Non small Cell Lung Cancer

PurposeAdjuvant chemotherapy for resected non–small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC.Patients and MethodsWithin 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m2intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival.ResultsThree hundred-forty-four patients...

A large variation in prognosis is observed despite the use of clinical prognostic factors in patients with advanced non-small cell lung cancer (NSCLC). It is likely that this variation is due to the different biological properties of the tumour cells. In this work we aimed to identify gene signature that could predict survival in advanced NSCLC. Total RNA was extracted from five 5 μm-thick sections of the FFPE using the High Pure RNA Paraffin Kit (Roche). RNA amplification was performed using WT-Ovation™ FFPE RNA Amplification System V2 (NuGen). The amplified cDNA was then labelled and hybridised onto Illumina HumanRef-8 v3.0 Expression BeadChips. Microarray data analysis was subsequently performed using Genespring GX version 9.0. Out of 75 FFPE samples, only 32 had sufficient RNA quality and quantity for microarray gene expression analysis. Patients were grouped into long and short survival groups based on the time to cancer-related death. After normalization and filtration, 19,002 genes were selected for differential gene expression analysis. A total of 440 genes differed significantly between the long and short survival groups (ANOVA, p <; 0.05, with Benjamini and Hochberg False Discovery Rate multiple testing correction). Unsupervised Hierarchial Clustering with Pearson correlation and average linkage identified two broad clusters of patients corresponding to the long and short survival. Thirteen genes were selected based on the TTest, 2-fold expression changes, principal components analysis and univariate Cox regression analysis and risk scores were calculated for each patient. These gene signatures were independent predictors of survival. The model was validated with a published microarray data from 130 patients with NSCLC. Using Gene Set Analysis (GSA), we found certain biological processes including metastasis and chemotherapy resistance were up-regulated in the short survival group while TID pathway and MAPKKK cascade were enriched in th- - e long survival group. As the conclusion, there is several distinct gene expression profiles associated with survival of patients with advanced stage NSCLC. Survival outcomes in advanced NSCLC could be predicted based on a 13-gene signature.

Most cytotoxic drugs have gross effects on the immune system, such as neutropenia and lymphopenia. However, their effects on tumor-specific immune responses are unknown. Gemcitabine is a nucleoside analogue that is frequently used to treat non-small cell lung cancer. It is also active in other malignancies, either alone or in combination with cisplatin. Here, we investigate its effects on antigen-specific antitumor immunity using a murine tumor cell line transfected to express influenza virus hemagglutinin (HA). CD4(+), CD8(+), and B220(+) lymphocyte numbers all decreased during chemotherapy (120 microg/g, i.p., every third day for five doses), but B cells were selectively depleted. Gemcitabine induced a profound suppression of the IgG antibody response to HA, and this was unrelated to tumor size. In contrast, in vitro T-lymphocyte recall responses to the class I- and class II-restricted dominant peptide epitopes of HA were enhanced in tumor-bearing, gemcitabine-treated mice. We fou...

Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T(2) versus T(1) = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T(2) versus T(1) = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P&amp;amp;amp;lt;.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

cancer Cytologically malignant margins of wedge resected stage I non-small cell lung http://ats.ctsnetjournals.org/cgi/content/full/74/6/1953 located on the World Wide Web at: The online version of this article, along with updated information and services, is Print ISSN: 0003-4975; eISSN: 1552-6259. Southern Thoracic Surgical Association.

The blue-dye staining method of sentinel lymph node identification in lung cancer patients has been scarcely reported. The study was designed to assess the sensitivity, accuracy and negative predictive value (NPV) of intraoperative sentinel lymph node mapping in patients with non-small cell lung cancer by means of staining with colloid or water solution of blue dye. Patients and Methods: One hundred and ten patients with clinically confirmed NO non-small cell lung cancer were enrolled into prospective study of intraoperative sentinel node identification. Four quadrants of the peritumoral tissue were injected with 4 ml of blue dye.After complete lymphadenectomy, all resected lymph nodes were examined with conventional hematoxylin-eosine staining. All negative sentinel nodes were searched for metastatic deposits with both serial sections and immunohistochemistry for cytokeratines. Results: The blue-dye technique was characterized by unacceptably low sentinel node identification rate (IR) and low sensitivity (27% and 67% respectively). No significant differences were found in either the sensitivity or NPV among the colloid or water solutions of the blue dye applied. Although patent blue (colloid) was superior to water solution of methylene blue in identifying sentinel lymph node (identification rate 36% and 22% respectively) the sensitivity and NPV were lower (63% and 80% for patent blue and 75% and 92% for methylene blue respectively). Conclusion: The blue-dye staining method of sentinel node identification in non-small cell lung cancer patients is inadequate and should not be recommended for clinical use. q

