations 4L, 7, 8 and 9. In terms of safety, EBUS and EUS have a low complication or serious adverse event rate of 1.4 and 0.3%, respectively.[4,5] The two staging strategies, surgical staging alone on the one hand and combined EUS/EBUS followed by surgical staging whenever endosonography was negative on the other hand, were compared in a pivotal randomized controlled trial (RCT).[6] It was concluded that invasive mediastinal nodal staging should start with combined linear endosonography, as the trial showed that a staging strategy starting with combined linear endosonography (EUS+EBUS) detected significantly (P=0.02) more mediastinal nodal N2/N3 disease compared to cervical mediastinoscopy alone, resulting in a significantly higher sensitivity of 0.94 (95%CI 0.85-0.98) compared to 0.79 (95%CI 0.66-0.88), respectively.[6] Another RCT suggested that EBUS-TBNA is the preferred primary procedure in combined linear endosonography for mediastinal nodal staging of resectable stage I-III lung cancer.[7] There is no RCT comparing combined EBUS-EUS(-B) to EBUS-TBNA alone for mediastinal nodal staging, but a recent meta-analysis suggested that the combined EBUS-EUS is more sensitive than EBUS-TBNA alone to detect mediastinal nodal disease.[8] The absolute increase in sensitivity of the combined approach compared to EBUS-TBNA alone depends on the quality of the EBUS-TBNA procedure, but published studies suggest an increase in sensitivity up to 10%. Overall, a confirmatory VAM is still warranted for the individual patient with a negative combined linear endosonography as this further lowers the post-test probability. This has been shown within ASTER for patients with clinical N2/3 disease on PET-CT (prevalence of mediastinal nodal disease 63%), as the post-test probability of a negative linear combined endosonography of 20% could be lowered to 5% by adding a cervical mediastinoscopy.[9] A recent prospective cohort study on clinical stage II lung cancer based on N1 disease on imaging (prevalence of mediastinal nodal disease 24%) showed that the post-test probability of a negative endosonography was 19%, which could be lowered to 9% by adding a cervical mediastinoscopy.[10] In conclusion, combined EBUS-EUS(-B) linear endosonography is the standard for initial baseline mediastinal nodal staging, but a VAM is still recommended after a negative (or incomplete) combined linear endosonography. Mediastinal restaging after induction therapy for locally advanced stage III NSCLC is an important prognostic factor. In the context of a 40-50% prevalence of residual mediastinal disease after induction therapy, a first cervical VAM as a restaging technique seems to be the most accurate method for nodal assessment.[1] Overall, limited literature reported a sensitivity and NPV for linear endosonography that is lower than for a first mediastinoscopy.

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Abstract:
Even in the era of precision medicine and immunotherapy, cytotoxic chemotherapies remain an essential component of lung cancer treatment, both in resectable disease as well as in advanced/metastatic lung cancer. We have chosen to focus on 2 new cytotoxic compounds, which are likely to emerge as new players in the field of lung cancer management. One (named PM1183) has activity in small-cell lung cancer (SCLC), the other TAS-114 has activity in non-small cell lung cancer (NSCLC). PM1183 is a DNA-binding chemotherapy with a new mechanism of action. PM1183 acts as an inhibitor of transcription. Binding of PM1183 to CG-rich motifs, triggers sequential phosphorylation of Pol II and stalling of elongating Pol II. This leads to recruitment of the ubiquitin-proteasome machinery, RNA Pol II degradation, and recruitment of XPF, generation of DNA breaks and induction of apoptosis. PM1183 has been tested in a phase IB trial in combination with doxorubicine. In the dose-finding part: recommended dose (RD) was defined at PM1183 4.0 mg flat dose (FD) or 2.0 mg/m2 + DOX 50 mg/m2 both on day (D)1 every three weeks (q3w). Myelosuppression was dose-limiting (DLT). Compelling activity was observed during escalation phase. It was especially remarkable as 2nd line in SCLC patients: 5 of 7 evaluable pts (71%) had objective partial response (PR) as per RECIST v.1.1. In an expansion cohort of 20 patients, PM1183 and DOX showed outstanding clinical activity: 67% response rate, including 10% of CRs, as 2nd line treatment in SCLC patients. A randomized phase III trial testing PM1183 + DOX is planned and will compare this combination with topotecan or CAV. TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor that acts as a modulator of the pyrimidine nucleotide metabolic pathway by blocking the conversion of 2’‑deoxyuridine-5’-triphosphate (dUTP; FdUTP) into 2’-deoxyuridine-5’-monophophate (dUMP; FdUMP) through reversible inhibition of dUTPase (gatekeeper protein), resulting in the enhanced incorporation of both uracil and fluorouracil into DNA. The activity of TAS-114, administered in combination with thymidine synthase (TS) inhibitors, 5-FU, S-1 or capecitabine, has been studied pre-clinically in various cancer cell lines and animal models. TAS-114 selectively inhibited dUTPase and showed a higher affinity than the substrates of dUTPase, dUTP and FdUTP, inhibition constant values of TAS-114 were 0.13 μM and 0.10 μM, respectively. The antitumor effect of TAS-114 combined with S-1 as compared to that of S-1 alone was investigated in vivo using a xenograft mouse