Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer.

Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.

Clinical features and prognostic factors in patients with bone metastases from non-small cell lung cancer.

OBJECTIVE: To investigate the clinical features and evaluate the prognostic factors in patients with bone metastases from non-small cell lung cancer (NSCLC). METHODS: We retrospectively investigated 356 patients with NSCLC with bone metastases from January 2012 to December 2017. The overall survival (OS) and 1-year survival rate were calculated by Kaplan-Meier analysis and compared by univariate analysis using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. RESULTS: A total of 694 sites of bone metastases were determined among the 356 patients. The most common site of bone metastases was the ribs. The median OS was 12.5 months and the 1-year survival was 50.8% in the overall population. Univariate analysis revealed that histological type, number of bone metastases, Eastern Cooperative Oncology Group performance status (ECOG PS), bisphosphonate therapy, and serum calcium, lactate dehydrogenase, and alkaline phosphatase were significantly correlated with prognosis. Multivariate analysis identified multiple bone metastases, ECOG PS ≥2, lactate dehydrogenase ≥225 U/L, and alkaline phosphatase ≥140 U/L as independent negative prognostic factors. CONCLUSION: Multiple bone metastases, high ECOG PS, and high serum alkaline phosphatase and lactate dehydrogenase are independent negative prognostic factors for bone metastases from NSCLC.

NALP3 orchestrates cellular bioenergetics to facilitate non-small cell lung cancer cell growth.

AIMS: Previous work has reported the closely correlation between inflammation and carcinogenesis, while the role of NALP3, the key component of inflammasome activation in NSCLC remains elusive. This study was to unravel the mechanism of NALP3 on modulating NSCLC cancer cell growth. METHODS: IHC and immuno-blot were performed to analyze expression of NALP3 and indicated molecules. CCK-8 and xenograft nude mice assay were used to evaluate cell growth in vitro and in vivo. Bioenergetics assay was performed to measure OXPHOS and aerobic glycolysis. siRNA and shRNA were constructed to knockdown endogenous NALP3 and DNMT1. Co-immunoprecipitation was applied to confirm the interaction between NALP3 and DMAP1. BioProfile FLEX analyzer and Lactate Reagent Kit were used to measure relative level glucose uptake and lactate production. KEY FINDINGS: We reported NALP3 were up-regulated in NSCLC tumor tissues. NALP3 depletion suppressed cancer cell growth in vitro and in vivo. Moreover, data showed depletion of NALP3 promoted cell bioenergetics switch from aerobic glycolysis to OXPHOS. Additionally, we found NALP3 interacted with DMAP1 and alteration of NALP3 increased DNMT1 level. Subsequently, we clarified depletion of DNMT1 significantly suppressed NSCLC cell growth and orchestrated cellular metabolism which was similar to the effects of NALP3 knockdown. Finally, our data showed high NALP3 was associated with poor outcomes, and correlated with TNM stage and differentiation. SIGNIFICANCE: Current study elucidated NALP3 could promote metabolic reprogramming to regulate NSCLC cell growth and suggested that NALP3 may be considered as a novel biomarker and therapeutic target for NSCLC patients.

Lymph Node Size Predicts for Asymptomatic Brain Metastases in Patients With Non-small-cell Lung Cancer at Diagnosis.

