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Small cell lung cancer (SCLC) is an aggressive, poorly differentiated neuroendocrine carcinoma with distinct clinical, pathological and molecular characteristics. Despite robust responses to initial chemotherapy and radiation, the prognosis of patients with SCLC remains poor with an overall 5-year survival rate of less than 10 %. Despite the fact that numerous molecularly targeted approaches have thus far failed to demonstrate clinical utility in SCLC, further advances will rely on better definition of the biological pathways that drive survival, proliferation and metastasis. Recent next-generation, molecular profiling studies have identified many new therapeutic targets in SCLC, as well as extreme genomic instability which explains the high degree of resistance. A wide variety of anti-angiogenic agents, growth factor inhibitors, pro-apoptotic agents, and epigenetic modulators have been evaluated in SCLC and many studies of these strategies are on-going. Perhaps the most promising approaches involve agents targeting cancer stem cell pathways and immunomodulatory drugs that interfere with the PD1 and CTLA-4 pathways. SCLC offers many barriers to the development of successful therapy, including limited tumor samples, inadequate preclinical models, high mutational burden, and aggressive tumor growth which impairs functional status and hampers enrollment on clinical trials.

Small cell lung cancer (SCLC) is an aggressive, poorly differentiated neuroendocrine carcinoma with distinct clinical, pathological and molecular characteristics. Despite robust responses to initial chemotherapy and radiation, the prognosis of patients with SCLC remains poor with an overall 5-year survival rate of less than 10 %. Despite the fact that numerous molecularly targeted approaches have thus far failed to demonstrate clinical utility in SCLC, further advances will rely on better definition of the biological pathways that drive survival, proliferation and metastasis. Recent next-generation, molecular profiling studies have identified many new therapeutic targets in SCLC, as well as extreme genomic instability which explains the high degree of resistance. A wide variety of anti-angiogenic agents, growth factor inhibitors, pro-apoptotic agents, and epigenetic modulators have been evaluated in SCLC and many studies of these strategies are on-going. Perhaps the most promising approaches involve agents targeting cancer stem cell pathways and immunomodulatory drugs that interfere with the PD1 and CTLA-4 pathways. SCLC offers many barriers to the development of successful therapy, including limited tumor samples, inadequate preclinical models, high mutational burden, and aggressive tumor growth which impairs functional status and hampers enrollment on clinical trials.

In phase I clinical trial design, it has become common to extend the protocol beyond the standard dose escalation phase (eg, the cohorts-of-three “3+3” algorithm, accelerated titration, or continual reassessment method [CRM] [1,2]), which estimates a maximum tolerated dose (MTD). This protocol extension, called a dose expansion cohort (DEC), treats additional patients at the estimated MTD, sometimes stratifying enrollment of the DEC by multiple disease sites. The typical aim is to ensure that a sufficient number of patients has been treated at the estimated MTD by the trial’s completion to begin to characterize efficacy, tolerability, and pharmacokinetic or pharmacodynamic (PK/PD) endpoints (3–11). Recent discussions have highlighted the increasing size and complexity of DECs as well as the need to prospectively justify corresponding aims and analyses, which may be lacking (9–11). This paper provides a statistically based assessment of DECs and offers recommendations based on these results. A systematic review of 611 single-agent phase I trials published from 2006 to 2011 found that 149 (24%) included a DEC, with the use of DECs increasing over time (9). Thirty-eight of these trials did not include any specific objectives for the DEC; among those that did, safety was most common (89 trials, 60%), followed by efficacy (50 trials, 34%). There is also heterogeneity in the size of DECs. Among the 149 trials identified by Manji, et al., the median DEC size was 17, and the range was two to 271 (9). In 10 case studies from Iasonos and O’Quigley, seven had a DEC of size less than 25, and the remaining three were 43, 97, and 100 (10). Dahlberg, et al. report a median DEC size of 27 from 60 phase I trials submitted at Harvard in 2011 (11). Reviewing all phase I trials at our institution (University of Michigan Comprehensive Cancer Center) currently enrolling patients (as of June, 2014), we found that 54 have a planned DEC in the trial protocol, with a median size of 19 and range of four to 105. Trials with a small DEC, eg, fewer than 25 patients, are of greatest relevance in a phase I context, where safety remains of primary importance and preliminary evidence of efficacy is secondary. Because these studies are not statistically powered to evaluate efficacy, they fall short of being true phase I/II trials. Recent papers have proposed dose-finding designs based on efficacy and toxicity (12–14). Although DECs may have additional endpoints beyond toxicity, a DEC strategy should first be rigorously evaluated with regard to patient safety, both to future patients, that is, finding the true MTD, as well as patients in the current trial, that is, treating many current patients at the true MTD (15–17). Thus, our focus here is on the role of DECs in traditional phase I designs based on toxicity considerations. A principled dose escalation mechanism should operate for the duration of the trial to satisfy the safety metrics just described. We support this assertion with a simulation study of trial designs with a 10 to 20 patient DEC. The benefit conferred by a DEC may depend on the trial design, and we evaluate two common dose escalation designs: the 3+3 algorithm and the CRM (18). Because the final sample size of a 3+3 is not predetermined, adding a DEC increases the size of a trial that might otherwise be small. In contrast, the sample size of the CRM design may be predetermined, leading to a decision between inclusion of a DEC following completion of the CRM or a larger CRM in which the dose assignment mechanism operates throughout the entire trial. In investigator-initiated trials at our institution, the CRM design is used exclusively, making this decision crucial and recurrent. To the best of our knowledge, however, the strategy of appending a DEC to a CRM trial has not been statistically justified. Thus, we consider a small CRM trial paired with a DEC and an equivalently sized “large” CRM trial with no DEC. Iasonos and O’Quigley provide guidance for safety monitoring during the DEC and present four strategies for reevaluating estimated dose-toxicity rates during and after the DEC based on safety or efficacy data (10). Also included was a simulation study of the 3+3 design to assess how frequently the final MTD estimate, after analyzing the DEC data, differs from the initial MTD estimate. Extending rule-based designs like the 3+3 with DECs is natural because such trials may otherwise terminate before enrolling enough patients to precisely evaluate secondary objectives such as efficacy or PK/PD (eg, 3–6). The authors found that the post-DEC MTD estimate from a complete analysis was more accurate than the pre-DEC estimate but did not report the frequency in which patients in the trial were assigned the true MTD. A final important and distinguishing feature of this paper is that we differentiate between the final estimated, or selected, MTD and the true, unknown MTD, the latter being the dose level that induces dose-limiting toxicity (DLT) in x% of patients, where x may be selected based on characteristics of a particular therapy. Treating more than six patients at the estimated MTD is the motivation for using DECs and drives how precisely efficacy endpoints such as response rates may be estimated. However, although it is often implicitly assumed that the MTD determined from the dose-escalation phase is the true MTD, eg, “[t]he MTD was defined as the highest dose level with DLTs in