model with NCI-H2228 (human NSCLC). Both regimens were administered orally (TAS-114: 600 mg/kg/day and S-1: 8.3 mg/kg/day vs S-1: 8.3 mg/kg/day through day 1 to 28) and resulted in relative tumor volumes of 1.61% vs 3.04%, p<0.01, inhibition rates of 52.7% vs 10.8%, and body weight changes of 6.8% vs 3.3%, respectively. A phase 1 clinical study of TAS-114 and S-1 combination treatment is currently ongoing to investigate the safety and to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in patients (pts) with advanced refractory solid tumors. TAS-114 and S-1 are administrated orally twice a day for 14 days followed by 7 days resting period for a 21-days cycle at the starting dosage of 5 mg/m² with the fixed dosage of 25 mg/m², respectively. To date, a total of 96 pts were enrolled with 37 pts in the dose escalation and 59 pts in the MTD expansion stages. TAS-114 and S-1 were escalated up to 240 mg/m² and 36 mg/m², respectively, with 2 DLTs observed at the highest dose level (1 patient with G3 rash and 1 patient with G2 rash/G2 HFS), therefore TAS-114 at 240 mg/m² and S-1 at 30 mg/m² was determined to be the MTD and RD. The most common treatment related adverse events were anemia and rash. There were 4 confirmed partial responses observed in 2 non-small cell lung (NSCLC) pts, 1 pancreas pt and 1 colorectal cancer patient to date. Amongst 6 evaluable NSCLC pts to date, there was an overall response rate of 33% (2/6) with 2 confirmed PR and a disease control rate of 100% (6/6). Pharmacodynamics analysis performed on patient tumor specimens treated at MTD indicated TAS-114 target engagement by reductions in the amount of intra-tumoral dUMP, a “surrogate” metabolite indicative of dUTPase inhibition, following TAS-114/S-1 combination as compared to S-1 alone administration. When TAS-114 is administered in combination with S-1, an additional cytocidal antitumor effect to TTP depletion by TS inhibition is expected as TAS-114 inhibits a gatekeeper protein, thereby allowing increased DNA incorporation of both uracil and 5-FU resulting in DNA damage.

Abstract:
The invited talk will firstly talk about the recent advances in novel TKIs overcoming resistance during EGFR-TKI and ALK-TKI treatment. Afterwards, several novel TKIs with CNS penetration that may substantially change the prognosis and treatment strategy of patients with brain metastases will be discussed. Finally, we will take an overview about targeted therapy against rare and novel, potentially druggable oncogenic drivers either in preclinical settings or early-stage clinical trials. As we know, the presence of EGFR activating mutations and ALK chromosomic rearrangements with corresponding tyrosine kinase inhibitors (TKIs) has revolutionized the treatment strategies of patients with non-small cell lung cancer (NSCLC) [1, 2]. Although tremendously initial response and manageable toxicity profiles, however, acquired resistance inevitably develops after approximately 1 year treatment with EGFR-TKIs (erlotinib and gefitinib) and ALK inhibitor (crizotinib). Encouragingly, third-generation EGFR-TKIs including AZD9291, CO1686 and HM61713 have showed striking efficacy overcoming acquired resisitance driven by T790M secondary mutations [3, 4]. In patients who get acquired resistance to first-generation EGFR-TKIs with T790M mutations, the objective response rate (ORR) of AZD9291 was 61% and median progression-free survival (PFS) was 9.7 months [4]. Other novel third-generation EGFR-TKIs such as ASP8274, EGF816, PF-06747775 and avitinib are also being investigated in early-stage clinical trials and the survival and safety data will be released in the near future. Another promising novel EGFR-TKI, namely AZD3759 has showed promising response in patients with brain metastases and leptomeningeal disease, a major case leading to treatment failure. In BLOOM study, 11 out of 21 patients with measurable brain metastases and heavily pre-treated progressed both extracranially and intracranially had tumor shrinkage in the brain at dose ≥50mg BID. Recently, EAI045, an EGFR allosteric inhibitor, in combination with cetuxmab exhibit antitumor activity in mouse models of lung cancer driven by L858R/T790M/C797S, a common resistant mechanism of AZD9291 [5]. Meanwhile, second-generation ALK inhibitors (ceritinib, alectinib and brigatinib) have entered clinical applications for NSCLC patients with ALK rearrangements after failure of crizotinib and third-generation ALK inhibitors (lorlatinib and ASP3026) are also being evaluated in clinical trials overcoming known ALK resistant mutations[6, 7]. In patients who progress on crizotinib, the ORR and PFS of brigatinib at 180mg was 54% and 12.9 months. Lorlatinib, a third-generation ALK inhibitor, also demonstrated robust clinical activity in ALK-rearrangement patients with NSCLC. The ORR was 57% in patients who received 1 prior ALK-TKI and 42% in patients who received ≥2 prior ALK-TKIs. On the other hand, with the development of high-throughput sequencing, called next-generation sequencing (NGS) and genomic technologies, more novel molecular targets such as MET 14 exon skipping splicing mutations[8]have been identified as potential therapeutic targets and simultaneously analyzing hundreds of molecular alterations have turned out reality with limited tumor tissues. In the recent years, the emergence of numbers of oncogenic drivers other than EGFR mutations and ALK rearrangements has divided NSCLC into multiple distinct subtypes amenable to corresponding