BACKGROUND: We questioned whether the National Comprehensive Cancer Network recommendations for brain magnetic resonance imaging (MRI) for patients with stage ≥ IB non-small-cell lung cancer (NSCLC) was high-yield compared with American College of Clinical Pharmacy and National Institute for Health and Care Excellence guidelines recommending stage III and above NSCLC. We present the prevalence and factors predictive of asymptomatic brain metastases at diagnosis in patients with NSCLC without extracranial metastases. MATERIALS AND METHODS: A retrospective analysis of 193 consecutive, treatment-naïve patients with NSCLC diagnosed between January 2010 and August 2015 was performed. Exclusion criteria included no brain MRI staging, symptomatic brain metastases, or stage IV based on extracranial disease. Univariate and multivariate logistic regression was performed. RESULTS: The patient characteristics include median age of 65 years (range, 36-90 years), 51% adenocarcinoma/36% squamous carcinoma, and pre-MRI stage grouping of 31% I, 22% II, 34% IIIA, and 13% IIIB. The overall prevalence of brain metastases was 5.7% (n = 11). One (2.4%) stage IA and 1 (5.6%) stage IB patient had asymptomatic brain metastases at diagnosis, both were adenocarcinomas. On univariate analysis, increasing lymph nodal stage (P = .02), lymph nodal size > 2 cm (P = .009), multi-lymph nodal N1/N2 station involvement (P = .027), and overall stage (P = .005) were associated with asymptomatic brain metastases. On multivariate analysis, increasing lymph nodal size remained significant (odds ratio, 1.545; P = .009). CONCLUSION: Our series shows a 5.7% rate of asymptomatic brain metastasis for patients with stage I to III NSCLC. Increasing lymph nodal size was the only predictor of asymptomatic brain metastases, suggesting over-utilization of MRI in early-stage disease, especially in lymph node-negative patients with NSCLC. Future efforts will explore the utility of baseline MRI in lymph node-positive stage II and all stage IIIA patients.

Site of Metastases as Prognostic Factors in Unselected Population of Stage IV Non-Small Cell Lung Cancer

Background: Advanced stage non-small cell lung cancer (NSCLC) is a heterogenous disease, yet, with the exception of targeted therapies, most guidelines recommended uniform treatment irrespective of tumor burden or sites of metastases and this may explain, in part, the wide range of responses to same lines of therapy. Aim of work: In this work we tried to explore the effect of metastatic sites in on overall survival (OS), in an unselected group of Non-small cell lung cancer patients who received different treatments line. Methods: A retrospective analysis was performed on patients with stage IV NSCLC who received systemic treatment at UAB Cancer Center (NCI designated comprehensive cancer center) between 2002 to 2012. The details of sites of metastases, systemic therapy and overall survival were recorded for each patient. Result: In 409 patients who received systemic treatment, there was statistically significant lower OS in those presenting with liver metastases (p<0.001), adrenal metastases (p=0.011) and metastases to abdominal lymph nodes (p=0.014). There was no statistically significance difference in OS in patient presenting with pleural metastases or effusion (p=0.908), metastases to heart or pericardium (p=0.654), metastases to bone (p=0.281), brain (p=0.717) or skin and subcutaneous tissue (p=0.642). Conclusion: Intra-abdominal metastases confer a particularly poor prognosis in stage IV NSCLC treated with systemic therapy and may identify patients in whom aggressive treatment beyond first line therapy is not appropriate.

Ophiopogonin B suppresses the metastasis and angiogenesis of A549 cells in vitro and in vivo by inhibiting the EphA2/Akt signaling pathway.

Lung adenocarcinoma is the most common metastatic cancer, and is associated with high patient mortality. Therefore, investigation of anti­metastatic treatments for lung adenocarcinoma is crucial. Ophiopogonin B (OP­B) is a bioactive component of Radix Ophiopogon Japonicus, which is often used in Chinese traditional medicine to treat pulmonary disease. Screening of transcriptome and digital gene expression (DGE) profiling data in NSCLC cell lines showed that OP­B regulated the epithelial­mesenchymal transition (EMT) pathway in A549 cells. Further results showed that 10 µmol/l OP­B downregulated EphA2 expression and phosphorylation (Ser897) in A549 cells but upregulated them in NCI­H460 cells. Meanwhile, the Ras/ERK pathway was unaffected in A549 cells and stimulated in NCI­H460 cells. More importantly, detection of the EMT pathway showed that OP­B treatment increased the epithelial markers ZO­1 and E­cadherin and decreased the expression of the mesenchymal marker N­cadherin and the transcriptional repressors Snail, Slug and ZEB1. Furthermore, through Transwell migration and scratch wound healing assays, we found that 10 µmol/l OP­B significantly reduced the invasion and migration of A549 cells. In vivo, we found that 75 mg/kg OP­B inhibited A549 cell metastasis in a pulmonary metastasis nude mouse model. In addition, we also found that 10 µmol/l OP­B significantly inhibited tube formation in EA.hy926 cells. The expression of VEGFR2 and Tie­2, the phosphorylation of Akt (S473) and PLC (S1248), and the levels of EphA2 and phosphorylated EphA2 (S897) were all inhibited by OP­B in this cell line. In vivo, using a Matrigel plug assay, we found that OP­B inhibited angiogenesis and the hemoglobin content of A549 transplanted tumors. Taken together, OP­B inhibited the metastasis and angiogenesis of A549 cells by inhibiting EphA2/Akt and the corresponding pathway. The investigation gives new recognition to the anticancer mechanism of OP­B in NSCLC and this compound is a promising inhibitor of metastasis and angiogenesis of lung adenocarcinoma cells.