and y Department of Radiation Oncology, Mayo Clinic Scottsdale, AZ Purpose: To investigate the effect of smoking during radiotherapy (RT), respiratory insufficiency before RT, hemoglobin levels during RT, and additional factors on overall survival, locoregional control (LRC), and metastasis-free survival in non-small-cell lung cancer patients. Methods and Materials: The following factors were investigated in 181 patients who underwent RT for nonsmall-cell lung cancer: age, gender, Karnofsky performance score, histologic type, grade, T/N stage, American Joint Committee on Cancer stage, surgery, chemotherapy, respiratory insufficiency before RT, pack-years, smoking during RT, and hemoglobin levels during RT. Additionally, in the 129 patients who did not undergo surgery, the effect of the equivalent dose in 2-Gy fractions (EQD2) (<60 Gy vs. 60 Gy vs. >60 Gy) on outcome was investigated. Results: On multivariate analysis, improved overall survival was associated with a lower T stage (p = 0.004), lower N stage (p = 0.040), surgery (p = 0.010), and no respiratory insufficiency (p = 0.023). A Karnofsky performance score >70 achieved borderline significance (p = 0.056). Improved LRC was associated with a lower T stage (p = 0.007) and no smoking during RT (p = 0.029). Improved metastasis-free survival was associated with lower T stage (p < 0.001) and lower N stage (p < 0.001). In those patients who did not undergo surgery, an EQD2 of $60 Gy was associated with a better outcome than an EQD2 of <60 Gy. Furthermore, an EQD2 >60 Gy resulted in better LRC than did an EQD2 of #60 Gy. Conclusions: Smoking during RT had a significant effect on LRC, but we did not find that hemoglobin levels or respiratory insufficiency significantly affected LRC or metastasis-free survival in our patient population. Furthermore, our data suggest a dose-effect relationship in those patients who did not undergo surgery. Ó 2008 Elsevier Inc.

To study the impact of fused (18)F-fluoro-deoxy-D-glucose (FDG)-hybrid positron emission tomography (PET) and computed tomography (CT) images on conformal radiation therapy (CRT) planning for patients with esophageal carcinoma. Thirty-four patients with esophageal carcinoma were referred for concomitant radiotherapy and chemotherapy with radical intent. Each patient underwent CT and FDG-hybrid PET for simulation treatment in the same radiation treatment position. PET-images were coregistered using five fiducial markers. Target delineation was initially performed on CT images and the corresponding PET data were subsequently used as an overlay to CT data to define the target volume. FDG-PET identified previously undetected distant metastatic disease in 2 patients, making them ineligible for curative CRT. The Gross Tumor Volume (GTV) was decreased by CT and FDG image fusion in 12 patients (35%) and was increased in 7 patients (20.5%). The GTV reduction was &gt;or=25% in 4 patients due ...

Introduction: Merkel cell carcinoma (MCC) of the skin is a rare, aggressive, malignant neuroendocrine neoplasm. The tumor classically demonstrates positive immunohistochemistry (IHC) staining for chromogranin A(ChrA), cytokeratin 20 (CK20), neuron specific enolase (NSE) and/or achaete-acute complex-like 1 (MASH1). The newly identified Merkel cell polyomavirus (MCPyV) has been found to be associated with most MCC cases. The primary histologic differential diagnoses of cutaneous MCC is small cell primary bronchogenic carcinoma (SCLC); moreover, both are of neuroendocrine origin. SCLC accounts for approximately 10-15% of all primary lung cancer cases; this histologic subtype is a distinct entity with biological and oncological features distinct from non-small cell lung cancer (NSCLC). In contradistinction to MCC, SCLC is classically IHC positive for cytokeratin 7 (CK7) and transcription factor (TTF-1). Similar to SCLC, MCC cell lines may be classified into two different biochemical subgroups designated as Classic and Variant. In our review and case report, we aim to emphasize the importance of a multidisciplinary approach to the approach to this difficult differential diagnosis. We also aim to comment about features of the cells of origin of MCC and SCLC; to summarize the microscopic features of both tumors; and to review their respective epidemiologic, clinical, prognostic and treatment features. We want to emphasize the initial workup study of the differential diagnosis patient, including evaluating clinical lymph nodes, a clinical history of any respiratory abnormality, and chest radiogram. If a diagnosis of primary cutaneous MCC is confirmed, classic treatment includes excision of the primary tumor with wide margins, excision of a sentinel lymph node, and computed tomography, positron emission tomography and/or Fluorine-18fluorodeoxyglucose positron emission tomography scan studies.

We evaluated the treatment outcome for 5-field 3-dimensional conformal radiation therapy (3D-CRT) in 46 consecutive patients with unresectable, nonmetastatic non-small-cell lung cancer treated from 1993-2001. Four percent of the patients had stage I tumors, 6% had stage II, 44% had stage IIIA, and 46% had stage IIIB tumors. The median radiation therapy (RT) dose to the gross tumor volume with a median of 467.5 cc (range, 75.0-3073.0 cc) was 6120 cGy (range, 3000-6840 cGy). Thirty-one of 46 patients (67.4%) received combined chemoradiotherapy. Mean follow-up was 13.2 months (range, 3-159 months). Survival for stage III patients was 48.7% ± 9.1% at 1 year and 25.0% ± 8.4% at 2 years, with a median survival of 12.0 months ± 4.4 months. The local control rate for stage III patients was 66.8% ± 9.4% at 1 year and 28.5% ± 10.4% at 2 years. Patients who received chemotherapy had better survival (P = 0.0533) and local control (P = 0.0984) compared with patients receiving RT alone. Esophageal toxicity ≥ grade 3 was significantly greater in combined chemoradiotherapy patients (29% early, 13% late) compared to the patients receiving RT alone (0% early and late). Pulmonary toxicity (early and late) was limited to grades 1/2 in 24% of patients and early grade 3 in 2% of patients. Chemotherapy appears to improve survival and local control when added to 3D-CRT in this series. The addition of concurrent chemotherapy to RT significantly increased esophageal toxicity (within acceptable levels) and did not effect pulmonary toxicity in this series.

The aim of this study was to investigate the improvement of quality of radiotherapy and compliance to the protocol amendment of EORTC study 08941. The radiotherapy-specific data were analysed from 154 patients with stage IIIA-N2 Non-Small-Cell Lung Cancer who were actually irradiated after response to 3 cycles of platinum-based induction chemotherapy. The parameters of quality, assessed in 93 patients before and in 61 after protocol amendment, included: time interval between last chemotherapy course and start of thoracic radiotherapy, the use of a 3-D planning CT, dose and fractionation scheme to the primary tumour, the involved and uninvolved mediastinum, duration of radiotherapy and toxicity. A significant improvement of all quality parameters was noted, except for the overall treatment time, which decreased slightly.

Microdeletions at exon 19 are the most frequent genetic alterations affecting the Epidermal Growth Factor Receptor (EGFR) gene in non-small cell lung cancer (NSCLC) and they are strongly associated with response to treatment with tyrosine kinase inhibitors. A series of 116 NSCLC DNA samples investigated by Sanger Sequencing (SS), including 106 samples carrying exon 19 EGFR deletions and 10 without deletions (control samples), were subjected to deep next generation sequencing (NGS). All samples with deletions at SS showed deletions with NGS. No deletions were seen in control cases. In 93 (88%) cases, deletions detected by NGS were exactly corresponding to those identified by SS. In 13 cases (12%) NGS resolved deletions not accurately characterized by SS. In 21 (20%) cases the NGS showed presence of complex (double/multiple) frameshift deletions producing a net in-frame change. In 5 of these cases the SS could not define the exact sequence of mutant alleles, in the other 16 cases the results obtained by SS were conventionally considered as deletions plus insertions. Different interpretative hypotheses for complex mutations are discussed. In 46 (43%) tumors deep NGS showed, for the first time to our knowledge, subpopulations of DNA molecules carrying EGFR deletions different from the main one. Each of these subpopulations accounted for 0.1% to 17% of the genomic DNA in the different tumors investigated. Our findings suggest that a region in exon 19 is highly unstable in a large proportion of patients carrying EGFR deletions. As a corollary to this study, NGS data were compared with those obtained by immunohistochemistry using the 6B6 anti-mutant EGFR antibody. The immunoreaction was E746-A750del specific. In conclusion, NGS analysis of EGFR exon 19 in NSCLCs allowed us to formulate a new interpretative hypothesis for complex mutations and revealed the presence of subpopulations of deletions with potential pathogenetic and clinical impact.

Methods and Materials: Between 1991 and 1998, 150 evaluable patients with Stage I-IIIB NSCLC were treated with three-dimensionally planned conformal radiotherapy and curative intent at Duke University Medical Center. On the treatment-planning CT, the primary tumor and nodal volumes were identified and subsequently combined to form the TTV. The TTV was compared with the stage and outcome with respect to OS, local progression-free survival, and distant failure-free survival using the Kruskall-Wallis analysis of variance and Kaplan-Meier actuarial method. To account for the potentially confounding effects of therapeutic and patientspecific covariates on survival, the Cox proportional hazard regression model was used.

countries. The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor and chemotherapy is the treatment of choice for most patients with metastatic NSCLC. Platinum-based chemotherapy has long been the standard of care for advanced NSCLC. The formation of new blood vessels (angiogenesis) is needed for the growth and invasiveness of primary tumours, and plays an important role in metastatic growth. Vascular endothelial growth factor (VEGF) has emerged as a key potential target for the pharmacological inhibition of tumour angiogenesis. This review discusses current data and the future potential of bevacizumab, a recombinant humanized monoclonal antibody that binds VEGF, in the treatment of NSCLC.

Dysregulation of human epidermal growth factor receptor pathways by over-expression or constitutive activation can promote lung tumor processing including angiogenesis and metastasis and is associated with poor prognosis in non-small cell lung cancers. Ganoderma also known as Lingzhi has been one of the most popular chemoprevention mushrooms in East Asia for centuries. Among many bioactive components identified from Ganoderma, an immunomodulatory protein is the major ingredient for the treatment of lung cancer. Recombinant fungal immunomodulatory protein, GMI, was cloned from Ganoderma microsporum and purified. However, knowledge on the pharmacological and molecular mechanisms in suppressing EGF-mediated tumor invasion and metastasis is poorly understood. The goal of study is investigate in suppressing tumor invasion and metastasis activity of GMI. GMI exhibited an inhibitory effect on EGF-induced migration and invasion. GMI treatment with EGF presented the most potent anti-migration and anti-invasion properties on Boyden chamber assay. GMI inhibited EGF-induced phosphorylation and activation of EGFR and AKT pathway kinases in a dose-dependent manner. Additionally, the EGF-induced activation of Cdc42 GTPase was inhibited by GMI, while GMI had little effect on the EGF-induced activation of Rac1 GTPase. GMI also inhibited the EGF-induced microfilament depolymerization. These findings are the first to reveal the novel functions of GMI in tumor anti-metastasis and the molecular basis for its anticancer action.

This study was carried out to provide a platform for the pre-clinical evaluation of anti-cancer properties of a unique CAM (complementary and alternative medicine) agent, Antrodia camphorata alcohol extract (ACAE), in a mouse model with the advantageous non-invasive in vivo bioluminescence molecular imaging technology. In vitro analyses on the proliferation, migration/invasion, cell cycle and apoptosis were performed on ACAE-treated non-small cell lung cancer cells, H441GL and control CGL1 cells. In vivo, immune-deficient mice were inoculated subcutaneously with H441GL followed by oral gavages of ACAE. The effect of ACAE on tumor progression was monitored by non-invasive bioluminescence imaging. The proliferation and migration/invasion of H441GL cells were inhibited by ACAE in a dose-dependent manner. In addition, ACAE induced cell cycle arrest at G0/G1 phase and apoptosis in H441GL cells as shown by flow cytometric analysis, Annexin-V immunoflourescence and DNA fragmentation. In vivo bioluminescence imaging revealed that tumorigenesis was significantly retarded by oral treatment of ACAE in a dose-dependent fashion. Based on our experimental data, ACAE contains anti-cancer properties and could be considered as a potential CAM agent in future clinical evaluation.

Dose-escalation study was performed to evaluate the maximum tolerated dose, recommended dose and toxicity profile of weekly irinotecan with daily carboplatin and concurrent thoracic radiotherapy in patients with locally advanced non-small-cell lung cancer. Thirty-one previously untreated patients with unresectable stage III non-small-cell lung cancer were enrolled in this study. Patients received weekly irinotecan plus carboplatin (20 mg x m(-2) daily for 5 days a week) for 4 weeks and thoracic radiotherapy (60 Gy in 30 fractions). The irinotecan dose was escalated from 30 mg x m(-2) in increments of 10 mg x m(-2). Four irinotecan dose levels were given and 30 patients were assessable. Their median age was 62 years (range: 52-72 years), 28 had a performance status of 0-1 and two had a performance status of 2, 12 had stage IIIA disease and 18 had IIIB disease. There were 19 squamous cell carcinomas, 10 adenocarcinomas, and one large cell carcinoma. The dose-limiting toxicities were p...

Background: The purpose of this study was to evaluate the efficacy of oral glutamine in the prevention of acute radiation-induced esophagitis (ARIE) and weight loss in lung carcinoma patients, and to determine the clinical/dosimetric predictors of ARIE. Patients and methods: Data from 41 patients with stage III lung carcinoma treated with thoracic irradiation were retrospectively analyzed. Twenty-two patients (53.6%) received prophylactic powdered glutamine in doses of 10 g/8 h. Prescribed radiation dose to planning target volume was 60 Gy, in 30 fractions, 5 days/week. The primary endpoint included the ARIE incidence and its correlation with clinical/dosimetric factors relative to treatment with glutamine. Results: Glutamine was well tolerated. Grade 2 or 3 ARIE occurred in 20 (48.8%) of 41 patients: seven in the glutamine-supplemented group, and 13 in the glutamine-free group (p = 0.002). All seven patients with grade 3 esophagitis were in the glutamine-free group (36.8% vs. 0%). Glutamine supplementation appeared to significantly delay ARIE onset for six days (22 days vs. 16 days; p = 0.002). Glutamine-supplemented patients demonstrated a lower incidence of grade 2 or 3 ARIE (27.2%), and gained weight during radiotherapy (p = 0.04). V55 was the only dosimetric parameter that correlated with the severity of ARIE in glutamine-free patients: a V55 of <35% had a 31% risk of ARIE grade 2 or 3, and the risk increased to 76% with a V55 of ≥35% (p = 0.01). Conclusion: This schedule and dosage of glutamine may be beneficial in the prevention of ARIE and weight loss in lung cancer patients undergoing thoracic irradiation.

Mutated or rearranged driver kinases in non-small cell lung cancer (NSCLC) cells are clinically amenable to treatment with tyrosine kinase inhibitors (TKIs) resulting in prolonged survival and significant benefit compared to cytotoxic chemotherapy. The most frequent genomic alterations are observed for epidermal growth factor receptor and anaplastic lymphoma kinase, which can be blocked by a range of specific TKIs in sequence. In clinics, resistance to TKIs emerges after approximately one year and comprises secondary mutations of the kinases (on-target) or alternative pathways circumventing the original kinase (off-target) alterations. A special feature of NSCLC is the occurrence of histological transformation to small cell lung cancer (SCLC) in up to 14% of cases, which, in general, is accompanied by resistance to the original TKIs. SCLC transformed tumors may be treated with the classical platinum/etoposide regimen but thus far there are no definitive guidelines. Four transformed pleural SCLC lines in our lab indicate the presence of a gradual NSCLC-SCLC shift with overlapping drug sensitivities. In conclusion, the treatment of NSCLC-SCLC transformed cancer cells would need a better chemosensitivity assessment using functional genomics to guide further therapy.

Histone proteins are modified in response to various external signals; however, their mechanisms are still not fully understood. Citrullination is a post-transcriptional modification that converts arginine in proteins into citrulline. Here we show in vivo and in vitro citrullination of the arginine 3 residue of histone H4 (cit-H4R3) in response to DnA damage through the p53-PADI4 pathway. We also show DnA damage-induced citrullination of Lamin C. Cit-H4R3 and citrullinated Lamin C localize around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 leads to chromatin decondensation and promotes DnA cleavage, whereas Padi4 − / − mice exhibit resistance to radiation-induced apoptosis in the thymus. Furthermore, the level of cit-H4R3 is negatively correlated with p53 protein expression and with tumour size in non-small cell lung cancer tissues. our findings reveal that cit-H4R3 may be an 'apoptotic histone code' to detect damaged cells and induce nuclear fragmentation, which has a crucial role in carcinogenesis.

In the present study the chromosomal status of seven invasive non small cell lung cancer specimens and associated premalignant lesions was investigated. By fluorescence in situ hybridisation (FISH) with centromere specific probes, an increase in the percentage of aneuploid cells from pre-invasive to invasive lesions could be demonstrated (mean 8.5 and 59%, respectively, for chromosome 7). Furthermore, mean chromosome copy numbers were higher in invasive carcinomas as compared to premalignant lesions, indicating polyploidization during tumor development. Increasing evidence suggests that aberrations of chromosome 7 occur early in the development of lung cancer. Whether these aberrations can be used as a biomarker for future neoplastic progression remains to be determined.