targeted therapy, including ROS1 rearrangement, RET arrangement, BRAF-V600E mutations, HER2 mutations and MET 14 exon skipping mutations et al. For instance, dabrafenib either as monotherapy or in combination with MEK inhibitor (trametinib) has displayed promising antitumor activity and manageable safety profile in patients with BRAF V600E mutations [9, 10]. In 57 previously treated metastatic NSCLC patients with BRAF-V600E mutations, 63.2% patients (36/57) achieved an overall response [9]. Other novel molecular targets maybe serving as oncogenic drivers including mutations in HER2 (neratinib and pyrotinib) and PI3KCA (BKM120 and GDC0941), ROS1 (entrectinib, foretinib and lorlatinib), RET (XL184) and NTRK (entrectinib) rearrangements and FGFR1 gene amplification (AZD4547, Lenvatinib and FP-1039) are being evaluated either in preclinical settings or early-stage clinical trials. Reference: 1. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361: 947-957. 2. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371: 2167-2177. 3. Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015;372: 1700-1709. 4. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372: 1689-1699. 5. Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016;534: 129-132. 6. Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol 2016;34: 661-668. 7. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370: 1189-1197. 8. Paik PK, Drilon A, Fan PD, Yu H, Rekhtman N, Ginsberg MS, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5: 842-849. 9. Planchard D, Besse B, Groen HJ, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016;17: 984-993. 10. Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17: 642-650.

Abstract:
Treatment of small-cell lung cancer (SCLC) has not been modified since decades : and consists in a chemotherapy (CT) with platin+etoposide+/-concurrent radiotherapy (RT) and prophylactic cranial irradiation in case of a (near)complete response to therapy. Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers and around 50% are metastatic at presentation. Systemic treatment (platin-based doublets) has been implemented for stage IV NSCLC but also for locally advanced and early stages as a (neo)adjuvant therapy to surgery or RT. By the end of the XXth century, a plateau has been reached with CT in stage IV disease with similar results whatever the drug used in conjunction with platin-salt. Since the beginning of the XXIst century there have been tremendous innovations in the systemic treatment of NSCLC. First, adjunction of bevacizumab to CT for stage IV non-squamous cell carcinoma and the use of maintenance therapy have led to an improvement in median survival time (MST) exceeding now one year. Second, targeted therapies proved to be of major interest for patients with EGFR activating mutations leading to a MST>2 years. Other targets of interest have been found such as ALK and ROS1 translocations, V600EBRAF mutations leading to prolonged survival with appropriate treatments. Third, immunotherapy represents now an exciting approach especially for those patients without targetable mutations/translocations. Lung cancer has long been considered as a poor candidate for immunotherapy because of low content of tumor-infiltrating lymphocytes (TIL) compared to other tumors. On the other hand, in case of the presence of TIL the prognosis is better (1). The fact that incidence of lung cancer is especially high in patients who were transplanted (2)or in patients with HIV infection (3)is against the assumption of lung cancer being non immunogenic. There are two types of immunotherapy : the immune checkpoint blockers which aim at enhancing a T-cell response directed against tumoral cells and abrogate the immune tolerance and the therapeutic vaccines designed to induce or amplify an immune response directed against tumor-associated antigens (TAA). The immune checkpoint blockers in current development are anti CTLA4 monoclonal antibodies (ipilimumab), first used in the treatment of melanoma and now investigated in NSCLC and SCLC, anti PD1 (nivolumab, pembrolizumab) or anti PDL1 (avelumab, atezolizumab). All these molecules are now either at an advanced stage of development or already authorized (4). Therapeutic vaccines have already a long story beginning with Coley toxins at the end of the nineteenth century (5). The Coley's toxins, (cultures of streptococci) were infused in patients with bone and soft tissue sarcomas and some impressive regressions were observed. The hypothesis was that the immune reaction provoked by the infusion of the "toxins" present in the infectious material was able to destroy the tumoral cells. However, due to the reluctance of doctors to administer dangerous bacterial culture and the appearance of novel treatments of cancer (CT and RT), the Coley's toxin approach has been abandoned although numerous articles were devoted to this subject (6). Non specific vaccines using for example BCG to stimulate innate immunity have been disappointing as well in SCLC (7-8)and NSCLC (9). Specific immunotherapy aims at the stimulation of adaptive immunity against the vaccine components and thus induces or amplifies an immune response against TAA. These vaccines are either peptides (Tecemotide, MAGE-A3), cellular vaccines (Belagenpumatucel) or vaccines using viral vector (TG4010). Tecemotide and TG4010 are a MUC1 antigen-specific cancer immunotherapy. MUC1 is expressed at the apical surface of mucin-secreting normal epithelial cells