Clinical Application of Genomic Profiling With Circulating Tumor DNA for Management of Advanced Non-Small-cell Lung Cancer in Asia.

BACKGROUND: Genomic profiling of cell-free circulating tumor DNA (ctDNA) is a potential alternative to repeat invasive biopsy in patients with advanced cancer. We report the first real-world cohort of comprehensive genomic assessments of patients with non-small-cell lung cancer (NSCLC) in a Chinese population. PATIENTS AND METHODS: We performed a retrospective analysis of patients with advanced or metastatic NSCLC whose physician requested ctDNA-based genomic profiling using the Guardant360 platform from January 2016 to June 2017. Guardant360 includes all 4 major types of genomic alterations (point mutations, insertion-deletion alterations, fusions, and amplifications) in 73 genes. RESULTS: Genomic profiling was performed in 76 patients from Hong Kong during the 18-month study period (median age, 59.5 years; 41 men and 35 women). The histologic types included adenocarcinoma (n = 10), NSCLC, not otherwise specified (n = 58), and squamous cell carcinoma (n = 8). In the adenocarcinoma and NSCLC, not otherwise specified, combined group, 62 of the 68 patients (91%) had variants identified (range, 1-12; median, 3), of whom, 26 (42%) had ≥ 1 of the 7 National Comprehensive Cancer Network-recommended lung adenocarcinoma genomic targets. Concurrent detection of driver and resistance mutations were identified in 6 of 13 patients with EGFR driver mutations and in 3 of 5 patients with EML4-ALK fusions. All 8 patients with squamous cell carcinoma had multiple variants identified (range, 1-20; median, 6), including FGFR1 amplification and ERBB2 (HER2) amplification. PIK3CA amplification occurred in combination with either FGFR1 or ERBB2 (HER2) amplification or alone. CONCLUSION: Genomic profiling using ctDNA analysis detected alterations in most patients with advanced-stage NSCLC, with targetable aberrations and resistance mechanisms identified. This approach has demonstrated its feasibility in Asia.

Torilis japonica extract fraction compound, EGFR-targeted inhibition of cancer abnormal metastasis in A549 lung cancer cells.

The number of patients who die from lung cancer is steadily increasing. According to the 2012 statistics, lung cancer accounts for the highest percentage of death from cancer in both sexes. Many research studies found that lung cancer can be caused not only by smoking but by outdoor pollution, and it leads to over-activation of various surface proteins in cancer cells. The over-activity of epidermal growth factor receptor (EGFR) is implicated as a crucial factor in inducing abnormal metastasis of lung cancer cells. In this study, we investigated the inhibitory effect of Torilis japonica extract (TJE) major fraction compound in A549 lung cancer cells by inhibiting EGFR activity. We confirmed that inhibitory effect of TJE on the abnormal metastasis using invasion assay and 3D cell culture method, as well as the inhibition of EGFR signaling pathway, co-binding with Stat3 and dimer formation for translocation to the nucleus. We confirmed the EGFR targets inhibition of TJE when compared with EGFR knockdown group using siRNA transfection. The CAM assay confirmed once again the efficacy of the TJE. We suggest that TJE is a new potential reagent for EGFR-targeted therapy and anti-abnormal metastasis in A549 lung cancer cells.

