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Purpose Preclinical data and subset analyses from immunotherapy clinical trials indicate that prior radiation therapy was associated with better progression-free survival and overall survival when combined with immune checkpoint inhibitors in patients with non-small cell lung cancer. We present a prospective study of hypofractionated image guided radiation therapy (HIGRT) to a single site of metastatic disease concurrently with atezolizumab in patients with metastatic non-small cell lung cancer. Methods and Materials Patients meeting eligibility criteria received 1200 mg of atezolizumab intravenously every 3 weeks with concurrent 3- or 5-fraction HIGRT starting no later than the second cycle. The 3-fraction regimen employed a minimum of 8 Gy per fraction compared with 6 Gy for the 5-fraction regimen. Imaging was obtained every 12 weeks to assess response. Results From October 2015 to February 2017, 12 patients were enrolled in the study (median age 64; range, 55-77 years). The best response by the Response Evaluation in Solid Tumors criteria was partial response in 3 and stable disease in 3, for a disease control rate of 50%. Five patients had a grade 3 immune-related adverse event, including choreoretinitis (n = 1), pneumonitis (n = 1), transaminitis (n = 1), fatigue (n = 1), and peripheral neuropathy (n = 1). The median progression-free survival was 2.3 months, and the median overall survival was 6.9 months (range, 0.4-not reached). There was no clear association between peripheral blood T cell repertoire characteristics at baseline, PD-L1, or tumor mutations and response or outcome. One long-term survivor exhibited oligoclonal T cell populations in a baseline tumor biopsy that were consistently detected in peripheral blood over the entire course of the study. Conclusions HIGRT plus atezolizumab resulted in an overall response rate of 25% and disease control rate of 50% in this pilot study. The incidence of grade 3 adverse events was similar to that of atezolizumab alone. Alhough it was a pilot study with limited sample size, the results generated hypotheses worthy of further investigation.

Radiation esophagitis (RE) is a common adverse event associated with radiotherapy for non–small cell lung cancer (NSCLC). While plasma cytokine levels have been correlated with other forms of radiation-induced toxicity, their association with RE has been less well studied. We analyzed data from 126 patients treated on 4 prospective clinical trials. Logistic regression models based on combinations of dosimetric factors [maximum dose to 2 cubic cm (D2cc) and generalized equivalent uniform dose (gEUD)], clinical variables, and pretreatment plasma levels of 30 cytokines were developed. Cross-validated estimates of area under the receiver operating characteristic curve (AUC) and log likelihood were used to assess prediction accuracy. Dose-only models predicted grade 3 RE with AUC values of 0.750 (D2cc) and 0.727 (gEUD). Combining clinical factors with D2cc increased the AUC to 0.779. Incorporating pretreatment cytokine measurements, modeled as direct associations with RE and as potential interactions with the dose-esophagitis association, produced AUC values of 0.758 and 0.773, respectively. D2cc and gEUD correlated with grade 3 RE with odds ratios (ORs) of 1.094/Gy and 1.096/Gy, respectively. Female gender was associated with a higher risk of RE, with ORs of 1.09 and 1.112 in the D2cc and gEUD models, respectively. Older age was associated with decreased risk of RE, with ORs of 0.992/year and 0.991/year in the D2cc and gEUD models, respectively. Combining clinical with dosimetric factors but not pretreatment cytokine levels yielded improved prediction of grade 3 RE compared to prediction by dose alone. Such multifactorial modeling may prove useful in directing radiation treatment planning.

Background and purpose Current methods to estimate risk of radiation-induced lung toxicity (RILT) rely on dosimetric parameters. We aimed to improve prognostication by incorporating clinical and cytokine data, and to investigate how these factors may interact with the effect of mean lung dose (MLD) on RILT. Materials and methods Data from 125 patients treated from 2004 to 2013 with definitive radiotherapy for stages I-III NSCLC on four prospective clinical trials were analyzed. Plasma levels of 30 cytokines were measured pretreatment, and at 2 and 4 weeks midtreatment. Penalized logistic regression models based on combinations of MLD, clinical factors, and cytokine levels were developed. Cross-validated estimates of log-likelihood and area under the receiver operating characteristic curve (AUC) were used to assess accuracy. Results In prognosticating grade 3 or greater RILT by MLD alone, cross-validated log-likelihood and AUC were −28.2 and 0.637, respectively. Incorporating clinical features and baseline cytokine levels increased log-likelihood to −27.6 and AUC to 0.669. Midtreatment cytokine data did not further increase log-likelihood or AUC. Of the 30 cytokines measured, higher levels of 13 decreased the effect of MLD on RILT, corresponding to a lower odds ratio for RILT per Gy MLD, while higher levels of 4 increased the association. Conclusions Although the added prognostic benefit from cytokine data in our model was modest, understanding how clinical and biologic factors interact with the MLD-RILT relationship represents a novel framework for understanding and investigating the multiple factors contributing to radiation-induced toxicity.