of various tissues and can be overexpressed and aberrantly glycosylated in some tumors and thus is an attractive target for immunotherapy. Tecemotide is a liposomal vaccine. In a randomized phase II trial (10), 171 NSCLC patients who were not progressing after induction CT or CT-RT received subcutaneous tecemotide plus best supportive care (BSC) or BSC alone as maintenance therapy . Median survival time (MST) was longer in patients receiving tecemotide (17.2 vs. 13.0 months) but this did not reach statistical significance. As in a post hoc analysis the benefit appeared to be more important for patients with stage IIIB disease, it was decided to perform a phase III study in locally advanced NSCLC (11,12)comparing in non-progressing patients after CT with platin-based doublet and RT, tecemotide versus placebo. MST was 25.8 months with tecemotide versus 22.4 months with placebo (HR 0.89, 95%CI 0.77-1.03, p=0.111). In the concurrent CT-RT subgroup, there was a significant survival benefit in favor of tecemotide whereas in the sequential CT-RT subgroup, survival did not differ between the two arms. A similar study (13)was initiated in Asian people. This trial was prematurely terminated as the sponsor decided to discontinue program with tecemotide in NSCLC MAGE-A3 is an antigen expressed in 76% of melanoma and in 35% of NSCLC. It is absent from normal tissues except for testis and placenta. This vaccine, has been investigated in early stage of NSCLC as an adjuvant treatment. A randomized phase II study(14)compared the MAGE-3A vaccine to a placebo in 182 patients operated of a stage IB or II NSCLC with their tumor expressing MAGE-A3 antigen. The randomization was on a 2 :1 basis. The main objective was to compare the Disease Free Interval (DFI) defined as the time from resection to the date of recurrence (any type) or second primary lung neoplasm. Although there was a trend toward a numerically longer DFI in the MAGE-A3 vaccine group, the main objective was not met. Nevertheless, even if these trends were by far not significant, the results appear promising to the sponsors and a phase III trial was launched (MAGRIT trial) with the same scheme(15). Unfortunately, the biggest trial ever performed with the inclusion of 2312 NSCLC patients is negative regarding as well the primary objective: disease-free survival (DFS) but also the secondary objective, DFS in the group of patients not receiving adjuvant chemotherapy or other subgroups. Belagenpumatucel-L is a vaccine comprising 4 tranforming growth factor-β2-antisense gene-modified irradiated allogeneic NSCLC cell lines. A randomized phase III trial (16)comparing this vaccine to a placebo was performed after platinum-based CT for stage III/IV disease in non progressing patients. This trial was negative with no difference in overall survival and in PFS. However, in a prespecified multivariate analysis, there was an improved survival for patients who were randomized within 12 weeks after CT and for patients who received prior radiation therapy. TG4010 is a suspension of a recombinant modified vaccinia virus strain Ankara coding for the MUC1 TAA and IL2. Feasibility of either upfront combination of TG4010 with cisplatine-vinorelbine or TG4010 alone until progression has been demonstrated in a phase II study(17). Sixty-five patients were randomized. Response rate was 30 % in the combined upfront schedule, MST was 12.7 months and one-year survival rate 53%. Taking into account these results, a phase II randomized study (18)comparing CT with cisplatin and gemcitabine to the same CT + TG4010 was performed. One hundred and forty eight patients with stage IIIB or IV disease were included. The primary endpoint was 6-month PFS with the hypothesis that it will be at least 40% in the combined arm. This objective was met with a 6-months PFS of 43% compared to 35.1% in the CT alone arm. There was a non significant trend toward a higher response rate and a longer time to progression in the combined arm. An exploratory analysis of the subgroups defined by the level of activated NK cells (CD16+CD56+CD69+lymphocytes or TrPAL) shows that a better outcome was observed for those patients with normal level of TrPAL and that the vaccine might be deleterious for those with high level of TrPAL. A phase IIB was then performed to confirm the role of the level of TrPAL(19). 222 patients were randomly allocated to CT+TG4010 or CT+placebo. Median PFS was 5.9 months in the TG4010 group versus 5.1 months in the placebo group (HR 0.74, 95%CI 0.55-0.98, p= 0.019). In patients with TrPAL values less or equal ULN, the HR for PFS was 0.75 (95%CI 0.51-1.03) with a posterior probability of HR being <1 of 98.4% and thus the primary endpoint was met. In patients with high level of TrPAL, there was no deleterious effect but no benefit as the HR for PFS was 0.77 (95%CI 0.42-1.40). As a conclusion, all studies with vaccines have been quite disappointing. To the best of my knowledge, the only vaccine still under investigation remains TG4010, but....phase III trial is not implemented at this time. In each vaccine study some efficacy has been observed in subgroups of NSCLC patients but mostly in post hoc analyses. All vaccine studies have shown that there is no safety problems. The fact that nowadays, considerable interest has been developed toward checkpoint inhibitors, probably explains the disaffection toward vaccines. Hopefully it will be only transient and the already long story of therapeutic vaccines will continue.