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.

A patient who presented with weight loss and recurrent left lower lobe pneumonia was diagnosed with endobronchial carcinoid. Chest CT scan demonstrated extensive mediastinal and hilar lymphadenopathy suggesting stage IIIB disease, but radionuclide imaging with In-111 pentetreotide and F-18 FDG PET diagnosed 2 distinct pathologic processes based on functional differences between neuroendocrine tumors (expressing somatostatin receptors) and sarcoidosis (intensely FDG-avid). The possible association of carcinoid with sarcoidosis and sarcoid-like reactions in regional lymph nodes should always be considered, and the staging process should include both anatomic and functional imaging and biopsy confirmation of suspected metastatic lesions.

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

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors and a crucial regulator of cellular differentiation. Differentiation-inducing and antiproliferative effects of PPAR-gamma suggest that PPAR-gamma agonists might be useful as effective anticancer agents. Few studies have examined the efficacy of these agonists in animal models of tumorigenesis, and their mechanism(s) of action are still not clear. Our studies indicate higher PPAR-gamma expression in primary tumors from non-small-cell lung cancer (NSCLC) patients when compared to normal surrounding tissue. The expression of PPAR-gamma was also observed in several NSCLC lines. The treatment of lung adenocarcinoma cells (A549) with troglitazone (Tro), a PPAR-gamma ligand, enhanced PPAR-gamma transcriptional activity and induced a dose-dependent inhibition of A549 cell growth. The observed growth arrest was predominantly due to the inhibition of cell proliferation without significant induction of apoptosis. Cell cycle analysis of Tro-treated cells revealed a cell cycle arrest at G(0)/G(1) with concomitant downregulation of G(0)/G(1) cyclins D and E. In addition, Tro treatment stimulated sustained Erk1/2 activation in A549 cells, suggesting the activation of a differentiation-inducing pathway. Furthermore, treatment of A549 tumor-bearing SCID mice with Tro or Pio inhibited primary tumor growth by 66.7% and significantly inhibited the number of spontaneous lung metastatic lesions. Collectively, our data demonstrate that activation of PPAR-gamma impedes lung tumor progression and suggest that PPAR-gamma ligands may serve as potential therapeutic agents for NSCLC.

Although race, in and of itself, is not a relevant biologic variable, racial differences in disease characteristics and outcomes have been reported in many malignancies, including lung cancer. The lung cancer incidence rate in blacks has been consistently higher than that in whites for many years. This racial disparity is seen primarily in men and is significantly greater in younger age groups. The reason for higher lung cancer incidence rates in blacks remains unclear, but racial differences in smoking habits, socioeconomic variables, and the metabolism of tobacco carcinogens may all play an important role. Blacks are also more likely than whites to present with squamous cell carcinoma and with advanced-stage disease. A significant racial difference in survival rates has developed over the past 30 years, with a poorer prognosis noted in black patients, particularly those with local- and regional-stage disease. This disparity appears to be due to a lack of improvement in the survival of black patients with lung cancer, but the biological and/or societal basis for racial variations in survival have not been determined. In summary, significant racial differences exist in lung cancer incidence and survival rates. Further research is required to determine the factors responsible for these differences and to develop effective preventative and therapeutic interventions that will impact favorably on the incidence and prognosis of this disease.

Importance Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18 F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. Objective To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non–small-cell lung cancer (NSCLC). Design, Setting, and Participants A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. Intervention Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. Main Outcomes and Measures The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. Results The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45-83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63-86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2-year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%-92%) and 62% (95% CI, 43%-77%), respectively. Median overall survival was 25 months (95% CI, 12-32 months). The 2-year and 5-year overall survival rates were 52% (95% CI, 36%-66%) and 30% (95% CI, 16%-45%), respectively. Conclusions and Relevance Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion. Trial Registration clinicaltrials.gov Identifier:NCT01190527