© 2017 International Association for the Study of Lung Cancer Introduction In malignant pleural mesothelioma, targeting angiogenesis with cediranib, a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, may have therapeutic potential. Methods S0905 phase I combined cediranib (two dose cohorts [30 mg and 20 mg daily]) with cisplatin-pemetrexed for six cycles followed by maintenance cediranib in unresectable chemonaive patients with malignant pleural mesothelioma of any histologic subtype. The primary end point established the maximum tolerated dose in combination with cisplatin-pemetrexed in a dose deescalation scheme. Results A total of 20 patients were enrolled (seven to the 30-mg cohort and 13 to the 20-mag cohort). In the cediranib 30-mg cohort, two of the initial six patients reported dose-limiting toxicities and the dose was deemed too toxic to continue. In the next cohort, two patients experienced dose-limiting toxicities, and thus, the maximum tolerated dose of cediranib was established as 20 mg. During the six cycles of cisplatin-pemetrexed-cediranib, 20 mg, there were grade 3 toxicities (neutropenia and gastrointestinal) and grade 4 thrombocytopenia. No patients had any significant episodes of bleeding. According to the Response Evaluation Criteria in Solid Tumors (n = 17 evaluable patients), the median progression-free survival was 12.8 months (95% confidence interval [CI]: 6.9–17.2); according to the Modified Response Evaluation Criteria in Solid Tumors (n = 19 evaluable patients), the median progression-free survival was 8.6 months (95% CI: 6.1–10.9). For all patients, the disease control rate at 6 weeks was 90% and median overall survival time was 16.2 months (95% CI: 10.5–28.7). Conclusions Cediranib combined with cisplatin-pemetrexed has a reasonable toxicity profile and preliminary promising efficacy. The phase II S0905 trial will evaluate the efficacy of the triplet regimen compared with the current standard of care, cisplatin-pemetrexed.

Introduction Most patients with lung cancer are elderly and poorly represented in randomized clinical trials. They are often undertreated because of concerns about their ability to tolerate aggressive treatment. We tested the hypothesis that elderly patients undergoing definitive lung radiation might tolerate treatment differently than younger patients. Methods A total of 125 patients who underwent definitive lung radiotherapy were identified from a prospective institutional database (University of Michigan cohort). Logistic regression modeling was performed to assess the impact of age on esophagitis grade 2 or higher or grade 2 or higher and pneumonitis grade 3 or higher or grade 2 or higher, with adjustment for esophageal and lung dose, respectively, as well as for chemotherapy utilization, smoking status, and performance status. The analysis was validated in a large cohort of 691 patients from the Michigan Radiation Oncology Quality Consortium registry, an independent statewide prospective database. Results In the University of Michigan cohort, multivariable regression models revealed a significant inverse correlation between age and rate of esophagitis for both toxicity levels, (adjusted OR = 0.93 for both models and 95% confidence intervals of 0.88–0.98 and 0.87–0.99), with areas under the curve of 0.747 and 0.721, respectively, demonstrating good fit. This same association was noted in the Michigan Radiation Oncology Quality Consortium cohort. There was no significant association between age and pneumonitis. Conclusions There is a lower incidence of esophagitis with increasing age even after adjustment for use of chemotherapy. This is a novel finding in thoracic oncology. No age dependence was noted for pulmonary toxicity. The elderly are able to tolerate definitive thoracic radiation well and should be offered this option when clinically warranted.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by early metastatic spread and responsiveness to initial therapy. The incidence of SCLC has been declining in the United States in parallel with the decreasing prevalence of cigarette smoking. Limited stage disease is potentially curable with chemoradiotherapy followed by cranial irradiation. Extensive stage disease is incurable, but systemic chemotherapy can improve quality of life and prolong survival. Nearly all patients relapse with chemoresistant disease. Molecularly targeted therapy has failed to yield convincing clinical benefits. Nevertheless, many biologically rational strategies, including immune checkpoint inhibition, show promise in ongoing clinical trials.

Background The hepatocyte growth factor receptor gene ( MET ) exon 14 skipping ( METex14 ) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-to-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs). Methods Well-validated hybrid capture–based comprehensive genomic profiling was performed at the request of individual treating physicians. Results Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14 , including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtype not otherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and SCLC (0.2%). Acinar features were present in 24% of the METex14 samples. Six cases (2%) harbored MET Y1003X mutations affecting binding of the MET-negative regulator, E3 ubiquitin protein ligase. The median age of all patients with METex14 was 73 years (range 43–95) and 60% were female. Concurrent, murine double minute gene ( MDM2 ) amplification, cyclin-dependent kinase 4 gene ( CDK4 ) amplification, and EGFR amplification were observed in 35%, 21%, and 6.4% of patients with METex14 , respectively. KRAS mutation was observed in 3% of cases. Concurrent MET amplification ( MET amp) (median copy number 10) was identified in 15% of METex14 samples. Significant differences in tumor mutational burden and type of the METex14 alterations were observed between the MET amp and non- MET amp samples. Response to MET TKI was observed in both in patients with MET amp and in patients without MET amp METex14 . Conclusion Diverse targetable METex14 alterations were identified in patients with NSCLC across age groups, including elderly patients, and in all major NSCLC histologic subtypes with an overall frequency of 2.7%. These findings support the use of hybrid capture–based molecular profiling across NSCLC subtypes to identify patients who will potentially benefit from MET TKIs.

Introduction: Perfusion (Q) single photon emission computed tomography (SPECT) has been used to divert dose away from higher-functioning lung during radiation therapy (RT) planning. This study aimed to (1) study regional lung function through coregistered pulmonary ventilation/perfusion (V/Q)-SPECT-CT and (2) classify these defects for its potential value in radiation planning in patients with non-small cell lung cancer (NSCLC). Methods: Patients with stages I to III NSCLC requiring radiation-based therapy were eligible for this prospective study. V/Q-SPECT performed within 2 weeks before the start of radiation was interpreted by nuclear medicine physicians and then measured by a semiquantitative score. The potential mechanism of V and Q defects was analyzed; the potential impact of V/Q-SPECT over Q-SPECT alone was completed through classified applications (high-dose RT versus RT avoidance) during planning. Results: Images of 51 consecutive patients were analyzed. The V and Q defects were matched, reverse mismatched (V defect > Q defect), and mismatched (Q defect > V defect) in 61, 31, and 8% of patients, respectively. Tumor was the leading cause of the defects of ipsilateral lung in 73% of patients. The defect scores of the ipsilateral lung were greater in patients with central primaries than those with peripheral primaries for both V-SPECT (2.3 ± 1.1 versus 1.5 ± 0.8, p = 0.017) and Q-SPECT (2.2 ± 0.8 versus 1.4 ± 0.6, p = 0.000). The patients with chronic obstructive pulmonary disease had greater defect scores in contralateral lung for both V-SPECT (1.5 ± 0.7 versus 1.0 ± 0.8, p = 0.006) and Q-SPECT (1.4 ± 0.6 versus 1.0 ± 0.4, p = 0.010). On assessing the potential value of SPECT on RT plan, 39% of patients could have their RT plan when applying V/Q-SPECT rather than Q-SPECT alone. Conclusions: V/Q-SPECT provides a more comprehensive functional assessment, may provide additional value over Q-SPECT alone in assessing local pulmonary function, and guide RT plan decisions in patients with NSCLC.