Radiotherapy for brain metastases near the end of life in an integrated health care system.

BACKGROUND: To examine radiotherapy (RT) patterns-of-care and utilization at the end of life (EOL) among non-small cell lung cancer (NSCLC) patients with brain metastasis (BrM) in an integrated health care system. METHODS: Central tumor registry identified 5,133 patients diagnosed with NSCLC from 2007-2011. BrM were determined by imaging. Patient and clinical characteristics were obtained by chart abstraction. In addition to abstracted variables, graded prognostic assessment (GPA) score of 0-1 was derived by collected data and tested as a predictor of death within 14 or 30 days of RT. RESULTS: On NSCLC presentation, 10% harbored BrM while 7% developed BrM thereafter. Of 900 BrM patients, 15% were not referred for RT, with median time to death of 21 days. Median time to death for 5% not recommended RT was 48 days. Among those receiving brain RT, 11.9% died within 14 days and 23.3% (cumulatively) died within 30 days of treatment. Over 50% with GPA score 0-1 received RT, 11% within 14 days and 21% within 30 days of death; median survival of GPA score 0-1 patients was 49 days. GPA score 0-1 independently predicted for death within 30 days of RT receipt. CONCLUSIONS: BrM are common in NSCLC, and most patients are referred for brain RT. A surprising proportion of patients received treatment near the EOL, as 23% died within 30 days of RT. GPA score of 0-1 predicted for death within 30 days of treatment. RT referral, recommendation, and timing should be better tailored to life expectancy, and additional benchmarks for quality of care are needed.

Targeted Therapy as an Alternative to Whole-Brain Radiotherapy in EGFR-Mutant or ALK-Positive Non-Small-Cell Lung Cancer With Brain Metastases.

CLINICAL QUESTION: Is up-front whole-brain radiotherapy required to treat multiple brain metastases from non-small-cell lung cancer when highly active targeted therapies are available? CLINICAL APPLICATION: Patients with EGFR-mutant or ALK-positive non-small-cell lung cancer with brain metastases now have the potential to achieve a prolonged survival. Through use of highly active targeted therapies, whole-brain radiotherapy can be safely postponed, diminishing toxic effects that could impair quality of life.

Assessment of the External Validity of the National Comprehensive Cancer Network and European Society for Medical Oncology Guidelines for Non-Small-Cell Lung Cancer in a Population of Patients Aged 80 Years and Older.

Non-small-cell lung cancer (NSCLC) is a disease of the elderly, who are under-represented in clinical trials. This challenges the external validity of the evidence base for its management and of current guidelines, that we evaluated in a population of older patients. We retrieved randomized clinical trials (RCTs) supporting the guidelines and identified 18 relevant topics. We matched a cohort of NSCLC patients aged older than 80 years from the Moffitt Cancer Center database with the studies' eligibility criteria to check their qualification for at least 2 studies. Eligibility > 60% was rated full validity, 30% to 60% partial validity, and < 30% limited validity. We obtained data from 760 elderly patients in stage-adjusted groups and collected 244 RCTs from the National Comprehensive Cancer Network (NCCN) and 148 from the European Society for Medical Oncology (ESMO) guidelines. External validity was deemed insufficient for neoadjuvant chemotherapy in stage III disease (27.37% and 25.26% of patients eligible for NCCN and ESMO guidelines, respectively) and use of bevacizumab (13.86% and 16.27% of patients eligible). For ESMO guidelines, it was inadequate regarding double-agent chemotherapy (25.90% of patients eligible), its duration (24.10%) and therapy for Eastern Cooperative Oncology Group performance status 2 patients (17.74%). For NCCN guidelines external validity was lacking for neoadjuvant chemoradiotherapy in stage IIIA disease (25.86% of patients eligible). Our analysis highlighted the effect of RCT eligibility criteria on guidelines' external validity in elderly patients. Eligibility criteria should be carefully considered in trial design and more studies that do not exclude elderly patients should be included in guidelines.