Product	Trials conducted	Author (ref)
Tecemotide (Stimuvax*) Merck Serono	Phase IIB maintenance study in stage III/IV NSCLC Phase III maintenance therapy after CT-RT in non resectable stage III disease	Butts(10) Butts(11) Mitchell(12) Wu(13)
MAGE A3 GSK	Adjuvant treatment after surgery Phase II randomized study Phase III study (Magrit trial)	Vansteenkiste(14) Vansteenkiste(15)
Belagenpumatucel Lucanix* NovaRx	Phase III study as maintenance in stage IV disease after 1st line CT	Giaccone(16)
TG4010 Transgene	In combination with first line CT in stage IV disease NSCLC Phase II study Phase IIB randomized study Phase IIB/III randomized study	Ramlau(17) Quoix(18) Quoix(19)

Table 1 Phase II and III vaccine studies in NSCLC References 1. Kawai O, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 2008;113:1387–95. 2. Engels EA, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011;306:1891–901. 3. Hleyhel M, et al. Risk of non-AIDS-defining cancers among HIV-1-infected individuals in France between 1997 and 2009: results from a French cohort. AIDS 2014;28:2109–18. 4. El-Osta H,et al. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment. OncoTargets Ther. 2016;9:5101–16. 5. Coley WB. The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med. 1910;3(Surg Sect):1–48. 6. Zacharski LR, Sukhatme VP. Coley’s toxin revisited: immunotherapy or plasminogen activator therapy of cancer? J Thromb Haemost 2005;3:424–7. 7. Maurer LH, et al. Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study. J Clin Oncol 1985;3:969–76. 8. Giaccone G, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer. J Clin Oncol 2005;23:6854–64. 9. Robinson E, et al.. Combined-modality treatment of inoperable lung cancer (i.v. immunotherapy, chemotherapy, and radiotherapy). Cancer Treat Rep. 1985;69:251–8. 10. Butts C, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 2005;23:6674–81. 11. Butts C, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:59–68. 12. Mitchell P, et al. Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses. Ann Oncol 2015;26:1134–42. 13. Wu Y-L, et al. INSPIRE: A phase III study of the BLP25 liposome vaccine in Asian patients with unresectable stage III non-small cell lung cancer. BMC Cancer. 2011;11:430. 14. Vansteenkiste J, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: phase II randomized study results. J Clin Oncol 2013;31:2396–403. 15. Vansteenkiste JF, et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17:822–35. 16. Giaccone G, et al. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 2015;51:2321–9. 17. Ramlau R, et al. A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV Non-small cell lung cancer. J Thorac Oncol 2008;3:735–44. 18. Quoix E, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol. 2011;12:1125–33. 19. Quoix E, et al. TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial. Lancet Oncol. 2016;17:212–23.

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Immunotherapy in the First-Line Setting of Advanced NSCLC Lung cancer remains the leading cause of cancer-related deaths worldwide. Advances in screening, surgery and treatment have helped to improve the median survival for patients with lung cancer over the past decade, however, the five-year survival rate remains less than 20%. The majority of patients are diagnosed with advanced stage disease, who are treated with platinum-based chemotherapy, followed by targeted, combination, or immunotherapies. Given the response rates seen with the use of immunotherapy in the second-line setting, it was appropriate to begin to explore if these agents could be given to patients earlier in their treatment. Immunotherapies have been found to be better tolerated than chemotherapy and have the potential for long-term survival, thus could benefit patients as first-line therapy, as some patients will never go on to receive second-line treatment. Two agents, nivolumab and pembrolizumab, both monoclonal antibodies targeting programmed cell death protein 1 (PD-1), are approved for use in patients with non-small cell lung cancer (NSCLC) who have received prior chemotherapy. The KEYNOTE-024 randomized phase III trial of pembrolizumab vs. standard of care (platinum-based chemotherapy), demonstrated superior progression-free survival (PFS) and overall survival (OS) for first-line treatment in patients with tumors expressing high levels of programmed cell death ligand 1 (PD-L1) (tumor proportion score ≥50%). The CheckMate-026 randomized, phase III study of nivolumab vs. standard of care in treatment-naïve patients with tumors expressing ≥5% PD-L1 did not meet the primary endpoint of PFS. For this presentation, the use of predictive markers in the front-line setting will be discussed and implications for combination therapy will be reviewed.

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Background: Hu5F9-G4 is a humanized monoclonal antibody that targets CD47, blocking its anti-phagocytic “don’t eat me” signal through macrophage receptor SIRPα, leading to tumor phagocytosis. CD47 is overexpressed on human cancers and also on red blood cells (RBCs). In primate toxicology studies, Hu5F9-G4 caused a transient anemia that was improved with a single lower Priming Dose allowing higher Maintenance Doses. Materials and Methods: Relapsed/refractory solid tumors and lymphomas were included. This dose escalation study included: Part A, to determine the Priming Dose and Part B, to determine the Maintenance Dose. The maximum tolerated dose (MTD) in part A was used for the single Priming Dose in part B (Hu5F9-G4 dosed weekly). The primary objective is to determine safety and secondary objectives are to determine PK and PD. Preliminary data reported from data cutoff of July 22, 2016.Results: 25 patients have enrolled. Part A included 0.1 (N=1), 0.3 (N=2), 1 (N=6), and 3 (N=2) mg/kg. There were 2 dose-limiting toxicities (DLTs) in Part A at the 3 mg/kg dose: grade (G) 3 abdominal pain and G3 hemagglutination (H) (protocol-specific scale of G1 H on peripheral blood smear (PBS) and G2 headache). 1 mg/kg was selected as the Priming Dose, with no >G2 anemia. Pharmacodynamic studies show almost 100% RBC receptor occupancy at the Priming Dose. Treatment-related adverse event (TRAE) in Part A included: anemia (3 G1, 3 G2), hyperbilirubinemia (3 G1, 2 G2; unconjugated), headache (6 G1, 1 G2), H on PBS (8 G1), and nausea (3 G1). Part B included 3 (N = 4), 10 (N = 3), and 20 mg/kg (N=6, ongoing). There have been no DLTs in 3 patients on 10 mg/kg, and one DLT (headache with hemagglutination) in 6 patients at the 20 mg/kg maintenance dose (ongoing). Most toxicities were was associated with the initial single Priming Dose and were completely reversible. TRAE in Part B at 3 mg/kg included: anemia (2 G1, 2 G2), hyperbilirubinemia (1 G1, 1 G3), headache (3 G1), H on PBS (1 G1), retinal toxicity (G2 protocol-specific scale, asymptomatic). TRAE at 10 mg/kg included: anemia (3 G1), headache (2 G1), and nausea (1 G1). Two patients with adenoid cystic carcinoma in Part A had stable disease for 16 and 8 months. In Part B, 2 of 3 patients have had prolonged stable disease at 10 mg/kg for 8+ months (follicular thyroid cancer) and 7+ months (myoepithelioma of the head and neck). Evaluation of subjects in the 20 mg/kg cohort is ongoing. Conclusions: Hu5F9-G4 is well tolerated at 10 mg/kg weekly, with 1 mg/kg Priming Dose. Part B with a Maintenance Dose of 20 mg/kg is ongoing. Acknowledgements: Stanford Clinical and Translational Research Unit; California Institute for Regenerative Medicine; Forty Seven, Inc.Trial Registration: NCT02216409References: 1. Willingham SB, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2. Liu J t al. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345. References 1. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2. Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, Willingham S, Howard M, Prohaska S, Volkmer J, Chao M, Weissman IL, Majeti R. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345.Figure: CD47 is a myeloid-specific immune checkpoint. Figure 1Figure 2

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Background Solitary pulmonary nodules are seen on approximately 0.1% of all chest X-ray films.[1] High-resolution computed tomography (HRCT), which is used in lung cancer screening programs, can detect pulmonary nodules that are smaller than those detected by conventional radiography. The radiological diagnosis and treatment of these small pulmonary nodules are now the focus of lung cancer research. The timely detection of lung cancers is essential for successful treatment. The guidelines and recommendations for the management of pulmonary nodules include follow up, nonsurgical biopsy, or surgery; and are based on the size of the nodule, and ground glass opacity (GGO) ratio or size of the solid component.[2-4] Diagnosis The diagnosis of a pulmonary nodule is frequently problematic. The management of pulmonary nodules is based on their characteristics. When a pulmonary nodule is monitored by CT, the important features include not only its size but also its density. According to the guidelines of the American College of Chest Physicians, solid nodules measuring > 8 mm in diameter need further examination.[3] The Fleischner Society for Thoracic Imaging and Diagnosis uses a cutoff diameter of 5 mm for decision making for subsolid nodules.[2] It should be kept in mind that solid nodules that are suspicious for lung cancer are frequently invasive. A subsolid nodule can be classified as a pure ground glass nodule (GGN) or part-solid nodule. Subsolid nodules grow slowly and may develop a solid component. The HRCT findings of early lung adenocarcinomas were significantly correlated with the histopathologic findings of the resected specimens.[5] In the evaluation of subsolid nodules, the features indicating noninvasive lung adenocarcinoma include tumor disappearance rate, diameter of consolidation, and GGO ratio.[6] However, even HRCT cannot accurately assess the areas of solid opacities or GGO, and results might vary between investigators. In the upcoming 8[th] TNM classification, the Lung Cancer Staging Project of the International Association for the Study of Lung Cancer showed that the solid part of a nodule on HRCT represents the clinical T factor, and that measurement of the solid part is essential for lung cancer staging.[5] Positron emission tomography (PET)-CT has a clearly established role in lung cancer clinical practice. Based on the pretest probability, PET-CT should be used for patients with a solid, indeterminate nodule > 8 mm in size.[3,4] For adenocarcinomas in situ (AIS) and minimally invasive adenocarcinomas (MIA) of the lung that show solid opacities on HRCT, the preoperative PET-CT and thin-section CT findings together can provide information on the aggressiveness of the tumor. Our study group found that these modalities used together could detect aggressive lung cancers in clinical stage IA (Fig. 1).[7] However, since PET-CT can show false-negative results for slow-growing and low-grade lung malignancies, we think that HRCT is the best modality for identifying indolent lung cancers. Transthoracic biopsy, bronchoscopy, or surgery is used for obtaining specimens for histopathological diagnosis. The definitive diagnosis of small pulmonary nodules, especially GGO-dominant nodules, is challenging. The diagnostic yields of percutaneous CT-guided fine needle aspiration biopsy for GGO-dominant and solid-dominant lesions were 51.2% and 75.6%, respectively (p = 0.018).[9] The diagnostic yield of GGO-dominant lesions < 10 mm was 35.2%. Since invasive biopsy is not without risk, a histopathological diagnosis should be limited to nonsurgical candidates. For cases with high likelihood of lung cancer, a surgical biopsy followed by lung resection might be warranted. Although surgery might be performed on patients with benign nodules, it does provide the definitive diagnosis. If surgery is performed after careful preoperative assessment, the surgical mortality is very low, and the surgical risk may be acceptable. Treatment While lobectomy is the standard procedure for lung cancers, sublobar resection, meaning segmentectomy or wedge resection, might be justified for patients with noninvasive small lung cancers. However, to date, which procedure, sublobar resection or lobectomy, provides a better outcome remains unclear in these cases, since prospective randomized control trials are ongoing (JCOG0802/WJOG4607L[8] and CALGB140503). One of the concerns in sublobar resection is recurrence at the surgical margin (Fig. 2). Recurrence at the surgical margin might be accounted for by tumor cells spreading via air spaces.[10] Accurate intraoperative cytology and adequate surgical margins have been reported to be important for preventing recurrence at the surgical margin. Another concern is lymph node metastasis. In a prospective radiological study for clinical stage IA lung cancer, 47 of 545 (8.6%) patients had lymph node metastasis.[6] Sublobar resection, especially wedge resection, dose not allow evaluation of lymph nodes for metastatic disease. Conclusion HRCT findings play an important role in discriminating the biological behaviors of pulmonary nodules. The definitive diagnosis by HRCT can be difficult, and the combination of HRCT and PET-CT might be beneficial. Randomized control trials should clarify the role of sublobar resection in treating patients with noninvasive lung cancer. Figure 1. Figure 1 Figure 2. Figure 2 References 1. Ost D, Fein AM, Feinsilver SH. The solitary pulmonary nodule. N Engl J Med 2003;348:2535-42. 2. Naidich D, Bankier AA, MacMahon H, Schaefer-Prokop CM, Pistolesi M, Goo JM, et al. Recommendations for the management of subsolid pulmonary nodules detected at CT: A statement from the Fleischner Society. Radiology 2013;266:304-17. 3. Gould MK, Donington J, Lunch WR, Mazzone PJ, Midthun DE, Naidich DP, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer 3[rd] ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e93s-120s. 4. National Comprehensive Cancer Network. Guidelines for surveillance following therapy for non-small cell lung cancer Ver 4.2016. Available at: www.nccn.com. 5. Travis WD, Asamura H, Bankier AA, Beaseley MB, Detterbeck F, Flieder DB, et al. The IASLC Lung Cancer Staging Project: Proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol 2016;11:1204-23. 6. Suzuki K, Koike T, Asakawa T, Kusumot M, Asamura H, Nagai K, et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-6. 7. Shiono S, Yanagawa N, Abiko M, Sato T. Detection of non-aggressive stage IA lung cancer using chest computed tomography and positron emission tomography/computed tomography. Interact Cardiovasc Thorac Surg. 2014;21:637-43. 8. Nakamura K, Saji H, Nakajima R, Okada M, Asamura H, Shibata T et al. A phase III randomized trial of lobectomy versus limited resection for smallsized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271–4. 9. Shimizu K, Ikeda N, Tsuboi M, Hirano T, Kato H. Percutaneous CT-guided fine needle aspiration for lung cancer smaller than 2 cm and revealed by ground-glass opacity at CT. Lung Cancer 2006;51:173-9. 10. Shiono S, Yanagawa N. Spread through air spaces is a predictive factor of recurrence and a prognostic factor in stage I lung adenocarcinoma. Interact Cardiovasc Thorac Surg. 2016 Jun 26. pii: ivw211.