EGFR resistant mutation, T790M, in lung adenocarcinoma is acquired through a specific cytosine deamination mechanism. Background: Epidermal growth factor receptor (EGFR) activation mutations occur in 15% of lung adenocarcinomas. This leads to constitutive activation of EGFR, which triggers multiple downstream survival and proliferation pathways. Currently, EGFR tyrosine kinase inhibitors (TKIs) are first line therapy for stage IV non-small cell lung cancer (NSCLC) patients with EGFR mutations. Despite initial significant response to TKIs, most tumors develop resistance. The main mechanism of resistance detected in 50-60% of cases is a cytosine to thymine (C>T) single nucleotide transition mutation at position 2369. This causes a threonine to methionine amino acid change at position 790 (i.e. T790M). Our data suggests that the C>T mutation is an acquired event secondary to cytosine deamination by Activation Induced Cytosine Deamination enzyme (AICDA). Results: Single cell clones of lung adenocarcinoma cell line, PC9, were treated with EGFR TKI. At baseline, these clones have EGFR exon 19 deletion but no evidence of T790M mutation by digital droplet PCR (ddPCR). However, after treatment with a serial increasing dose of EGFR TKI, T790M mutation was detected by ddPCR. Assessing whether cytosine deamination enzymes were altered by this treatment, a significant increase in AICDA expression was seen. Furthermore, recombinant AICDA protein could deaminate cytosine at position 2369 in vitro. In addition, using mass spectrometry and methylation specific primers, we determined that cytosine at position 2369 is in fact methylated. This further supports our hypothesis since 5-methyl cytosine is deaminated into thymine directly. Since in germinal center B-lymphocytes, AICDA is activated through a non-canonical NFkB mechanism, we assessed NFkB pathway in PC9 cell line. RelB and p52 expression were significantly increased after TKI treatment. In addition direct interaction between RelB and AICDA promoter was confirmed by ChIP Assay. These findings were also seen in a mouse PC9 xenograft model. Daily oral gavage of EGFR TKI caused significant increase in the expression of RelB as well as AICDA. Adding NFkB inhibitor twice weekly inhibited the expression of RelB and AICDA. Finally, knocking down AICDA by shRNA prevented the development of T790M mutation in PC9 cell lines after TKI exposure. Conclusion: Our data suggest that the T790M mutation could be actively acquired after TKI treatment through a cytosine deamination process by AICDA. This would have significant implications for treatment with targeted therapy. In fact, Imatinib resistance in CML and GIST tumors have a similar C>T single nucleotide transition mutation. Citation Format: Khaled Hassan, Najwa El Kadi, April Davis, Gregory Kalemkerian, Luo Wang, Hasan Korkaya. The development of EGFR resistant mutation, T790M, in lung adenocarcinoma is acquired through a specific cytosine deamination mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4119. doi:10.1158/1538-7445.AM2017-4119

e20607 Background: The PD-1 inhibitors nivolumab and pembrolizumab are approved for the treatment of advanced non-small cell lung cancer (NSCLC), but little is known about patterns of disease progression when these agents fail. Understanding patterns of failure is key to developing strategies to improve duration of response to these agents. Methods: We gathered clinical and radiographic data on patients treated at the University of Michigan and the Ann Arbor VA for advanced NSCLC with standard-dose nivolumab (n = 68) or pembrolizumab (n = 23) after progression on platinum-based chemotherapy. Sites of disease progression were described as local (within the same lobe as primary disease), nodal (thoracic), or distant. Results: 91 patients were evaluable, of whom 56 (61.5%) had progression of disease after an average duration of therapy of 3.2 months (95%CI, 2.6-3.8). 10 (17.9%) patients had progression at local sites alone, 3 (5.4%) at nodal sites alone, 12 (21.4%) at distant sites alone, and 31 (55.4%) at a combination of sites. Overall, 41 (73.2%) had progression at distant sites. There was no statistically significant difference in clinical factors ( i.e. age, histology, comorbidity index) between progressors vs. non-progressors or distant-progressors vs. non-distant progressors. Of 37 patients who had prior radiation, 17 (45.9%) had progression at an irradiated site, with patients who had local and/or nodal progression more likely to have received radiation at site of progression (p = 0.01). The most common distant sites of progression were liver (13), bone (10), and brain (9). Conclusions: The most common site of disease progression was distant, with the liver being the most commonly involved site. This may be due to the immunotolerogenic environment of the liver, which is characterized by high IL-10 concentration and propagation of suppressive regulatory T cells, which can dampen activation of cytotoxic T cells. Prior irradiation did not seem to prevent disease progression. Our preliminary analysis suggests that the efficacy of checkpoint inhibitors is hindered in immune-privileged sites. Strategies to overcome immune tolerance should be investigated to improve duration of response to these agents.

8504 Background: The median progression free survival (PFS) and overall survival (OS) following initial chemotherapy in ES-SCLC pts are 2 and 7 months, respectively (Ready N, J Clin Oncol 2015). We evaluated the benefits of maintenance pembro in ES-SCLC pts who had response/stable disease after 4-6 cycles of platinum/etoposide. Methods: Pts were required to begin pembro within 8 weeks of completion of chemotherapy, with restaging scans no more than 3 weeks prior to start of pembro. Prophylactic cranial radiation was permitted. Pts were treated with pembro 200 mg I.V. every 3 weeks for a maximum of 2 years. Disease assessment was done every 2 cycles for the first 6 cycles and then as per investigator discretion. Primary end point of the study was PFS. PFS according to immune related response criteria (irPFS) and OS were also assessed. Tumor tissue was analyzed for PD-L1 expression by the DAKO 22C3 antibody. Any level of expression was considered as positive for PDL1. Blood for circulating tumor cells (CTCs) was collected prior to first, second and third cycle of pembro. Results: Of the 45 pts enrolled, 55% were males and 22% had brain metastases. Median age was 66 years. The median time from end of chemotherapy to start of pembro was 5 weeks. Median number of pembro cycles was 4 (1-20 cycles). 35 pts had measurable disease at study entry. The disease control rate with pembro was 42% (1 CR, 3 PR, 15 SD). At a median follow up of 6 months, the median PFS was 1.4 months (90% CI-1.3-4.0) and the irPFS was 4.7 months (90% CI- 1.8-6.7). The median OS was 9.2 months (90% CI-6.1-15.2). 11 pts are still on therapy (3-20 cycles). The median CTC prior to pembro was 1 (0-256, n=37 pts). Each unit increase in baseline CTC correlated with worse PFS (p = 0.052; adjusted for brain mets, age and sex). PDL1 could be assessed in 35 pts and was positive in 1 pt. Most common adverse events were fatigue, nausea, cough and dyspnea. One pt developed atrio-ventricular conduction block and 1 pt type 1 diabetes. Conclusions: Maintenance pembro did not improve PFS in these patients but favorable OS suggests that some SCLC patients can benefit from maintenance pembro. Biomarkers to identify patients most likely to benefit from pembro need to be defined. Clinical trial information: NCT02359019.

Defining treatment-susceptible or -resistant populations of patients with cancer through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies, because potential patient populations are divided into ever smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists, and information developers.