Response of brain metastasis from lung cancer patients to an oral nutraceutical product containing silibinin.

Despite multimodal treatment approaches, the prognosis of brain metastases (BM) from non-small cell lung cancer (NSCLC) remains poor. Untreated patients with BM have a median survival of about 1 month, with almost all patients dying from neurological causes. We herein present the first report describing the response of BM from NSCLC patients to an oral nutraceutical product containing silibinin, a flavonoid extracted from the seeds of the milk thistle. We present evidence of how the use of the silibinin-based nutraceutical Legasil® resulted in significant clinical and radiological improvement of BM from NSCLC patients with poor performance status that progressed after whole brain radiotherapy and chemotherapy. The suppressive effects of silibinin on progressive BM, which involved a marked reduction of the peritumoral brain edema, occurred without affecting the primary lung tumor outgrowth in NSCLC patients. Because BM patients have an impaired survival prognosis and are in need for an immediate tumor control, the combination of brain radiotherapy with silibinin-based nutraceuticals might not only alleviate BM edema but also prove local control and time for either classical chemotherapeutics with immunostimulatory effects or new immunotherapeutic agents such as checkpoint blockers to reveal their full therapeutic potential in NSCLC BM patients. New studies aimed to illuminate the mechanistic aspects underlying the regulatory effects of silibinin on the cellular and molecular pathobiology of BM might expedite the entry of new formulations of silibinin into clinical testing for progressive BM from lung cancer patients.

Imaging and Clinical Characteristics Predict Near-Term Disablement From Bone Metastases: Implications for Rehabilitation.

OBJECTIVE: To distinguish which patients with bone metastases are at risk for near-term disablement in order to assist clinicians in assessing the appropriateness of referrals for rehabilitation services. DESIGN: Prospective cohort study. SETTING: National Cancer Institute-designated comprehensive cancer center imbedded in a tertiary medical center. PARTICIPANTS: Data were collected from members (n=78) of a patient cohort (N=311) with stage IIIB or IV non-small-cell lung cancer or extensive-stage small-cell lung cancer who developed new or progressive imaging-confirmed bone metastases during the 2-year course of the study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional capabilities were assessed at 3- to 4-week intervals over the study's 2-year duration with the Activity Measure for Post-Acute Care Computer Adaptive Testing. RESULTS: Seventy-eight participants developed new or progressive bone metastases during the study. Most were men, and 83% had non-small-cell lung cancer. Metastases were most frequently located in the ribs (n=62), pelvis (n=49), or the thoracic (n=60) and lumbar spine (n=44). While neither the number of bone metastases nor their specific location was associated with near-term changes in patient mobility, their association with pain or a focal neurologic deficit was strongly associated with large declines in mobility. Similarly, patients whose imaging studies revealed new metastases and the expansion of established metastases were more likely to lose mobility. CONCLUSIONS: The total burden, specific locations, and overall distribution of bone metastases did not predict disablement. Patients with lung cancer-associated bone metastases are at markedly increased risk for declining mobility when their metastases are expanding in size and increasing in number, or are associated with pain or with new neurologic deficits.

Respiratory motion variability of primary tumors and lymph nodes during radiotherapy of locally advanced non-small-cell lung cancers.

BACKGROUND AND PURPOSE: The need for target adjustment due to respiratory motion variation and the value of carina as a motion surrogate is evaluated for locally advanced non-small-cell lung cancer. MATERIAL AND METHODS: Using weekly 4D CTs (with audio-visual biofeedback) of 12 patients, respiratory motion variation of primary tumors (PT), lymph nodes (LN) and carina (C) were determined. RESULTS: Mean (SD) 3D respiratory motion ranges of PT, LN and C were 4 (3), 5 (3) and 5 (3) mm. PT and LN (p = 0.003), and LN and C motion range were correlated (p = 0.03). Only 20 %/5 % of all scans had variations >3 mm/5 mm. Large respiratory motion range on the initial scan was associated with larger during-treatment variations for PT (p = 0.03) and LN (p = 0.001). