Limited Small Cell Lung Cancer Research Articles

Effect of Lymph Node Assessment on Outcomes in Surgery for Limited Stage Small Cell Lung Cancer

The National Comprehensive Cancer Network guidelines recommend surgery for limited stage small cell lung cancer (SCLC). However, there is no literature on minimum acceptable lymph node retrieval in surgery for SCLC. The National Cancer Database was queried for adult patients undergoing lobectomy for limited stage (cT1-2N0M0) SCLC from 2004 to 2015. Patients with unknown survival, staging, or nodal assessment, and patients who received neoadjuvant therapy were excluded. The number of lymph nodes assessed was studied both as a continuous variable and as a categoric variable stratified into distribution quartiles. The primary outcome was overall survival and the secondary outcome was pathologic nodal upstaging. A total of 1051 patients met study criteria. In multivariable analysis, only a retrieval of eight to 12 nodes was associated with a significant survival benefit (hazard ratio 0.73; 95% confidence interval, 0.56 to 0.98). However, when modeled as a continuous variable, there was no association between number of nodes assessed and survival (hazard ratio 1.00; 95% confidence interval, 0.98 to 1.02). The overall rate of pathologic nodal upstaging was 19%. Modeled as a continuous variable, more than seven lymph nodes assessed at time of resection was significantly associated with nodal upstaging in multivariable regression (odds ratio 1.03; 95% confidence interval, 1.01 to 1.06). In this study, there was no clear difference in survival based on increasing the number of lymph nodes assessed during lobectomy for limited stage SCLC. However, the number of retrieved lymph nodes was associated with pathologic nodal upstaging. Therefore, patients may benefit from retrieval of more than seven lymph nodes during lobectomy for SCLC.

Once daily versus twice-daily radiotherapy in the management of limited disease small cell lung cancer – Decision criteria in routine practise

BackgroundIn limited disease small cell lung cancer (LD-SCLC), the CONVERT trial has not demonstrated superiority of once-daily (QD) radiotherapy (66 Gy) over twice-daily (BID) radiotherapy (45 Gy). We explored the factors influencing the selection between QD and BID regimens. MethodsThirteen experienced European thoracic radiation oncologists as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) were asked to describe their strategies in the management of LD-SCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies. ResultsLogistic reasons, patients’ performance status and radiotherapy dose constraints were the three major decision criteria used by most experts in decision making. The use of QD and BID regimens was balanced among European experts, but there was a trend towards the BID regimen for fit patients able to travel twice a day to the radiotherapy site. ConclusionBID and QD radiotherapy are both accepted regimens among experts and the decision is influenced by pragmatic factors such as availability of transportation.

NRG Oncology/Alliance LU005: A phase II/III randomized clinical trial of chemoradiation versus chemoradiation plus atezolizumab in limited stage small cell lung cancer.

TPS9082 Background: Limited stage small cell lung cancer (LS-SCLC) is treated with standard of care platinum/etoposide (EP) and thoracic radiation therapy (TRT) with curative intent, however the majority of patients are not cured and median overall survival is approximately 30 months. Addition of atezolizumab to chemotherapy in extensive stage SCLC has improved progression free and overall survival in a non-curative setting leading to hope that addition of an immune checkpoint inhibitor to standard chemoradiotherapy could benefit LS-SCLC patients. LU005 is a randomized phase II/III trial of standard concurrent chemoradiation with or without atezolizumab for patients with LS-SCLC. Methods: Patients are randomly assigned in a 1:1 ratio to standard EP chemotherapy with concurrent TRT (45 Gy BID or 66 Gy QD) with or without atezolizumab beginning concurrently with TRT, and continued every 3 weeks for up to 12 months. Eligible patients have LS-SCLC, PS 0-2, adequate organ function, no concerning comorbidities (including no active autoimmune disease) and are eligible for TRT. Patients are randomized prior to their second cycle of EP and thoracic radiation begins with the second overall cycle of chemotherapy (first cycle of study therapy) in both treatment arms. Prophylactic cranial radiation (PCI) is recommended for patients who respond to treatment. The phase II/III primary endpoints are progression free (PFS) and overall survival (OS) respectively. Secondary endpoints include objective response rates, local and distant disease control, and quality of life/patient reported outcomes assessment. Translational science component includes blood and tissue based immune related assays. This study activated in May 2019. 50 of 506 planned patients have been accrued as of 2/1/2020. Supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U23CA180803 (IROC) from the National Cancer Institute (NCI) and Genentech. *Authors Ross and Higgins are co-first authors and contributed equally to this work. Clinical trial information: NCT03811002.

Prognostic value of SOX2 and CD8+TIL in limited stage small cell lung cancer.

e21108 Background: SOX2 is a transcriptional factor that drives embryonic stem cell to neuroendocrine cells in lung development and is highly expressed in SCLC. The serum SOX2 antibody in SCLC has been known to mediate neurologic paraneoplastic syndrome. In this study, we evaluated the expression of SOX2 and CD8+ tumor infiltrating lymphocyte (TIL) in LS-SCLC from clinical tumor tissue and their impact on PFS and OS. Methods: Among the total 245 patients with SCLC treated between 2010 and 2018, 75 patients with LS-SCLC with available tumor tissue were enrolled. SOX2 and CD8+ TIL were evaluated by immunohistochemistry. High SOX2 expression was defined as above 100 of H score that was derived from multiplying intensity by the proportion of stained tumor cells. The number of CD8+TILs was counted under high magnification (x400) with four fields in intratumoral area. The cut value for high CD8+TIL was the above the median of total case. Results: 64 patients (85.4%) received etoposide/platinum and definite local therapy (radiation therapy or surgery) and 18 patients (24.0%) received surgical resection. High expression of CD8+ TIL was related to significantly longer PFS (13.9 vs. 8.0 months, P = 0.014) and tended to related to longer OS (32.1 vs. 17.4 months, P = 0.056) than low expression. High expression of SOX2 was tended to related with longer OS and PFS compared to low expression of SOX2 (median, 21.7 vs. 17.1 months, P = 0.118; 12.7 vs. 9.0 months, P = 0.110, respectively) without statistical significance. 29 patients with high CD8+TIL among 52 patients with high SOX2 had significantly longer PFS and OS compared to the other groups (median PFS 19.3 vs. 8.4 months, P = 0.002 and median OS 35.7 vs. 17.4 months, P = 0.004, respectively). Multivariate Cox regression analysis showed that combined high expression SOX2 and CD8+ TIL was an independent good prognostic factor for OS (HR = 0.449, P = 0.018) and PFS of SCLC (HR = 0.481, P = 0.021). Conclusions: In our study, high expression level of combined SOX2 and CD8+ TIL were related to longer OS and PFS, and it could be used as a prognostic biomarker for LS-SCLC. [Table: see text]

The role of surgery in stage I small-cell lung cancer: A national VA database analysis.

e21109 Background: Historically, limited stage Small Cell Lung Cancer (SCLC) has been treated with concurrent chemoradiation (CRT). While current NCCN guidelines recommend consideration of lobectomy in node-negative cT1-T2 SCLC, real world data regarding the role of surgery in very limited SCLC is lacking. To our knowledge, only one retrospective study has evaluated the role of surgery in stage I SCLC. Methods: Data from the National VA Cancer Cube were compiled. A total of 1,028 patients with pathologically confirmed Stage I SCLC were studied. Only 661 patients that either received surgery or CRT were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Subset analysis was performed based on the location of the tumor in the upper vs lower lobe as delineated by ICD-10 codes C34.1 and C34.3. Results: Four-hundred and forty-two patients received concurrent CRT; while 219 underwent treatment that contained surgery (92 surgery only, 84 surgery/chemo, 39 surgery/chemo/radiation and 4 surgery/radiation). The median OS for the surgery-inclusive treatment was 3.87 years (95% CI 3.25-4.60) while median OS for the CRT cohort was 2.43 years (95% CI 2.15-2.72). HR of death for surgery-inclusive treatment when compared to CRT was 0.65 (95% CI 0.54-0.79; p < 0.001). Subset analysis based on the location of the tumor in upper lobe and lower lobe showed improved survival with surgery as compared to CRT regardless of the location. HR for upper lobe was 0.61 (95% CI 0.48-0.78; p < 0.001) and lower lobe 0.60 (95% CI 0.41-0.87; p = 0.007). Multivariable regression analysis accounting for age and ECOG-PS shows a HR 0.60 (95% CI 0.42-0.85; p = 0.004) favoring surgery. Conclusions: Surgery was used in less than a third of patients with stage I SCLC who received treatment. Surgery-inclusive multimodality treatment was associated with a longer overall survival as compared to chemoradiation, independent of age, performance status or tumor location. Our study supports a more expansive role for surgery in stage I SCLC.

Conduction mechanism and defect density of states in amorphous Te15 (Se100-xBix)85 glassy alloys

The present paper reports the dc conductivity measurement up to 100 V for pallets of Te 15 (Se 100-x Bi x ) 85 (x=0, 1, 2, 3, 4 at %) glassy alloys in temperature range (303-343 K). The dc conductivity is calculated from the I-V characteristics curves of the pellets of bulk samples prepared by melt quenching technique. The samples obey Ohm’s law in the lower (0-25 V) voltage range whereas the behaviour in the higher (25-100 V) voltage range is non-ohmic. The experimental results for all the samples fit well with the theory of space charge limited conduction SCLC for uniform distribution of localized states in the mobility gap. The density of defect states is calculated for the glassy alloys and is found to increase with Bi content. The increase in defect density of states can be explained on basis of electro negativity difference of Bi as compared to host elements. The increase in dc conductivity is probably due to Se-Bi bond concentration in the Se-Te-Bi glasses.

Outcomes and the role of adjuvant therapy of limited stage small cell lung cancer undergoing surgical treatment

Objective: To investigate the outcomes of limited stage small cell lung cancer (L-SCLC) undergoing surgical therapy and to explore the value of adjuvant therapy for those patients. Methods: A retrospective analysis was initialed for the L-SCLC patients who underwent the surgical treatment in the Zhongnan Hospital of Wuhan University from January 2012 to December 2018. The median disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method. Cox regression was used to explore the prognostic factors. Results: A total of 44 patients were included in our study. The median DFS was 25 months, 1- and 2-year DFS rate were 70.2% and 51.9%, respectively. The median OS was 41 months, 1- and 2- year OS rate were 88.4% and 69.9%, respectively. Multivariate analysis showed male (RR=6.56, P=0.03), T3-4 (RR=6.23, P=0.01), pathological lymph node metastasis (RR=6.52, P=0.03) and adjuvant radiotherapy (RR=0.13, P=0.002) were associated with disease relapse significantly. Moreover, pathological lymph node metastasis (RR=3.62, P=0.01) coupled with sufficient adjuvant chemotherapy (≥4 cycles) (RR=0.12, P=0.01) were independent prognostic factors of OS. Conclusions: Surgical therapy may be an alternative primary treatment for L-SCLC. Additional adjuvant radiotherapy can reduce the risk of recurrence. Giving sufficient course of adjuvant chemotherapy can improve OS.

The effect of extent of resection on outcomes in patients with limited stage small cell lung cancer

BackgroundThere is poor understanding of the comparative effectiveness of lobar and sublobar resections for limited-stage small cell lung cancer (SCLC). We analyzed the National Cancer Database to examine the outcomes of patients undergoing wedge resection (WR), segmentectomy (SR), and lobectomy (LB) for limited-stage SCLC. MethodsPatients with cT1-2N0M0 SCLC (2004-2015) who underwent definitive surgery were identified and stratified by extent of resection: WR, SR, or LB. The primary outcome was overall survival (OS) and secondary outcomes were margin-positive resection (>R0) and pathologic nodal upstaging. ResultsA total 1948 patients met study criteria: 619 (32%) underwent WR, 96 (5%) SR, and 1233 (63%) LB. Patients receiving LB were more likely to be younger, have fewer comorbidities, and be privately insured. The unadjusted 5-year OS of WR, SR, and LB patients was 31% (95% confidence interval [CI], 27-35), 35% (95% CI, 25-49), and 45% (95% CI, 42-49), respectively. In a multivariable Cox model, WR was associated with worse OS (hazard ratio, 1.53; 95% CI, 1.31-1.79) and SR similar OS (hazard ratio, 1.20; 95% CI, 0.87-1.67) compared with LB. SR was associated with similar survival compared with LB in a propensity score–matched multivariable analysis as well. WR was also associated with greater odds of >R0 resection compared with LB. ConclusionsIn this study, patients with limited-stage SCLC undergoing WR experienced worse survival compared with those undergoing LB; survival was similar between segmentectomy and LB.

Study protocol: watchful observation of patients with limited small cell lung cancer instead of the PCI\u2014prospective, multi-center one-arm study

BackgroundProphylactic cranial irradiation (PCI) is a current standard of care after confirmed response to radical chemoradiotherapy for limited disease small cell lung cancer (LD-SCLC). This standard is mostly based on results of old randomized studies when brain imaging with magnetic resonance (MRI) was not available. Survival benefit of PCI in extended disease SCLC was recently challenged by the results of randomized phase III study from Japan.MethodsEighty patients with LD-SCLC after response to chest chemoradiotherapy will be enrolled. Patients will be followed up by brain MRI every 3 to 6 months up to 3 years. Neurocognitive function tests will be performed at baseline and after 12 and 24 months. Patients who develop brain metastases will be irradiated with stereotactic (SRT) or whole brain RT (WBRT). The primary endpoint is overall survival. The secondary endpoints are: response rate to radiotherapy of early detected brain metastases, analysis of efficacy of SRT and WBRT; assessment and analysis of neurocognitive functions and QoL in the studied cohorts: QLQ-C30 questionnaire and the California Verbal Learning Test, Color connection test, Benton visual retention test, and verbal fluency test will be carried out.DiscussionThe results of this trial may contribute to changing of LD-SCLC clinical management by deescalating the treatment. There is a lack of prospective, recent studies in LD-SCLC patients with omission of PCI and modern radiation therapy technologies for developed brain metastases. The comprehensive neurocognitive function testing will help to assess the impact of modern radiotherapy (SRT) compared with WBRT and no-PCI in SCLC patients. A subgroup of long-term survivors, who will not develop brain metastases, will not be exposed to unnecessary brain irradiation with its deleterious consequences. The limitation of our study is a lack of parallel randomized control arm. This is a potential source of bias; however, randomized study will be difficult to complete for two major reasons: (1) limited population of LD-SCLC eligible for the study and (2) opinions of our patients, who after information and discussion about benefits and potential harms of PCI, often choose to omit PCI in our practice.Trial registrationClinicalTrials.gov Identifier: NCT04168281, 19 Nov. 2019.

Analysis of local recurrence pattern for limited stage small cell lung cancer after IMRT plus chemotherapy

Objective To investigate localized regional recurrence after chemotherapy and chest radiotherapy in limited stage small cell lung cancer (LS-SCLC), and explore the relationship between recurrence location and radiotherapy and chemotherapy and its influencing factors. Methods From 2006 to 2014, pathological LS-SCLC treated in CAMS, 125 patients had local recurrence, Kaplan-Meier statistical method was used to analyze the survival rate and PFS of each recurrence site. Log-rank was used to compare the survival rate of each group. Univariate analysis includes Chi-squareand t-test for the factors for the recurrence site. Multivariate analysis using Logistic regression. Results The 1-, 2-and 5-year overall survival rates were 92.0%, 46.4% and 14.7%, respectively. The median progression time was 12.96 months, The median survival time after progression was 11.5 months, and the 1-, 2-, and 5-year overall survival rates were 45.0%, 23.0%, and 10.0%, respectively. The recurrence sites include intrapulmonary recurrence (67 patients), regional lymph nodes (21 patients), simultaneous intrapulmonary and regional lymph nodes (28 patients), and contralateral or supraclavicular lymph nodes (9 patients). The median survival time were 23.96 months, 24.76 months, 23.23 months, and 18.66 months, and the 2-year survival rates were 49%, 52%, 46%, and11%, respectively (P=0.000, 0.004, 0.008). In 6 patients (4.0%), 5 patients were located in the supraclavicular region, and 1 patient (0.8%) in the field. Conclusions For LS-SCLC undergoing IMRT and chemotherapy, the local failure location is mainly located in the pulmonary, and further treatment of the split dose and targets requires further clinical exploration. Key words: Lung neoplasms/radiochemoradiation; Radiotherapy, intensity-modulated; Patterns of failure

Sequential chemotherapy followed by radical thoracic radiotherapy (50 Gy in 25 fractions) in limited stage small cell lung cancer.

IntroductionFor limited stage small cell lung cancer (LS-SCLC) where concurrent chemoradiotherapy is inappropriate due to tumour bulk, co-morbidities or performance status, sequential treatment using chemotherapy followed by radiotherapy is the standard of care. The outcomes are not well established; we assessed in a single institution, the survival of these patients, prognostic factors and compared to the limited existing literature.Materials and MethodRetrospective data was collected on all 59 patients diagnosed with LS-SCLC from 2011 to 2016 who received chemotherapy consisting of Carboplatin or Cisplatin + Etoposide followed by thoracic radiotherapy (50 Gy in 25 fractions) +/- prophylactic cranial irradiation (PCI).ResultsMedian age at diagnosis was 66 years (range 46–90). Patients received a median of four cycles of chemotherapy (range: 1–6) and all the patients completed a full course of radiotherapy with only one patient experiencing grade >2 radiation induced toxicity. With a median follow up of 20.6 months, 45 patients had died with a median survival of 20.6 months. 2-year overall survival (OS) rates were 42%. Age using a cut-off of 65 was prognostic (median OS 25.6 months ≤65 years versus 14.1 months >65 years, p = 0.013) but gender, stage and receipt of PCI were not.ConclusionsMost of the literature reporting outcome from sequential treatment in LS-SCLC is old and used a variety of radiotherapy regimens. Our data shows inferior outcomes to the gold standard concurrent chemoradiotherapy but support its usage in less fit patients with reasonable outcome observed.

The impact of quantitative CT-based tumor volumetric features on the outcomes of patients with limited stage small cell lung cancer

IntroductionLimited stage small cell lung cancer (LS-SCLC) has a poor prognosis. Additional prognostic markers are needed for risk-stratification and treatment intensification. This study compares quantitative CT-based volumetric tumor measurements versus International Association for the Study of Lung Cancer (IASLC) TNM staging to predict outcomes.Materials & methodsA cohort of 105 patients diagnosed with LS-SCLC and treated with chemoradiation (CRT) from 2000 to 2013 were analyzed retrospectively. Patients were staged by the Union for International Cancer Control (UICC) TNM Classification, 8th edition. Tumor volumes and diameters were extracted from radiation planning CT imaging. Univariable and multivariable models were used to analyze relationships between CT features and overall survival (OS), locoregional recurrence (LRR), in-field LRR, any progression, and distant metastasis (DM).ResultsMedian follow-up was 21.3 months. Two-year outcomes were as follows: 38% LRR, 31% in-field LRR, 52% DM, 62% any progression, and 47% OS (median survival 16.5 months).On univariable analysis, UICC T-stage and N-stage were not associated with any clinical outcome. UICC overall stage was only statistically associated with in-field LRR. One imaging feature (3D maximum tumor diameter) was found to be significantly associated with LRR (HR 1.10, p = 0.003), in-field LRR (HR 1.10, p = 0.007), DM (HR 1.10, p = 0.02), any progression (HR 1.10, p = 0.008), and OS (HR 1.10, p = 0.03). On multivariable analysis, this feature remained significantly associated with all outcomes.ConclusionFor LS-SCLC, quantitative CT-based volumetric tumor measurements were significantly associated with outcomes after CRT and may be better predictors of outcome than TNM stage.

Rationale and protocol design for the TORG1835/NEXT-SHIP study: a phase II study of carboplatin, etoposide and nintedanib for unresectable limited/extensive disease small cell lung cancer with idiopathic pulmonary fibrosis.

Background:Interstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with small cell lung cancer (SCLC). The pharmacotherapy for SCLC occasionally induces fatal acute exacerbation of comorbid IP, especially in patients with idiopathic pulmonary fibrosis (IPF). Safe and effective pharmacotherapy is of greater importance in patients with SCLC and IPF, because SCLC presents a poor prognosis without systemic treatment. Nintedanib is expected to restrain acute exacerbation and present angiogenesis-inhibiting effects.Methods:The TORG1835/NEXT-SHIP study is the world’s first multi-center, single-arm, phase II trial for unresectable limited or extensive disease SCLC with IPF. The patients receive carboplatin (area under the curve 5, day 1), etoposide (<75 years old: 100 mg/m2; ⩾75 years old: 80 mg/m2; days 1–3), and nintedanib (150 mg twice a day) every 3 weeks for four cycles. After completion or discontinuation of carboplatin plus etoposide, the patients continue nintedanib until the discontinuation criteria are met. The primary endpoint is the incidence of acute exacerbation of IPF at 28 days after last administration of cytotoxic anti-cancer agents. We set an expected value of 5% and a threshold value of 20%. Taking statistical points (a/b errors: 0.05/0.75) and ineligible patients into account, the sample size was set at 33. The key secondary endpoints are time to first acute exacerbation of IPF, overall response rate, progression-free survival, overall survival, and toxicities.Discussion:Because there is no clinical trial for unresectable SCLC with IPF, our study would provide a major impact on clinical practice.Trial registration:Japan Registry of Clinical Trials, jRCTs031190119, registered date: October 18, 2019 – Retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190119

NCMP-04. OPSOCLONUS-MYOCLONUS SYNDROME ASSOCIATED WITH CONTACTIN-ASSOCIATED PROTEIN-LIKE 2 AUTOANTIBODY IN THE SETTING OF NON-SMALL CELL LUNG CARCINOMA

Abstract INTRODUCTION Opsoclonus–myoclonus syndrome (OMS) is a rare neurological disorder characterized by spontaneous multidirectional saccadic eye movements, myoclonus, and ataxia. It is suspected to be an autoimmune mediated process precipitated by a paraneoplastic or infectious trigger. Among the pediatric population, OMS is often associated with neuroblastoma and anti-Hu antibody. Paraneoplastic syndromes in adults manifesting as OMS are most commonly described in breast, gynecological and small cell lung cancer with associated anti-neuronal antibodies (ANNA-2; anti-Ri). We describe the first case of OMS associated with lung adenocarcinoma and Contactin-associated protein-like 2 (Caspr2) antibody. CASE REPORT: A 46-year-old-woman with history of limited small cell lung cancer (SCLC) status-post chemotherapy with cisplatin and etoposide and prophylactic whole brain radiation, presented with new onset gait instability, nausea, vomiting, vertigo, and opsoclonus. Two months prior to her presentation, a chest computed topography (CT) revealed no evidence of recurrent disease. Brain MRI revealed T2 hyperintensities in the white matter and central pons presumably related to chronic small vessel ischemic changes, unchanged from prior imaging. CSF studies revealed normal cell count, glucose, and protein. Gram stain, culture and meningoencephalitis panel were negative. Her paraneoplastic panel revealed a positive Caspr2 antibody. A repeat CT chest for cancer surveillance revealed a new lung mass. Immunotherapy treatment included plasmapheresis, corticosteroids, and intravenous immunoglobulin therapy. She underwent a biopsy of the new pulmonary lesion and the pathology was consistent with non-small cell lung carcinoma. Her symptoms slowly improved after treatment. Unfortunately, her disease progressed on repeat PET scan despite surgical resection of the lung mass. She ultimately elected for hospice. CONCLUSION We report a novel antibody, Caspr2, occurring in association with paraneoplastic OMS. While SCLC is the most common neoplasm associated with OMS among adults, non-small cell lung carcinoma should be considered. Prompt immunotherapy and neoplasm treatment may result in improvement.

1743P - Low expression of Notch1 and combined Notch1/HES1 are associated with adverse survival factor for limited stage small cell lung cancer

BackgroundLimited stage small cell lung cancer (LS-SCLC) could be potentially curable with chemotherapy and radiation therapy. Notch pathway could be critically implicated with SCLC development, but there are few studies about its expression and clinical implications in SCLC. In this study, we evaluated the expression of Notch1, Notch2, and HES1 in LS-SCLC from clinical tumor tissue and their impact on PFS and OS. MethodsA total of 75 patients with LS-SCLC, treated between 2010 and 2018, were enrolled, and their retrospective data were analyzed. Notch1, Notch2 and HES1 protein as Notch transcription factor were evaluated by immunohistochemistry. Staining was considered as low expression when 50% or less of the tumor cells expressed Notch1, Notch2, and HES1 with weak intensity. ResultsAmong 75 patients, 42 patients (62.7%) received concurrent chemoradiotherapy, and 13 (17.3%) were diagnosed SCLC combined with NSCLC. Notch1, Notch2, and HES1 were identified in 50 (66.7%), 54 (72.0%), 24 (32.0%). There was no correlation of expression between Notch1 and HES1 (P=0.115). Low expression of Notch1 or Notch2 was not associated with shorter PFS compared to high expression of them (median, 10.0 vs. 14.23, P=0.172; 9.93 vs. 12.43, P=0.759). Low expression of HES1 was tended to shorter PFS than high expression (8.40 vs. 13.57, P=0.068). Low Notch1 expression was significantly associated with poor OS (median, 17.37 vs. 49.83, P=0.022), but Notch2 and HES1 were not with OS (median; 21.73 vs. 18.40, P=0.930; 15.37 vs. 27.90, P=0.076). Of note, combined low expression of Notch1 and HES1 was significantly related with poor OS (median 15.37 vs. 28.63, P=0.012). Multivariate Cox regression analysis showed that combined low expression Notch1 and HES1 was an independent poor prognostic factor for SCLC (HR=1.23, P=0.423). ConclusionsDespite dramatic response rate of current standard treatment for LS-SCLC, more than half of patients experience failure within 2 years. It is clinically important to previse who the poor responder to the treatment is. In our study, low expression level of Notch1 and combined low expression of Notch1 and HES1 were related to poor overall survival, and these could be used as a prognostic biomarker for LS-SCLC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

P2.12-03 Building and Validating a Lymphocyte Nadir Based Model to Predict Survival in Patients with Limited Stage-Small Cell Lung Cancer

Increasing evidence indicates host immunity participate in cancer progression and metastases. It has been reported that the lymphocyte nadir is an independent prognostic marker for survival in various cancers. We have previously reported a survival significance of baseline lymphocyte in limited stage small cell lung cancer (LS-SCLC). Here we hypothesize that treatment induced lymphopenia, like the lymphocyte nadir during the course of treatment, in combination of clinical factors can predict survival better than conventional models in patients with LS-SCLC. This is a retrospective study of 616 patients from a single Institution. Consecutive patients with LS-SCLC treated with thoracic radiation (with or without concurrent chemotherapy) from 2013 to 2017 were included. Additional eligibility included availability of complete-blood-count data from baseline and at least two time points during the course of radiotherapy. These 616 patients were randomly divided into a training dataset (n=308) and a validation dataset (n=308). The primary endpoint was overall OS. Univariate proportional hazard (PH) cox model was used to assess potential clinicopathological predictors on OS. The multivariable Cox PH model was constructed by the forward selection. According to the final Cox model built using significant variables from training dataset, we calculated the risk score for every patient and validate the predictive valuable of the risk score on OS in the validation set. Under univariate analysis, younger age (HR 1.02 per 1 yr, 95%CI 1.006-1.043, p=0.008), female gender (HR 1.40, 95%CI 0.95-2.07, p=0.09), earlier stage (stage I-II vs stage III, HR 2.2, 95%CI 1.11-4.33, p=0.02), concurrent chemotherapy (concurrent vs. not, HR 0.61, 95%CI 0.42-0.88, p=0.01) and a higher lymphocyte nadir (HR 0.48, 95% CI 0.20-1.14, per 103 lymphocytes/μL, p=0.097) was significantly associated with increased OS in the training dataset. Using lymphocyte nadir in combination of significant clinical factors from univariate analysis, we developed a multivariable Cox PH model (lymphocyte nadir: HR 0.39, 95% CI 0.16-0.99, per 103 lymphocytes/μL, p=0.048) with concordance (C)-index of 0.63. In the validation dataset, the multivariable model revealed that lymphocyte nadir had a borderline significance on OS (HR 0.45, 95% CI 0.19-1.06, per 103 lymphocytes/μL, p=0.067) with a comparable c-index of 0.60. Moreover, the risk score calculated using the coefficients from the final Cox model built using the training dataset remained to be a significant predictor for OS (HR 2.04, 95% CI 1.36-3.07, per 1 risk score increase, p<0.0001) in validation dataset. This may be the first study validated a survival predictive model based on lymphocyte nadir in a large sample of patients with LS-SCLC. Should it should be validated in an external dataset, this model might provide some prediction for each patient and provide an opportunity to individualize treatment based on the individual’s survival probability.

EP1.12-01 Does PCI Still Have a Role in Limited SCLC?

Prophylactic cranial irradiation (PCI) has long been an integral part of treatment protocols for limited stage small cell lung cancer (SCLC). PCI stands for "prophylactic” while it may be not really prophylactic, rather therapeutic for un-detectable brain disease. A survey of 39 questions was conducted on the online platform “Survey Monkey” for practicing oncologists, radiotherapists, pulmonologists and thoracic surgeons. The aim of this survey is to establish a practice baseline for a future multicenter study of overall survival (OS) benefits of PCI versus MRI follow-up in limited SCLC. 41 respondents participated from 14 European countries (26 oncology centers) and from 4 US radiotherapy centers: medical oncologists (31%), radiation oncologist (25%), pulmonologists (34%). Brain imaging at diagnosis of SCLC is performed by MRI in 83% and CT with contrast in 49%. Brain follow up after chemotherapy is performed by MRI in 49%, CT with contract in 41%, and no imaging in asymptomatic patients in 20%. PCI is recommended to 67% of patients and performed immediately after the last chemotherapy in 37%, or 2 months after chemotherapy in 49%. The most important criteria whether patient needs PCI are performance status and response to chemotherapy. The most common schedule of PCI is 25Gy in 10 fractions, 41% of respondents. In case of a single brain metastasis after PCI the 1st choice of treatment is SRS, in 93%. Regarding the role of PCI 46% of respondents think that PCI prevents brain metastases from occurring, and 54% think that PCI treats occult brain metastases. The lack of clinical trials about PCI for limited SCLC patients is undisputed. Our survey shows practice patterns to PCI for patients with limited SCLS depends on Institution and/or specialty. These results establish a practice baseline for a multicentral trial of PCI versus MRI observation, and 93% of our respondents agreed to take part in this trial.