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)

Small cell lung cancer (SCLC) is characterised by neuroendocrine differentiation, early metastatic potential and initial responsiveness to cytotoxic therapy. Unfortunately, despite recent therapeutic advances, most patients relapse and the overall five-year survival rate is only 5%. Standard treatment of SCLC consists of platinum-based combination chemotherapy, with thoracic irradiation added for patients with limited-stage disease. Several newer chemotherapeutic drugs have recently been shown to have significant activity in patients with untreated or relapsed SCLC. These agents include: the topoisomerase I inhibitors, topotecan and irinotecan; the taxanes, paclitaxel and docetaxel; the pyrimidine analogue, gemcitabine; and the vinca alkaloid, vinorelbine. Recent advances in our understanding of the molecular events involved in the pathogenesis and progression of SCLC have led to the identification of a variety of potential targets for novel therapeutic interventions. Strategies aimed at inhibiting the myriad of growth factor pathways that control the proliferation of SCLC cells, include: broad spectrum neuropeptide antagonists (e.g., substance P analogues); growth factor/receptor-specific inhibitors (e.g., anti-GRP monoclonal antibodies, bradykinin antagonist dimers); and a variety of selective protein kinase inhibitors. The importance of cell death pathways in carcinogenesis and treatment-resistance has led to several novel strategies targeting apoptotic mediators, such as bcl-2, that are frequently dysregulated in SCLC (e.g., bcl-2 antisense). Our current challenges are to further refine these promising therapeutic strategies, efficiently evaluate their activity in the clinical setting and integrate them into more effective treatment regimens to improve the overall prognosis of patients with SCLC.

Standard chemotherapeutic regimens, such as cisplatin and etoposide, may improve quality of life and prolong survival in patients with incurable non-small cell lung cancer (NSCLC). This trial was designed to evaluate the activity and toxicity of a regimen combining three of the most active agents against advanced-stage NSCLC: mitomycin C, etoposide, and cisplatin (MEP). Sixty-eight patients with stage IIIB (pleural effusion) or IV NSCLC received cisplatin 80 mg/m2 i.v. on day 1 and etoposide 80 mg/m2 i.v. on days 1, 2, and 3 every 3 weeks along with mitomycin C 10 mg/m2 i.v. on day 1 of the first and third cycles for a median of four cycles (range, 1-11). Median age was 59 years, and nine patients were enrolled after relapse from previously treated early-stage NSCLC. Eighty-eight percent of patients had stage IV disease, and 14 (21%) had brain metastases at diagnosis. Palliative radiotherapy was given to 10 patients (15%) before MEP and to 17 (25%) concurrent with MEP. The major toxicity of MEP was myelosuppression, with grade 3-4 neutropenia in 74% of patients. Sixteen patients (24%) had documented infections, and there were eight (12%) treatment-related deaths. Partial response was observed in 24 patients (35%) with a median duration of 4.4 months, (range 1.4-13 months). Median survival was 8.1 months (range, 1-34 months), and 1-year survival was 32%. The addition of mitomycin C to cisplatin and etoposide resulted in response and survival rates comparable with those achieved with standard regimens in patients with advanced NSCLC but was associated with substantial hematologic toxicity and unacceptable treatment-related mortality.

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.

The vascular endothelial growth factor (VEGF) family is a novel regulator of endothelial cell proliferation. We assessed the mRNA expression of VEGF, VEGF type C (VEGF-C) and their receptors together with the microvessel density (VD) and microlymphatic vessel density (LVD) in pursuit of their connection and prognostic value in malignant pleural mesothelioma (MPM). We used four human MPM cell lines, 54 MPM tumours and five normal pleural tissues. Expression levels for receptors and ligands were assessed by semiquantitative reverse transcriptase polymerase chain reaction analysis. Microvessels were highlighted by immunohistochemical staining for factor VIII. The discrimination of lymphatics was performed by enzyme-histochemistry for 5′-nucleotidase after adequate inhibition of non-specific activity. The expression levels of VEGF, VEGF-C and VEGFRs were high in all MPM cell lines. The percentages of tumours with higher expression compared to the mean values of normal pleural tissues were 31.5% (17/54) for VEGF, 66.7% (36/54) for VEGF-C, 20.4% (11/54) for fms-like tyrosine kinase (flt)-1, 42.6% (23/54) for kinase insert domain-containing recepter (KDR) and 59.3% (32/54) for flt-4. Significant positive correlations were found between VEGF-C and flt-4, VEGF and KDR, VEGF and flt-1 in tumour tissues. The association between LVD and VEGF-C expression level was especially strong (P < 0.0001, r = 0.63). There were also significant correlations between LVD and flt-4, and VD and VEGF. No correlation, however, was found between LVD and nodal metastasis. VD was a negative prognostic indicator in this study. The associations between VEGF/VEGF-C and vessel density suggest that these factors play an important role in angiogenesis and lymphangiogenesis in this tumour, and assessment of vascularity may be a useful prognostic indicator for MPM patients. © 1999 Cancer Research Campaign

BACKGROUND The role of thrombospondin-1 (TSP-1) in tumor angiogenesis and progression is controversial. The authors assessed the impact of TSP-1 as a prognostic indicator in malignant pleural mesothelioma (MPM). METHODS TSP-1 expression was assessed by reverse transcriptase-polymerase chain reaction using 5 normal pleural samples, 78 MPM tumors, and 43 surrounding normal lung samples. In MPM tumors, vascular endothelial growth factor (VEGF) expression also was examined. Differences between different valuables were analyzed using the Mann–Whitney U test. Survival curves were obtained by the Kaplan–Meier method and the survival rate was assessed by the log rank test. RESULTS TSP-1 was highly expressed in 74 of the 78 MPM tumors (95%) with a mean value of 2.27 ± 0.42 compared with normal pleura (0.50 ± 0.06) and surrounding normal lung (0.96 ± 0.20) (P = 0.05 vs. normal pleura and P = 0.0006 vs. surrounding normal lung). The mean TSP-1 expression was significantly greater in high VEGF-expressing tumors (2.63 ± 0.51) compared with low VEGF-expressing tumors (1.17 ± 0.39; P < 0.0001) and TSP-1 expression was lower in patients with TNM Stage III/IV disease (n = 60) (1.85 ± 0.37) than in patients with Stage I/II disease (n = 13) (4.46 ± 1.74) (P = 0.025). The TSP-1 expression levels in tumors with lymph node metastases were significantly lower than in those without lymph node metastases (P = 0.0305). Although high TSP-1 expression was associated with good prognosis in patients with low VEGF-expressing tumors, TSP-1 itself appeared to have no overall impact on survival. The methylation status of a CpG island associated with the TSP-1 promoter was evident in MPM tumor samples despite high levels of TSP-1 mRNA expression. CONCLUSIONS TSP-1 is overexpressed in MPM tumors but its expression is of little value as a prognostic indicator in MPM. However, the relations between TSP-1 and VEGF in MPM merit further investigation for possible innovative therapeutic interventions. Cancer 1999;85:2570–6. © 1999 American Cancer Society.

Human lung cancer cells, including small cell lung carcinoma (SCLC), frequently lose expression of retinoic acid receptor β (RAR-β) and are resistant to the growth inhibitory activity of all-trans retinoic acid (RA). To elucidate the role of RAR-β in the growth regulation of SCLC by retinoids, we restored RAR-β expression in RAR-β-negative H209 SCLC cells by retroviral transduction (H209-RAR-β). We found that H209-RAR-β, but not parental H209 cells, underwent growth inhibition upon RA treatment. RA-treated H209-RAR-β cells arrested in G1 and displayed reduced L-myc expression and cyclin-dependent kinase 2 (cdk2) activity compared with untreated cells. RA treatment of H209-RAR-β cells was also accompanied by increased expression of the cdk inhibitor p27Kip1, whereas no differences in the expression of L-myc or p27Kip1 were detected upon RA treatment of parental H209 cells. The RA-induced growth arrest of H82 SCLC cells, which express endogenous RAR-β, was also associated with reduced c-myc and increased p27Kip1 expression. We found that ectopic expression of p27Kip1 induced growth inhibition in both H209 and H82 cells, and that sustained myc expression in H209-RAR-β cells promoted the induction of apoptosis upon RA addition. Our observations indicate that RAR-β gene transfer can restore RA sensitivity in SCLC cells and suggest that myc and p27Kip1 may represent critical mediators of the RA-induced cell cycle arrest in SCLC cells expressing RAR-β. Int. J. Cancer 80:935–943, 1999. © 1999 Wiley-Liss, Inc.

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.

BACKGROUND The dysregulation of both myc gene expression and retinoid signaling pathways commonly occurs in small cell lung carcinoma (SCLC). Because preclinical data showed that all-trans-retinoic acid (RA) inhibited SCLC growth, altered myc expression, and blocked transition to a treatment-resistant phenotype, a Phase II trial was designed to determine the effects of the combination of RA, cisplatin, and etoposide in patients with SCLC. METHODS Patients with untreated, extensive stage SCLC were treated with up to 8 cycles of cisplatin, 60 mg/m2, intravenously (i.v.) on Day 1 and etoposide, 120 mg/m2, i.v. on Days 1-3 in addition to up to 1 year of oral RA, 150 mg/m2/day. RESULTS Of 22 assessable patients 1 had a complete response and 9 had a partial response, for an overall response rate of 45% (95% confidence interval, 24-68%). The median survival was 10.9 months and the 1-year survival was 41%. The median duration of chemotherapy was 6 cycles and the median duration of RA treatment was 2.8 months. Thirteen patients discontinued RA prematurely due to toxicity and only 4 responders were receiving RA at the time of recurrence. Toxicity-limiting RA treatment mainly was comprised of mucocutaneous changes and headaches. CONCLUSIONS RA at a dose of 150 mg/m2/day was tolerated poorly in combination with cisplatin plus etoposide, leading to early discontinuation of RA in the majority of patients. The hematologic toxicity, response rate, and survival were similar to those associated with cisplatin and etoposide in prior trials. Further studies with more active and less toxic agents will be required to determine the role of retinoids in the treatment of SCLC. Cancer 1998;83:1102-1108. © 1998 American Cancer Society.

PURPOSE A large community-based cancer registry was analyzed to determine if the clinicopathologic characteristics and/or survival rates of lung cancer patients under 50 years of age at diagnosis differ from those of patients 50 years of age or greater at diagnosis. PATIENTS AND METHODS Data regarding demographics, stage, histology, initial therapy, and survival were obtained on all patients with primary bronchogenic carcinoma registered in the metropolitan Detroit Surveillance, Epidemiology and End Results (SEER) registry from 1973 to 1992. RESULTS Of 31,266 patients, 9.0% were under 50 years of age at diagnosis. Females (40.1% v 31.2%; P < .001) and blacks (28.7% v 21.9%, P < .001) were overrepresented in the younger group compared with the older group. Younger patients had a significantly higher incidence of adenocarcinoma and were less likely to present with local-stage disease (18.6% v 25.2%; P < .001). Younger patients were significantly more likely to undergo surgery and/or combined-modality therapy. Relative survival at 5 years was significantly better in the younger group (16.1% v 13.4%; P < .001), mainly because of better survival in patients with local-stage disease (48.7% v 35.4%; P < .001). In a multivariate analysis, advanced-stage, nonsurgical initial therapy, age 50 years or greater at diagnosis, and male gender were independent negative prognostic factors. CONCLUSION The overrepresentation of females and blacks in the group of younger patients with lung cancer suggests an increased susceptibility to lung carcinogens in these populations. Overall, this study suggests that lung cancer is not a more aggressive disease in younger patients and that all patients with lung cancer should be managed along the same therapeutic guidelines.

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.

Cytogenetic and molecular analysis of DNA sequences with highly polymorphic microsatellite markers have implicated allele loss in several chromosomal regions including 3p, 6p, 6q, 8p, 9p, 9q, 11p and 14q in the pathogenesis of sporadic renal cell carcinomas (RCCs). Deletions involving the long arm of chromosome 7 have not been described in RCCs although they have been seen in several other tumor types. However, there have been no detailed analysis of loss of heterozygosity (LOH) of 7q sequences in sporadic RCCs. We therefore studied LOH for DNA sequences on 7q with 10 highly polymorphic markers in 92 matched normal/tumor samples representing sporadic RCCs including papillary, nonpapillary, and oncocytomas in order to determine whether allelic loss could be detected in a tumor type with no visible 7q rearrangements at the cytogenetic level. We found chromosome 7q allele loss in 59 of 92 cases (64%) involving one, two, or more microsatellite markers. The most common allele loss included loci D7S522 (24%) and D7S649 (30%) at 7q31.1-31.2, a region that contains one of the common fragile sites, FRA7G. By comparative multiplex PCR analysis, we detected a homozygous deletion of one marker in the 7q 31.1-31.2 region in one tumor, RC21. These results support the idea that a tumor suppressor gene in 7q31 is involved in the pathogenesis of sporadic renal cell carcinomas.

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.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.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.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.

For many years, small cell lung cancer (SCLC) has been staged using the Veterans Affairs classification system, which includes only 2 stages: limited (primary tumor and regional lymph nodes within a tolerable radiation field) and extensive (anything beyond limited stage). The TNM staging system used for non-small cell lung cancer is also prognostic for SCLC and should be integrated into the classification scheme for patients with SCLC. The staging workup for SCLC has traditionally included contrast-enhanced CT scans of the chest and abdomen, bone scan, and MRI or CT scan of the brain. Recent data suggest that PET can improve both staging accuracy and treatment planning in patients with SCLC, although further prospective studies are needed to fully define its role.

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.

Background : Lung cancer is the major cause of cancer-related death in the United States, with small-cell lung cancer (SCLC) constituting approximately 20% of all cases of lung cancer. Numerous epidemiologic and molecular studies have suggested that alterations in retinoid-signaling pathways play a role in the pathogenesis of lung cancer. Fenretinide [N-(4-hydroxyphenyl)retinamide ; HPR] is a synthetic retinoid with minimal toxicity and favorable pharmacokinetics during long-term administration to patients in clinical trials. Purpose : The aim of this investigation was to study the effect of HPR on the growth of SCLC cells in vitro. Methods : Seven SCLC cell lines (NCI-H69, NCI-H82, NCI-H146, NCI-H209, NCI-H345, NCI-H446, and NO.H510A) were exposed continuously to a broad range of concentrations of HPR or all-trans-retinoic acid (RA), and cell viability was determined on day 3 and day 7 by the trypan blue dye exclusion assay. The growth of these cells was compared with that of control vehicle-treated cells to determine survival fraction and the dose resulting in a 50% inhibition of growth when compared with growth of control cells (IC 50 ). The induction of apoptosis was evaluated by fluorescent microscopy, DNA content analysis, and a terminal deoxyribonucleotidyl transferase-based assay that labels 3'-hydroxyl ends of DNA fragments (TUNEL assay) combined with flow cytometric analysis. Results : HPR inhibited growth of a panel of SCLC cell lines at IC 50 values that ranged from 0.1 to 3.0 μM (concentrations that are clinically achievable). In all cell lines tested, HPR was a more potent growth inhibitor than RA. By use of fluorescent microscopy, HPR was found to induce morphologic changes consistent with apoptosis in NCI-H82 SCLC cells, including cellular shrinkage, chromatin condensation, and nuclear fragmentation. Flow cytometric analysis revealed decreased DNA content, and TUNEL assay showed increased digoxigenin-uridine triphosphate incorporation in HPR-treated NCI-H82 SCLC cells ; these findings are consistent with the induction of apoptosis. Conclusions : HPR inhibited the in vitro growth of SCLC cells. In NCI-H82 cells, HPR inhibited growth via the induction of apoptosis.

9017Background: Immune checkpoint inhibitor (ICPI) therapies, including nivolumab and pembrolizumab, have been FDA-approved in squamous and non-squamous non-small cell (LC). Current IHC based diagnostics are challenged by assay and slide scoring issues, and more robust and comprehensive biomarkers of ICPI efficacy are needed. Methods: Comprehensive genomic profiling (CGP) was performed on FFPE specimens during the course of clinical care. TMB (mutations/Mb) was assessed as the number of somatic, coding, base substitution and indel alterations per Mb of genome. The top quartile of LC was classified as TMB high. Microsatellite instable (MSI-H) or stable (MSS) status was determined using a proprietary computational algorithm. Results: TMB was similar across all LC histologies, but elevated compared to an average TMB of 7.3 for all 60,000+ samples in the database. TMB was consistently low in LC harboring known drivers, with the exception of BRAF or KRAS mutant tumors. (See Table.) 22/5,895 LC cases (0.4%) ass...

Lung cancer is a heterogenous disease with 2 main subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Early-stage NSCLC is managed primarily by surgical resection, with adjuvant chemotherapy for selected patients with stage IB, II, and III disease. Patients with locally advanced stage III NSCLC are usually treated with combined modality therapy. Advanced NSCLC remains an incurable disease. Further advances will rely on improvements in understanding of the molecular events driving the malignant phenotype and the development of novel, targeted therapeutic strategies.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) allow many systemic therapy options for patients with metastatic non-small cell lung cancer (NSCLC). This analysis uses the NCCN NSCLC Outcomes Database to report on first-line therapy practice patterns and concordance with NCCN Guidelines. The analysis was limited to patients diagnosed with metastatic NSCLC between September 2006 and November 2009 at 1 of 8 participating NCCN Member Institutions. Patient characteristics, regimens used, and guidelines concordance were analyzed. Institutional variation and changes in practice over time were also measured. A total of 1717 patients were included in the analysis. Of these, 1375 (80%) were treated with systemic therapy, most often in the form of a carboplatin-based doublet (51%) or carboplatin-based doublet with targeted therapy (17%). Overall, 76% of patients received care that was concordant with NCCN Guidelines. Among patients with good performance status (n = 167), the most common reasons for not receiving first-line therapy were that therapy was not recommended (39%) or death occurred before treatment (33%). The most common reason for receiving nonconcordant drug therapy was the administration of pemetrexed or erlotinib before its incorporation into the NCCN Guidelines for first-line therapy (53%). Most patients in this cohort received care that was concordant with NCCN Guidelines. The NSCLC Outcomes Database is a valuable resource for evaluating practice patterns and concordance with NCCN Guidelines among patients with NSCLC.

The objectives of this study were to evaluate survival among current smokers, former smokers, and never smokers who are diagnosed with non-small cell lung cancer (NSCLC).The study included patients who participated in the National Comprehensive Cancer Network's NSCLC Database Project. Current, former, and never smokers were compared with respect to overall survival by fitting Cox regression models.Data from 4200 patients were examined, including 618 never smokers, 1483 current smokers, 380 former smokers who quit 1 to 12 months before diagnosis, and 1719 former smokers who quit12 months before diagnosis. Among patients with stage I, II, and III disease, only never smokers had better survival than current smokers (hazard ratio, 0.47 [95% confidence interval, 0.26-0.85] vs 0.51 [95% confidence interval, 0.38-0.68], respectively). Among patients with stage IV disease, the impact of smoking depended on age: Among younger patients (aged ≤55 years), being a never smoker and a former smoker for ≥12 months increased survival. After age 85 years, smoking status did not have a significant impact on overall survival.Patients who were smoking at the time of diagnosis had worse survival compared with never smokers. Among younger patients with stage IV disease, current smokers also had worse survival compared with former smokers who quit12 months before diagnosis. It is likely that tumor biology plays a major role in the differences observed; however, to improve survival, it is prudent to encourage all smokers to quit smoking if they are diagnosed with NSCLC.

Recent advances in basic research have greatly increased our understanding of the biologic events involved in the pathogenesis and progression of lung cancer. A multitude of genetic aberrations have been detected in both small-cell and non-small-cell lung cancer, many of which affect the function of known oncogenes and tumor-suppressor genes, which may serve as molecular targets for interventional trials. Recently identified abnormalities in oncogene expression and signal transduction pathways in premalignant lesions will be useful in devising future early diagnosis and chemoprevention studies. Numerous growth factor pathways control the proliferation and invasiveness of lung cancer cells and offer relatively tumor-specific targets for novel therapeutic approaches. Recent studies have defined several drug resistant mechanisms in lung cancer and have suggested methods for preventing and reversing treatment resistance. Insight into the biology of lung cancer will allow the improvement of current approaches to the prevention, diagnosis, and treatment of this devastating disease.

EGFR and KRAS mutation analyses are of increasing importance for guiding the treatment of non–small cell lung carcinomas. Insufficient cellularity of cell blocks can represent an impediment to the performance of these tests. We investigated the usefulness of cytologic direct smears as an alternative specimen source for mutation testing. Tumor cell–enriched areas from freshly prepared and archived rapid Romanowsky–stained direct smears in 33 cases of lung carcinoma were microdissected for DNA isolation and evaluated for EGFR and KRAS mutations. EGFR mutations were detected in 3 adenocarcinomas; 2 tumors had the L858R substitution and 1 an exon 19 deletion. KRAS mutations affecting codon 12, 13, or 61 were detected in 11 cases (8 adenocarcinomas and 3 non–small cell carcinomas). EGFR and KRAS mutations were mutually exclusive. Hence, archived and freshly prepared direct smears represent a robust and valuable specimen source for molecular studies, especially when cell blocks exhibit insufficient cellularity.

Objective To determine the optimal anatomic coverage at CT that would provide the most accurate staging for patients with non-small cell lung cancer. Methods We reviewed lung cancer staging PET-CT scans and correlated them with staging chest CT scans performed within 50 days of the PET-CT study. There were 113 patients who underwent both studies within our time frame. We reviewed the results of subsequent imaging studies and surgical and biopsy procedures to determine the final stage for each patient. This study was approved by the local institutional review board. Results In 86 (76%) of 113 patients, staging by PET-CT and by CT from the lung apices through the lung bases was identical. PET-CT upstaged 21 patients (19%) compared with CT findings; in 13 of these patients the PET-CT noted disease that was either outside of the anatomic range of any lung cancer staging CT or was within the area scanned by CT, but was not evident by CT. In the other 8 upstaged patients, extending the anatomic scope of the CT scan to the supraclavicular region (5), adrenal glands (2) or abdomen (1) would have resulted in correct staging. Conclusions CT scanning from the supraclavicular region through the caudal adrenal glands improves the accuracy of CT staging of lung cancer compared with scanning from the lung apices through the lung bases. Anatomic coverage beyond the adrenal glands has a low yield for improved staging, at the cost of requiring administration of oral contrast to all patients. Summary To determine the optimal anatomic coverage at CT that would provide the most accurate staging for patients with non-small cell lung cancer, we reviewed lung cancer staging PET-CT scans and correlated them with staging chest CT scans performed within 50 days of the PET-CT study. CT scanning from the supraclavicular region through the caudal adrenal glands improves the accuracy of CT staging of lung cancer compared with scanning from the lung apices through the lung bases. Anatomic coverage beyond the adrenal glands has a low yield for improved staging, at the cost of requiring administration of oral contrast to all patients undergoing lung cancer staging.

Use of PET is widespread and increasing in the United States, mainly for oncologic applications. In November 2006, the National Comprehensive Cancer Network (NCCN) gathered a panel of experts to review the literature and develop clinical recommendations for using PET scans in lymphoma and non-small cell lung, breast, and colorectal cancers. However, because its use is not restricted to these diseases, and evidence is accumulating for its application in other types of cancers, NCCN convened a second meeting in December 2008 to expand on the initial report. A multidisciplinary panel met to discuss the current data on PET application for various tumor types, including genitourinary, gynecologic, pancreatic, hepatobiliary, thyroid, brain, small cell lung, gastric, and esophageal cancers, and sarcoma and myeloma. This report summarizes the proceedings of this meeting, including discussions of the background of PET, the role of PET in oncology, principles of PET use, emerging applications, and possible future developments.