Background The prognosis for patients with extensive-stage small-cell lung cancer remains poor. This trial was designed to evaluate irinotecan/cisplatin plus maintenance imatinib in patients with c-Kit–positive disease (the transmembrane receptor c-Kit is the product of the c-KIT protooncogene). Patients and Methods Immunohistochemistry for c-Kit was performed before enrollment. Treatment consisted of irinotecan 65 mg/m 2 on days 1 and 8 plus cisplatin 60 mg/m 2 on day 1 and every 21 days for 4 cycles. Imatinib was administered at 400 mg twice a day until progression or unacceptable toxicity occurred. Results Fourteen patients were enrolled. Slow accrual led to early study termination. Six patients did not begin treatment with imatinib because of disease progression, persistent toxicity, or referral for radiation therapy. Eight patients had a partial response with irinotecan/cisplatin and received imatinib. The median number of weeks on imatinib was 6.1 (range, 4.1-25.1 weeks). Reasons for imatinib discontinuation included disease progression (n = 7) and persistent neutropenia (n = 1). No objective responses to imatinib were evident, but 3 patients (21%) exhibited stable disease for 12, 15, and 25 weeks. The median progression-free survival was 4.3 months (95% CI, 2.9-4.8 months). The median overall survival was 7.8 months (95% CI, 5.7-10.0 months). The irinotecan/cisplatin regimen was well tolerated (grade 1/2 neutropenia, 29%; anemia, 43%; thrombocytopenia, 14%; and diarrhea, 29%), except in 1 patient with grade 3 vomiting. Imatinib toxicity included grade 1/2 nausea in 50% of the patients, peripheral edema in 75% of the patients, grade 3 fatigue in 13% of the patients, and neutropenia in 13% of the patients. Conclusion Despite the selection of tumors expressing c-Kit, imatinib did not appear to delay disease progression after response to chemotherapy. However, this trial was underpowered because of its early termination. Although disease stability with imatinib was evident in 3 patients and the therapy was well tolerated, this approach does not appear to warrant further clinical study.

Introduction To evaluate the efficacy and toxicity of the combination of celecoxib and docetaxel in patients with advanced non-small cell lung cancer after failure of platinum-based therapy. Methods Patients with relapsed non-small cell lung cancer received celecoxib 400 mg orally twice daily beginning 7 days before the first cycle of docetaxel and the celecoxib was continued with no interruption. Docetaxel 75 mg/m 2 was administered intravenously on a 21-day cycle. The primary end point of the study was the 6-month survival rate. Results Twenty-four patients were enrolled and twenty patients were treated (median age 60, M:F 16:8). Most patients had a baseline performance status of 1. The objective response rate was 10% (95% confidence interval [CI], 0–25%) and the 6-month survival rate was 59% (95% CI 37–80%). Median survival time was 6.9 months (95% CI, 2.8–15.2 months) and the 1- and 2-year survival rates were 36% (95% CI, 15–57%) and 1% (95% CI, 0–10%), respectively. The most frequent grade ≥3 adverse events were neutropenia (58%) and neutropenic fever (21%) which resulted in early closure of the trial. Conclusions The addition of celecoxib to docetaxel did not seem to improve the response rate and survival compared with docetaxel alone. The combination demonstrated considerable neutropenia and complications from febrile neutropenia that suggests celecoxib may enhance the marrow toxicity of docetaxel.

We aimed to report the final toxicity results on a radiation-dose escalation trial designed to test a hypothesis that very high doses of radiation could be safely administered to patients with non-small-cell lung cancer (NSCLC) by quantifying the dose-volume toxicity relationship of the lung.A total of 109 patients with unresectable or medically inoperable NSCLC were enrolled and treated with radiation-dose escalation (on the basis of predicted normal-lung toxicity) either alone or with neoadjuvant chemotherapy by use of 3D conformal techniques. Eighty-four patients (77%) received more than 69 Gy, the trial was stopped after the dose reached 103 Gy. Estimated median follow-up was 110 months.There were 17 (14.6%) Grade 2 to 3 pneumonitis and 15 (13.8%) Grade 2 to 3 fibrosis and no Grade 4 to 5 lung toxicity. Multivariate analyses showed them to be (1) not associated with the dose prescribed to the tumor, and (2) significantly (p0.001) associated with lung-dosimetric parameters such as the mean lung dose (MLD), volume of lung that received at least 20 Gy (V20), and the normal-tissue complication probability (NTCP) of the lung. If cutoffs are 30% for V20, 20 Gy for MLD, and 10% for NTCP, these factors have positive predictive values of 50% to 71% and negative predictive value of 85% to 89%.With long-term follow-up for toxicity, we have demonstrated that much higher doses of radiation than are traditionally administered can be safely delivered to a majority of patients with NSCLC. Quantitative lung dose-volume toxicity-based dose escalation can form the basis for individualized high-dose radiation treatment to maximize the therapeutic ratio in these patients.