Abstract:
Radiologic Techniques for the Evaluation of Pulmonary Nodules The incidental detection of pulmonary nodules has increased with improved CT technology and thin section imaging techniques[1][,][2]. Adding to this increased detection of nodules is the heightened interest in the purposeful search for nodules such as in oncology patients and lung cancer screening programs. The management of CT detected nodules is a subject of much debate and dependent upon the clinical setting. For instance, in a lung cancer screening setting, there has been a large volume of investigation of solid, semi-solid and ground glass nodules that is the foundation of management recommendations such as LungRads[3]. In patients with a known malignancy, there is minimal literature on management recommendations and thus more influenced by pulmonary metastatic potential of the malignancy and clinician experience[4]. Finally incidentally detected nodule management is greatly influenced by cancer risk factors and nodule texture; for these situations, the Fleischner criteria have been the most widely used and accepted management guidelines[5]. The radiologic evaluation of nodules most often utilizes conventional imaging techniques of chest radiographs, computed tomography (CT), PET/CT. Occasionally MRI and ultrasound may be employed. Most recent changes involve risk stratification, computer software applications to enhance nodule analysis such as nodule enhancement patterns, volumetric computations, and texture analysis[6-8]. Future directions include incorporation of genomics into imaging as well as radiomic analysis and machine learning[9][,][10]. This presentation will review the highlights of the radiologic methods for evaluating pulmonary nodules with a focus on current guidelines and future directions. Reference: 1. Frank L, Quint LE. Chest CT incidentalomas: thyroid lesions, enlarged mediastinal lymph nodes, and lung nodules. Cancer imaging : the official publication of the International Cancer Imaging Society 2012;12:41-8. 2. Jacobs PC, Mali WP, Grobbee DE, van der Graaf Y. Prevalence of incidental findings in computed tomographic screening of the chest: a systematic review. Journal of computer assisted tomography 2008;32:214-21. 3. Lung CT Screening Reporting and Data Systen (Lung-RADS). 2014. (Accessed March 27, 2015, at www.acr.org/Quality-Safety/Resources/LungRADS ) 4. Munden RF, Erasmus JJ, Wahba H, Fineberg NS. Follow-up of small (4 mm or less) incidentally detected nodules by computed tomography in oncology patients: a retrospective review. J Thorac Oncol 2010;5:1958-62. 5. McMahon PM, Meza R, Plevritis SK, et al. Comparing benefits from many possible computed tomography lung cancer screening programs: extrapolating from the National Lung Screening Trial using comparative modeling. PloS one 2014;9:e99978. 6. McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910-9. 7. Revel MP, Merlin A, Peyrard S, et al. Software volumetric evaluation of doubling times for differentiating benign versus malignant pulmonary nodules. AJR Am J Roentgenol 2006;187:135-42. 8. Talwar A, Gleeson FV, Rahman NM, Pickup L, Gooding M, Kadir T. A Review Of The Use Of Computer Aided Texture Analysis For Pulmonary Nodules Classification. American journal of respiratory and critical care medicine 2015;191. 9. El-Zein RA, Lopez MS, D'Amelio AM, Jr., et al. The cytokinesis-blocked micronucleus assay as a strong predictor of lung cancer: extension of a lung cancer risk prediction model. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2014;23:2462-70. 10. Gillies RJ, Kinahan PE, Hricak H. Radiomics: Images Are More than Pictures, They Are Data. Radiology 2016;278:563-77.

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