Purpose To determine whether time to treatment (TTT) has an effect on overall survival (OS) in patients with unresectable or medically inoperable Stage III non–small cell lung cancer (NSCLC) and whether patient or treatment factors are associated with TTT. Methods and Materials Included in the study were 237 consecutive patients with Stage III NSCLC treated at University of Michigan Hospital (UM) or the Veterans Affairs Ann Arbor Healthcare System (VA). Patients were treated with either palliative or definitive radiotherapy and radiotherapy alone ( n = 106) or either sequential ( n = 69) or concurrent chemoradiation ( n = 62). The primary endpoint was OS. Results Median follow-up was 69 months, and median TTT was 57 days. On univariate analysis, the risk of death did not increase significantly with longer TTT ( p = 0.093). However, subset analysis showed that there was a higher risk of death with longer TTT in patients who survived ≥ 5 years ( p = 0.029). Younger age ( p = 0.027), male sex ( p = 0.013), lower Karnofsky Performance Score (KPS) ( p = 0.002), and treatment at the VA ( p = 0.001) were significantly associated with longer TTT. However, on multivariate analysis, only lower KPS remained significantly associated with longer TTT ( p = 0.003). Conclusion Time to treatment is significantly associated with OS in patients with Stage III NSCLC who lived longer than 5 years, although it is not a significant factor in Stage III patients as a whole. Lower KPS is associated with longer TTT.

Lung cancer is the leading cause of cancer-related death in the world and 90% of all cases are caused by tobacco smoking. Lung cancer is divided into two major histologic subtypes, non-small cell (NSCLC) and small cell (SCLC), with distinct biological behavior, genetic alterations, and therapy. Thus far, screening for lung cancer has not been proven effective since no modality has been shown to decrease mortality. Most patients with both SCLC and NSCLC present with symptoms of either locally advanced or metastatic disease, with only about 25% of patients with NSCLC having early-stage, resectable disease. For patients with stage I or II NSCLC, surgical resection is the treatment of choice and results in long-term survival in 60–80% or 40–50% of patients, respectively. For patients with stage III, locally advanced NSCLC or limited-stage SCLC, aggressive chemotherapy plus radiotherapy can offer a cure in 20–25% of patients. Stage IV, or metastatic, NSCLC and extensive-stage SCLC are incurable diseases in which chemotherapy can prolong survival and palliate symptoms. Recent advances in our understanding of the molecular biology of lung cancer have led to novel therapeutic strategies targeting relevant pathways that regulate the proliferation and/or progression of lung cancer. Several of these molecularly targeted therapies have now demonstrated significant clinical benefits in subsets of patients with lung cancer.

Introduction The utility of two-drug chemotherapy regimens in elderly or performance status (PS 2) patients with advanced non-small cell lung cancer (NSCLC) remains to be established. Preclinical studies suggested that celecoxib, a Cyclooxygenase-2 inhibitor, has antitumor activity in NSCLC and can enhance the activity of chemotherapy drugs. We conducted a phase II study to evaluate the efficacy of the combination of weekly docetaxel and celecoxib in advanced NSCLC patients, who were either elderly (≥70 years) or PS2. Methods Patients with stage IIIB (with pleural effusion) or IV NSCLC who were ≥70 years and had a PS of 0–2 or patients of any age with a PS of 2 were included. Patients should have been off any nonsteroidal anti-inflammatory drug for 30 continuous days before study enrollment. Patients were treated with weekly docetaxel 36 mg/m 2 i.v. on days 1, 8, 15 of a 28 day cycle and Celecoxib 400 mg po twice daily. Disease assessment was performed after every two cycles. The study design required 39 patients. Results Study was terminated after 34 patients were enrolled due to safety concerns regarding celecoxib. Thirty patients were evaluable. The response rate was 15%. The median progression free survival and median survival were 2.3 months and 5.0 months, respectively. The median survival of patients ≥70 years old with a PS of 0–1 was 8.3 months and the median survival of PS2 patients was 2.8 months. The combination was well tolerated with fatigue as the most common adverse effect. Two patients developed arterial thrombotic events. Conclusion In these ‘special populations' of patients with advanced NSCLC, the addition of celecoxib to docetaxel did not seem to improve the outcome compared with single agent docetaxel.

Purpose: To study the effects of radiation dose, chemotherapy, and their interaction in patients with unresectable or medically inoperable Stage III non-small-cell lung cancer (NSCLC). Methods and Materials: A total of 237 consecutive Stage III NSCLC patients were evaluated. Median follow-up was 69.0 months. Patients were treated with radiation therapy (RT) alone (n = 106), sequential chemoradiation (n = 69), or concurrent chemoradiation (n = 62). The primary endpoint was overall survival (OS). Radiation dose ranged from 30 to 102.9 Gy (median 60 Gy), corresponding to a bioequivalent dose (BED) of 39 to 124.5 Gy (median 72 Gy). Results: The median OS of the entire cohort was 12.6 months, and 2- and 5-year survival rates were 22.4% and 10.0%, respectively. Multivariable Cox regression model demonstrated that Karnofsky performance status (p = 0.020), weight loss < 5% (p = 0.017), chemotherapy (yes vs. no), sequence of chemoradiation (sequential vs. concurrent; p < 0.001), and BED (p < 0.001) were significant predictors of OS. For patients treated with RT alone, sequential chemoradiation, and concurrent chemoradiation, median survival was 7.4, 14.9, and 15.8 months, and 5-year OS was 3.3%, 7.5%, and 19.4%, respectively (p < 0.001). The effect of higher radiation doses onmore » survival was independent of whether chemotherapy was given. Conclusion: Radiation dose and use of chemotherapy are independent predictors of OS in Stage III NSCLC, and concurrent chemoradiation is associated with the best survival. There is no interaction between RT dose and chemotherapy.« less