Purpose: To identify a clinically relevant and available parameter upon which to identify non-small cell lung cancer (NSCLC) patients at risk for pneumonitis when treated with three-dimensional (3D) radiation therapy. patients were treated definitively for inoperable NSCLC. Patients were selected for good performance status (96%) and absence of weight loss (82%). All patients had full 3D treatment planning (including total lung dose-volume histograms [DVHs]) prior to treatment delivery. The total lung DVH parameters were compared with the incidence and grade of pneumonitis after treatment. Results: Univariate analysis revealed the percent of the total lung volume exceeding 20 Gy (V 20 ), the effective volume (V eff ) and the total lung volume mean dose, and location of the tumor primary (upper versus lower lobes) to be statistically significant relative to the development of > Grade 2 pneumonitis. Multivariate analysis revealed the V 20 to be the single independent predictor of pneumonitis. Conclusions: The V 20 from the total lung DVH is a useful parameter easily obtained from most 3D treatment planning systems. The V 20 may be useful in comparing competing treatment plans to evaluate the risk of pneumonitis for our individual patient treatment and may also be a useful parameter upon which to stratify patients or prospective dose escalation trials.

Background First-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) is usually limited to four to six cycles. Maintenance therapy can delay progression and prolong survival. The oral epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib has proven effi cacy and tolerability in second-line NSCLC. We designed the phase 3, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study to assess use of erlotinib as maintenance therapy in patients with non-progressive disease following fi rst-line platinumdoublet chemotherapy.

Purpose: Overprediction of the potency and toxicity of high-dose ablative radiotherapy such as stereotactic body radiotherapy (SBRT) by the linear quadratic (LQ) model led to many clinicians' hesitating to adopt this efficacious and well-tolerated therapeutic option. The aim of this study was to offer an alternative method of analyzing the effect of SBRT by constructing a universal survival curve (USC) that provides superior approximation of the experimentally measured survival curves in the ablative, high-dose range without losing the strengths of the LQ model around the shoulder. Methods and Materials: The USC was constructed by hybridizing two classic radiobiologic models: the LQ model and the multitarget model. We have assumed that the LQ model gives a good description for conventionally fractionated radiotherapy (CFRT) for the dose to the shoulder. For ablative doses beyond the shoulder, the survival curve is better described as a straight line as predicted by the multitarget model. The USC smoothly interpolates from a parabola predicted by the LQ model to the terminal asymptote of the multitarget model in the high-dose region. From the USC, we derived two equivalence functions, the biologically effective dose and the single fraction equivalent dose for both CFRT and SBRT. Results: The validity of the USC was tested by using previously published parameters of the LQ and multitarget models for non-small-cell lung cancer cell lines. A comparison of the goodness-of-fit of the LQ and USC models was made to a high-dose survival curve of the H460 non-small-cell lung cancer cell line. Conclusion: The USC can be used to compare the dose fractionation schemes of both CFRT and SBRT. The USC provides an empirically and a clinically well-justified rationale for SBRT while preserving the strengths of the LQ model for CFRT.

Purpose: Overprediction of the potency and toxicity of high-dose ablative radiotherapy such as stereotactic body radiotherapy (SBRT) by the linear quadratic (LQ) model led to many clinicians' hesitating to adopt this efficacious and well-tolerated therapeutic option. The aim of this study was to offer an alternative method of analyzing the effect of SBRT by constructing a universal survival curve (USC) that provides superior approximation of the experimentally measured survival curves in the ablative, high-dose range without losing the strengths of the LQ model around the shoulder. Methods and Materials: The USC was constructed by hybridizing two classic radiobiologic models: the LQ model and the multitarget model. We have assumed that the LQ model gives a good description for conventionally fractionated radiotherapy (CFRT) for the dose to the shoulder. For ablative doses beyond the shoulder, the survival curve is better described as a straight line as predicted by the multitarget model. The USC smoothly interpolates from a parabola predicted by the LQ model to the terminal asymptote of the multitarget model in the high-dose region. From the USC, we derived two equivalence functions, the biologically effective dose and the single fraction equivalent dose for both CFRT and SBRT. Results: The validity of the USC was tested by using previously published parameters of the LQ and multitarget models for non-small-cell lung cancer cell lines. A comparison of the goodness-of-fit of the LQ and USC models was made to a high-dose survival curve of the H460 non-small-cell lung cancer cell line. Conclusion: The USC can be used to compare the dose fractionation schemes of both CFRT and SBRT. The USC provides an empirically and a clinically well-justified rationale for SBRT while preserving the strengths of the LQ model for CFRT.

Positron Emission Tomography (PET) is a significant advance in cancer imaging with great potential for optimizing radiation therapy (RT) treatment planning and thereby improving outcomes for patients. The use of PET and PET/CT in RT planning was reviewed by an international panel. The International Atomic Energy Agency (IAEA) organized two synchronized and overlapping consultants' meetings with experts from different regions of the world in Vienna in July 2006. Nine experts and three IAEA staff evaluated the available data on the use of PET in RT planning and considered practical methods for integrating it into routine practice. For RT planning, 18 F fluourodeoxyglucose (FDG) was the most valuable pharmaceutical. Numerous studies supported the routine use of FDG-PET for RT target volume determination in nonsmall cell lung cancer (NSCLC). There was also evidence for utility of PET in head and neck cancers, lymphoma and esophageal cancers, with promising preliminary data in many other cancers. The best available approach employs integrated PET/CT images, acquired on a dual scanner in the radiotherapy treatment position after administration of tracer according to a standardized protocol, with careful 2 Mac Manus MP et al PET in Radiation Therapy Planning optimization of images within the RT planning system and carefully considered rules for contouring tumor volumes. PET scans that are not recent or were acquired without

Objective: The role of preoperative chemotherapy in squamous cell esophageal carcinoma remains controversial. A prospective trial was initiated to investigate whether preoperative chemotherapy followed by surgery results in increased progression-free survival in patients with resectable thoracic esophageal carcinoma. Methods: Patients with Stage IIb-IIIa/b resectable esophageal carcinoma were eligible for the study. They received two cycles of FLEP regimen chemotherapy (cisplatin, etoposide, leucovorine, 5-fluorouracil) followed by transthoracic extended 2-or 3-field esophagectomy. Two-year progressionfree survival was the primary endpoint. To evaluate the potential benefit of the dual-modality approach we compared these results with the outcome of patients who were treated in our center in the same period of time and were non-randomly allocated to surgery alone. Results: From 2001 to 2008, 63 patients were included in the study (bimodality group) and 58 patients into the surgery-alone group. Median follow-up was 68 (range, 4-123) months. Squamous cell carcinoma had 93% patients. Two-year progression-free survival for all patients was 45.3 and 30.7% (hazard ratio 0.71, 95% confidence interval 0.46-1.08) and median overall survival was 26.5 months and 18.0 months (hazard ratio 0.67, 95% confidence interval 0.41-1.01) in bimodality-and surgeryalone groups, respectively. Patients who underwent R0-resection after bimodality treatment had significantly better overall survival (40.9 months) than after surgery alone (19.0 months, hazard ratio 0.51, 95% confidence interval 0.30-0.81). Conclusions: Two cycles of preoperative chemotherapy did not improve progression-free survival of patients with resectable thoracic esophageal carcinoma in intent-to-treat population. However, significantly better results of bimodality approach was seen in R0-resected patients which warrants further trials with more effective chemotherapy combinations.

Lung cancer is the number one cancer killer in the United States. This disease is clinically divided into two sub-types, small cell lung cancer, (10-15% of lung cancer cases), and non-small cell lung cancer (NSCLC; 85-90% of cases). Early detection of NSCLC, which is the more common and less aggressive of the two sub-types, has the highest potential for saving lives. As yet, no routine screening method that enables early detection exists, and this is a key factor in the high mortality rate of this disease. Imaging and cytology-based screening strategies have been employed for early detection, and while some are sensitive, none have been demonstrated to reduce lung cancer mortality. However, mortality might be reduced by developing specific molecular markers that can complement imaging techniques. DNA methylation has emerged as a highly promising biomarker and is being actively studied in multiple cancers. The analysis of DNA methylation-based biomarkers is rapidly advancing, and a large number of potential biomarkers have been identified. Here we present a detailed review of the literature, focusing on DNA methylation-based markers developed using primary NSCLC tissue. Viable markers for clinical diagnosis must be detectable in 'remote media' such as blood, sputum, bronchoalveolar lavage, or even exhaled breath condensate. We discuss progress on their detection in such media and the sensitivity and specificity of the molecular marker panels identified to date. Lastly, we look to future advancements that will be made possible with the interrogation of the epigenome.

This study comprised a total of 7 553 patients with non-small cell lung cancer (2 660 women and 4 893 men) treated at a comprehensive cancer centre between 1974 and 1998. Significant differences in tumour histology were associated with gender (pB/0.001); adenocarcinoma was the most common diagnosis in both men (50.0%) and women (41.7%); squamous cell carcinoma was the second most prevalent diagnosis (21% and 31% in women and men, respectively); and bronchioalveolar tumours were more prevalent in men (3% compared with 7% in women). Frequency distributions with local, regional or distant disease at registration were similar between men and women (p0/0.906). In a multivariable Cox regression analysis the indications were that gender is an important risk factor for survival. Adjusting for age, stage, treatment received and ability to pay for care, a statistically significant interaction between gender and tumour histology (p0/0.043) was found, where, in relation to female sex and histologies other than squamous carcinoma, women who presented with squamous carcinoma had an increased risk of death (HR0/1.09, 95% CI 1.02 Á/1.18) while men had an increased risk of death for all histologies (HR0/1.29, 95% CI 1.21 Á/1.40, and HR 0/1.15, 95% CI 1.07 Á/1.24 for squamous and other histologies, respectively). This study confirms previous reports of strong gender-dependent differences in survival in patients with non-small cell lung cancer, including a histology-specific effect in women.