Objectives In order to further characterize the effect of gender on the clinicopathologic features and survival of patients with lung cancer, and to determine gender-associated differences in temporal trends, we analyzed data that had been entered into a population-based cancer database Patients and methods Data on demographics, stage at diagnosis, histology, initial therapy, and survival were obtained on all patients with primary bronchogenic carcinoma registered in the national Surveillance, Epidemiology, and End Results database from 1975 to 1999 Results Of the 228,572 eligible patients, 35.8% were female. The median age at diagnosis was 66 years for both men and women. However, women accounted for 40.9% of patients who were Conclusion The incidence rate of lung cancer in women in the United States has reached a plateau. However, women are relatively overrepresented among younger patients, raising the question of gender-specific differences in the susceptibility to lung carcinogens. At each stage of the disease, the relative survival of women is better than that of men, with the largest difference noted in patients with local disease

Study objectives: We analyzed data from a community-based cancer database over a 26-year period in order to characterize clinicopathologic differences between black and white patients with lung cancer, and to identify relevant temporal trends in incidence and survival. Design, setting, and patients: Data on demographics, stage, histology, and survival were obtained on all black and white patients with primary bronchogenic carcinoma registered in the community-based metropolitan Detroit Surveillance, Epidemiology, and End Results database from 1973 to 1998. Results: Of 48,318 eligible patients, 23% were black. Lung cancer incidence rates decreased for men of both races from 1985 to 1998, with a greater decline occurring in black men (p < 0.0001). Although incidence rates declined over time for men of both races < 50 years of age, this decrease was greater in white men, resulting in an increase in the racial differential in younger men. Temporal trends in incidence rates were similar for women of both races. The incidence of distant-stage disease was higher among blacks throughout the study period. The incidence of local-stage disease decreased for both races, though this decline was greater in blacks. A significant racial difference in 2-year and 5-year survival rates developed during the study period, due to a distinct lack of improvement in black patients. In a multivariate model, the relative risks of death for black patients, relative to white patients, were 1.24 (p < 0.0001) for local stage, 1.14 (p < 0.0001) for regional stage, and 1.03 (p 5 0.045) for distant stage. Conclusion: Significant racial differences exist in the incidence and survival rates for lung cancer in metropolitan Detroit. Since 1973, several disturbing trends have developed, particularly with regard to the lack of improvement in overall survival in black patients. Further study is required to determine the factors responsible for these temporal trends. (CHEST 2001; 120:55‐ 63)

Although combined modality therapy appears to be superior to radiotherapy alone for the treatment of locally advanced non-small cell lung cancer (NSCLC), the optimal treatment regimen has not been determined. We designed this trial to determine the maximal tolerated doses (MTD) of continuous intravenous infusion (CI) cisplatin and etoposide that could be administered concurrently with thoracic irradiation.19 patients with stage IIIA or IIIB NSCLC were treated at three different dose levels of CI cisplatin and etoposide with concurrent single daily fraction thoracic radiotherapy to 4500 cGy. This chemoradiotherapy phase of treatment was followed by a 1500-2000 cGy radiotherapy boost and three cycles of standard intermittent bolus cisplatin 80 mg/m2 i.v. on day 1 and etoposide 80 mg/m2 i.v. on days 1, 2 and 3.The MTD of CI chemotherapy was determined to be cisplatin 5 mg/m2/day plus etoposide 18 mg/m2/day for 5 days per week over 5 weeks along with thoracic irradiation. Overall, 37% of patients required breaks in the chemoradiotherapy course and 32% required attenuation of the planned duration of CI chemotherapy. Only 42% of patients received all three planned cycles of bolus chemotherapy and 16% received6000 cGy of thoracic irradiation. The major toxicities during concurrent chemoradiotherapy were grade 3-4 esophagitis (42%) and myelosuppression (47%). Subsequent chemotherapy was complicated by grade 3-4 myelosuppression in 38% of patients. An objective response was documented in 58% of patients (CR 11%, PR 47%). Median survival was 18 months with 2- and 5-year survival rates of 42 and 11%, respectively.These results demonstrate that CI cisplatin and etoposide can be administered safely to patients with locally advanced NSCLC, and that such potentially radiosensitizing strategies deserve further evaluation in this setting.

Despite recent advances in combined modality therapy, long-term survival remains elusive in most patients with limited-stage small cell lung cancer (SCLC). The present study was designed to evaluate the activity and toxicity of concurrent hyperfractionated radiotherapy and weekly, alternating-regimen chemotherapy. Twelve patients with limited-stage SCLC and performance status 0-1 were treated with cyclophosphamide 250 mg/m 2 , etoposide 100 mg/m 2 , and cisplatin 50 mg/m 2 on day 1 every other week, and vincristine 1 mg/m 2 on day 8, and ifosfamide 1.2 mg/m 2 on days 8 and 9 every other week. Hyperfractionated thoracic radiotherapy, consisting of three daily doses of 1.1 Gy for 20 days to a total dose of 66 Gy, was started on day 1 of chemotherapy. Ten patients (83%) exhibited an objective response (9 CRs and 1 PR) with a median duration of response of 8.6 months. Two complete responders died at 50 and 53 months without evidence of progression and two remain alive and free of SCLC at 73 and 87 months. Median survival was 19.8 months with 2- and 5-year survival rates of 50 and 17%, respectively. Severe toxicity, including grade 3–4 esophagitis (67%) and granulocytopenia (83%), as well as debilitating fatigue and pneumonitis, prompted early termination of the trial. Hyperfractionated radiotherapy and concurrent weekly alternating-regimen chemotherapy resulted in promising response and survival rates, but induced excessive toxicity, in patients with limited-stage SCLC.

Small cell lung cancer (SCLC) cells express a variety of neuropeptides which act as autocrine growth factors. Although several neuropeptide analogs have been reported to antagonize SCLC proliferation, the development of these compounds has been limited by their low potency and the cytostatic nature of their effects. In the present study we evaluated the cytotoxic activity of four short-chain substance P analogs (NY3460, NY3238[-pHOPA], NY3238[Phe1], NY3238[Lys5]) against a panel of five SCLC cell lines. NY3460 was the most potent compound in all five SCLC cell lines (IC50 = 2.8–3.7 μ M) as assessed by a MTT growth inhibitory assay. NY3238[Phe1] was also relatively active in all cell lines (IC50 = 3.5–11.2 μ M), while NY3238[Lys5] and NY3238[-pHOPA] were substantially less active. NY3460 was the only agent to induce an increase in the percentage of cells with subdiploid DNA content suggestive of apoptosis by flow cytometric DNA content analysis. The induction of apoptosis was confirmed by fluorescent microscopy in NCI-H69, NCI-H82, NCI-H446, and NCI-H510 cells after exposure to 5.0 μ M NY3460 for 48 h. These findings suggest that NY3460 is a relatively potent cytotoxic inhibitor of SCLC growth, and that short-chain neuropeptide analogs deserve further evaluation as anti-SCLC agents.

Expression of v-ras(H) in NCI-H82 human small cell lung cancer (SCLC) cells results in a line (NCI-H82ras(H)) with a non-small cell phenotype (Mabry et al., Proc Natl Acad Sci USA 85: 6523-6527, 1988). This v-ras(H) -associated phenotypic change is prevented by treatment with trans-retinoic acid (tRA) (Kalemkarian et al., Cell Growth Differ 5: 55-60, 1994). The present studies were performed to examine changes in drug sensitivity that accompanied these phenotypic changes. v-ras(H) expression was associated with increased metallothionein-IIa (MT-IIa) mRNA and decreased levels of nonprotein sulfhydryls in NCI-H82ras(H) cells compared with -H82 cells. These changes were accompanied by the development of CdCl2 resistance without any change in cisplatin sensitivity. In contrast, growth of parental NCI-H82 cells in 1 microM tRa resulted in increased MT-IIa mRNA without any change in nonprotein sulfhydryls. In these cells, a 3.3-fold increase in cisplatin IC50 was observed. Examination of the action of topoisomerase (topo) poisons revealed that NCI-H82 and -H82ras(H) cells had indistinguishable levels of topo II polypeptides and indistinguishable sensitivities to etoposide, an agent that is often combined with cisplatin clinically. On the other hand, v-ras(H) expression was accompanied by a 2-fold increase in topo I activity and a 1.7-fold decrease in IC50 for the topo I-directed agent camptothecin. These changes resulted in 30-fold lower survival of NCI-H82ras(H) cells compared with -H82 cells at camptothecin concentrations as low as 10 nM. In summary, these studies demonstrate that chronic tRA treatment is accompanied by decreased cisplatin sensitivity in NCI-H82 human SCLC cells. In contrast, v-ras(H) expression is not associated with any change in cisplatin or etoposide sensitivity, but is accompanied by increased camptothecin sensitivity.

2. The binary logistic regression analysis:  Pericardium V50 was positively associated with PCE; while the age, hypertension were negatively with the PCE. • The mean, maximum dose, and V5-V65 for heart were not significantly related to PCE. 3. The cox regression analysis:  Pericardium V55 was positively associated with survival; while the radiation tumor dose was negatively with the survival. • The mean, maximum dose, and V5-V65 for heart were not significantly related to survival.

Aim: The Notch pathway plays a central role in embryonic development, the regulation of stem and progenitor cells, and is implicated centrally in many human cancers, including SCLC. OMP-59R5, a fully human IgG2 antibody, inhibits signaling of Notch2 and 3 receptors. Anti-tumor activity was noted in 7 of 9 pt-derived SCLC xenografts expressing Notch 2 and 3 with OMP-59R5 treatment. The maximum tolerated dose (MTD) of single agent OMP-59R5 was 7.5mg/kg IV every 3 weeks (Smith, EORTC 2012); the main dose-limiting toxicity (DLT) was Grade 3 diarrhea. This study is to determine the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of OMP-59R5 in combination with EP in ED-SCLC. Methods: Cohorts of 3 to 6 pts were treated at each dose level of OMP-59R5. OMP-59R5 was given IV on Day 1 of each 21 day cycle along with etoposide 100 mg/m2 on Days 1, 2, and 3 and cisplatin 80 mg/m2 on Day 1. After 6 cycles, pts continued OMP-59R5 alone every 21 days in the absence of disease progression or unacceptable toxicities. Results: By April 4, 2014, 11 pts were treated. One DLT of Grade 3 nausea was reported from a subject in the 10 mg/kg dose cohort that lasted more than 48 hours despite daily IV fluids and antiemetics. Frequently reported (≥30%) adverse events (all grades) regardless of relationship were: fatigue (81.8%), nausea (72.7%), anemia (63.6%), diarrhea (63.6%), decreased appetite (54.5%), weight loss (54.4%), hypomagnesemia (45.5%), peripheral edema (45.5%), dehydration (36.4%), neutropenia (36.4%), thrombocytopenia (36.4%), vomiting (36.4%) and elevated creatinine (36.4%). Of these, fatigue (54.5%), anemia (36.4%), diarrhea (36.4%) and nausea (36.4%) were considered related to OMP-59R5. The events were mostly Grade 1 or 2, and managed with supportive care. Additional data are below: OMP-59R5 Dose (mg/kg) 5 (n=3) 7.5 (n=3) 10 (n=5) Etoposide (mg/m2) 100 Cisplatin (mg/m2) 80 DLT evaluable 3 3 5 incidence - - 1 RECIST 1.1 evaluable 3 3 4 Best Response/ Partial Response 3 2 4 Stable Disease - 1 - Progressive Disease - - - pts still on treatment - 2 4 Conclusions: OMP-59R5 with EP is well tolerated. The MTD has not been reached. Encouraging anti-tumor activity is observed. Updated safety, PK/PD, and efficacy data will be presented. The Phase 2 part of PINNACLE will start in 2014. Disclosure: A. Kapoun: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; L. Xu: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; D. Hill: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; L. Zhou: Paid consultant for OncoMed Pharmaceuticals (sponsor); J. Dupont: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks. All other authors have declared no conflicts of interest.