PP-99 - A case with a late recurring limited stage small cell lung cancer

PP-99 - A case with a late recurring limited stage small cell lung cancer

P2.12-20 NRG Oncology/Alliance LU005: A Phase II/III Randomized Study of Chemoradiation Versus Chemoradiation Plus Atezolizumab in LS-SCLC

Clinical outcomes for limited stage small cell lung cancer (LS-SCLC) remain suboptimal. Standard of care chemoradiation with platinum/etoposide and thoracic radiation to 45 Gy delivered twice daily followed by prophylactic cranial irradiation yields a median overall survival of 30 months. LU005 is a randomized phase II/III trial designed to test the addition of atezolizumab to concurrent chemoradiation (ClinicalTrials.gov Identifier: NCT03811002). Patients with LS-SCLC (Tx-T4, N0-N3, M0) are randomly assigned in a 1:1 ratio to either standard chemoradiation, consisting of thoracic radiation (45 Gy twice daily or 66 Gy daily) with concurrent platinum/etoposide chemotherapy, or the experimental arm, consisting of the same chemoradiation regimen plus the addition of atezolizumab beginning concurrently with thoracic radiation, and continued every 3 weeks for 12 months duration. Thoracic radiation begins with the second cycle of chemotherapy in both treatment arms. Stratification variables include radiation schedule (once daily vs. twice daily), chemotherapy (cisplatin vs. carboplatin), sex, and performance status (PS 0/1 vs. 2). Prophylactic cranial radiation is recommended for patients who have a response to treatment. The phase II primary endpoint is progression free survival (PFS) and the phase III primary endpoint is overall survival (OS). It is hypothesized that the addition of atezolizumab will yield a hazard ratio of 0.62 for PFS, for a sample size of 280 patients in the phase II portion of this study. The overall sample size for phase II/III will be 506, with the OS analysis designed to provide at least 85% power to detect a hazard ratio of 0.71 at a 1-sided significance level of 0.025. Secondary endpoints include objective response rates, local control, distant metastases free, and quality of life. This study includes a robust translational science component including blood and tissue based assays to further understand which patients may benefit most from immunotherapy. This study activated in May 2019 and is currently enrolling patients. NRG Oncology/Alliance LU005 is a randomized II/III trial testing the addition of atezolizumab to standard chemoradiation for LS-SCLC. The estimated date of study completion is May 2024. *Authors Higgins and Ross are co-first authors and contributed equally to this work.

1737O - Interim toxicity analysis for patients with limited stage small cell lung cancer (LSCLC) treated on the experimental thoracic radiotherapy (TRT) arms of CALGB 30610 (Alliance) / RTOG 0538

BackgroundThe optimal TRT regimen for LSCLC remains to be defined. CALGB 30610/RTOG 0538 started as a 3 arm study designed to discontinue one of 2 experimental TRT arms based on interim toxicity assessment, while the remaining arm would be compared against standard 4500 cGy (twice-daily) TRT. MethodsPer protocol, the interim endpoint was calculated based on treatment related grade 3+ non-hematologic toxicity, grade 4 hematologic toxicity, failure to complete 4 cycles of chemotherapy, and any grade 5 toxicity. The analysis included the initial 70 patients assigned to each of the 7000 cGy (once daily) and the 6120 cGy (concomitant boost) study arms. The initial analysis was conducted May 21, 2012 and an updated analysis of the same patient population was performed April 15, 2019. ResultsThere was not a significant difference in toxicity scoring between the regimens, either in the 2012 assessment or the updated analysis. Overall grade 3, 4, and 5 treatment related adverse events were 21.4%, 54.3%, and 0% for 7000 cGy TRT compared with 20.0%, 57.1% and 1.4% for 6120 cGy TRT, while rates of non-hematologic toxicity were 10.0%. 12.9% and 0% for 7000 cGy TRT compared with 12.9%, 14.3%, and 1.4% with 6120 cGy TRT. Grade 3 pneumonitis was reported in 2 patients (2.9 %) in each cohort. Grade 4 dyspnea was observed in 4 patients (5.7 %) in the 6120 cGy cohort but was not reported in patients treated with 7000 cGy. ConclusionsBoth TRT regimens, 7000 cGy daily and 6120 cGy concomitant boost, concurrent with cisplatin and etoposide chemotherapy, appear to be tolerable without unexpected toxicity. A decision to discontinue the 6120 cGy arm in December 2012 was based on the toxicity distribution, as a significant difference in overall toxicity was not observed. Further details of toxicity and the scoring system applied will be presented. The phase III portion of the study comparing 7000 cGy TRT to 4500 cGy TRT is near completion. Clinical trial identificationCALGB 30610 / RTOG 0538 Identifier: NCT00632853. Legal entity responsible for the studyAlliance for Clinical Trials in Oncology. FundingNational Cancer Institute. Support: U10CA180821, U10CA180882, U10CA180868, U10CA180820, U10CA233330, U10CA180888; https://acknowledgments.alliancefound.org. DisclosureAll authors have declared no conflicts of interest.