Molecular imaging, in particular, PET, has brought an additional dimension to management for patients with cancer. 18F-FDG, which is the most widely available tracer, has been shown to be of value for the selection of target volumes in radiation oncology. Depending on its sensitivity and specificity, 18F-FDG has been shown to influence the selection of target volumes for non-small cell lung cancers (NSCLC) or for esophageal tumors. On the other hand, for tumors such as head and neck squamous cell carcinomas (HNSCC) and rectal carcinomas, convincing data on the value of 18F-FDG for target volume selection are still lacking. For target volume delineation, given that an adequate method is used for volume segmentation, the added value of 18F-FDG has been demonstrated for HNSCC and NSCLC. For both types of tumors, modifications in target volume delineation translated into differences in dose distribution compared with the results of CT scan-based plans. Studies are in progress for rectal...

Fluorodeoxyglucose positron emission tomography (FDG-PET) plays an increasingly important role in radiotherapy, beyond staging and selection of patients. Especially for non-small cell lung cancer, FDG-PET has, in the majority of the patients, led to the safe decrease of radiotherapy volumes, enabling radiation dose escalation and, experimentally, redistribution of radiation doses within the tumor. In limited-disease small cell lung cancer, the role of FDG-PET is emerging. For primary brain tumors, PET based on amino acid tracers is currently the best choice, including high-grade glioma. This is especially true for low-grade gliomas, where most data are available for the use of 11 C-MET (methionine) in radiation treatment planning. For esophageal cancer, the main advantage of FDG-PET is the detection of otherwise unrecognized lymph node metastases. In Hodgkin's disease, FDG-PET is essential for involved-node irradiation and leads to decreased irradiation volumes while also decreasing geographic miss. FDG-PET's major role in the treatment of cervical cancer with radiation lies in the detection of para-aortic nodes that can be encompassed in radiation fields. Besides for staging purposes, FDG-PET is not recommended for routine radiotherapy delineation purposes. It should be emphasized that using PET is only safe when adhering to strictly standardized protocols.

Objective: The prognosis of non-small cell lung cancer (NSCLC) with brain metastasis is very poor, with median survival rate below 6 months, even if treated with palliative radio and/or chemotherapy. To assess the effectiveness of surgical treatment for this kind of patients we reviewed our experience. Methods: From January 1989 to October 1999, 30 patients (26 males and four females; mean age: 58.7 years) with NSCLC and single brain metastasis underwent surgical treatment of both primary lung cancer and secondary cerebral lesion. Patients (pts) were divided into two major groups. In group 1 (G1) 20 pts (18 males and two females) presented a synchronous brain metastasis. In group 2 (G2) 10 pts (eight males and two females) presented a metachronous brain metastasis during the follow-up period (range 3±24 months since the primary tumor). Patients selected in G1 had T1±2, N0±1 clinical staging, good`performance status' (ECOG:0±1; Karnofsky index .70%), age , 75 years. Craniotomy has always been the ®rst approach. In G2 also patients with locally advanced tumors (T3 and/or N2) were included. Whole brain radiotherapy and/or chemotherapy was the post-operative choice treatment. Results: Histologic ®ndings have shown: adenocarcinoma in 17 cases (12 in G1; ®ve in G2), squamous cell carcinoma in 10 cases (six in G1; four in G2), large cell carcinoma in 2 (one in G1; one in G2) and large cell neuroendocrine carcinoma in one (G1). Survival analysis (Kaplan±Meier method) has shown an overall value of 80% at 1 year (95% in G1; 50% in G2), 41% at 2 years (47% in G1; 30% in G2) and 17% at 3 years (14% in G1; 20% in G2). Overall median survival is 23 months (23 in G1; 11 in G2); mean survival 27.8 months (30.3 months in G1; 22.8 months in G2). According to univariate analysis prognosis is de®nitively better in N0 tumors compared to N1±2 tumors and in adenocarcinoma cases compared to other histotypes (P , 0:05). Conclusions: We can conclude that combined surgical therapy is, nowadays, the choice treatment for this kind of patients, even though restricted to selected cases. The knowledge of prognostic factors may optimize indications for surgery. q