Background Small cell lung cancer (SCLC) is a lethal disease for which there have been only small advances in diagnosis and treatment in the past decade. Our goal was to revise the evidence-based guidelines on staging and best available treatment options. Methods A comprehensive literature search covering 2004 to 2011 was conducted in MEDLINE, Embase, and five Cochrane databases using SCLC terms. This was cross-checked with the authors' own literature searches and knowledge of the literature. Results were limited to research in humans and articles written in English. Results The staging classification should include both the old Veterans Administration staging classification of limited stage (LS) and extensive stage (ES), as well as the new seventh edition American Joint Committee on Cancer/International Union Against Cancer staging by TNM. The use of PET scanning is likely to improve the accuracy of staging. Surgery is indicated for carefully selected stage I SCLC. LS disease should be treated with concurrent chemoradiotherapy in patients with good performance status. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle 1 or 2 of chemotherapy. Chemotherapy should consist of four cycles of a platinum agent and etoposide. ES disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. Prophylactic cranial irradiation prolongs survival in those individuals with both LS and ES disease who achieve a complete or partial response to initial therapy. To date, no molecularly targeted therapy agent has demonstrated proven efficacy against SCLC. Conclusion Evidence-based guidelines are provided for the staging and treatment of SCLC. LS-SCLC is treated with curative intent with 20% to 25% 5-year survival. ES-SCLC is initially responsive to standard treatment, but almost always relapses, with virtually no patients surviving for 5 years. Targeted therapies have no proven efficacy against SCLC.

Purpose/Objective(s): A recent analysis from 7 RTOG trials suggested that patients treated more than 63 Gy in 1.8 - 2 Gy fractions was significantly associated with better outcome. This study aims to examine whether higher dose (.70 Gy) through personalized prescription can further improve local regional tumor control and overall survival, particularly in patients treated with concurrent chemotherapy. Materials/Methods: This is a secondary analysis of prospective trials from one single Institution. Patients received a definitive dose of fractionated RT, enrolled in imaging and treatment trials, with a minimum follow-up of 6 months were eligible. For the imaging trial,subjectswere treated per standard practice(60 - 70Gy) with or without concurrentchemotherapy basedon the stage of the diseases. For the treatment protocol, all subjects had an opportunity of receiving individualized higher dose RT based on the timing of treatment, and dosimetry of OARs (mainly the normal tissue complication probability of both lungs). Tumor local regional and distant progression free and overall survival (LRPFS, DPFS, and OS) were computed for tumor control outcome assessment. Results: A total of 85 consecutive patients treated between 2004 and 2010 were eligible. The median physical dose was 70 Gy (range60-86Gy)in2to3.8Gydailyfractionations.MinimumFUforsurvivalptswas6months.TheRTdosesweresignificantly associated with LRPFS,DPFS and OS,with hazard ratios of 0.92 (P=0.001),0.94 (P=0.016) and 0.91 (P=0.001),respectively. The median LRPFS (95%CI) was 9.9 (7.5, 12.4) and not reached (not reached) months (P\0.001), for PD\and .70 Gy, respectively. In patients with ‘‘no’’ chemotherapy, median LRPFS was 8.3 (5.8, 10.8) and not reached (P =0.2), for PD\70 Gy and.70 Gy, respectively. For patients treated with concurrent chemotherapy, median LRPFS was 10.7 (8.4, 13.0) months and not reached (not reached) months (P = 0.001), for PD\70 Gy and .70 Gy, respectively. The median OS (95%CI) was 18.2 (10.9, 25.4) and 41.9 (20.6, 63.1) months (P = 0.003), for PD\and .70 Gy, respectively. In those with ‘‘no’’ chemotherapy, median OS was 18.2 (0, 38.6) and not reached (P = 0.443), for PD\70 Gy and .70 Gy, respectively. For patients treated with concurrent chemotherapy, median survival was 15.5 (6.5 - 24.4) and 41.9 (18.3 - 65.5) months (P = 0.003), for PD\70 Gy and .70 Gy, respectively. Using 74 Gy PD (75 percentile of dose) as a cut-off, the median OS and LRPFS were also significantly better in the higher dose group (\74 Gy vs. $ 74 Gy). Conclusions: High dose (.70 Gy) RT improves local regional tumor control and overall survival in patients with and without concurrent chemotherapy. Randomized trials are needed to validate this promising result.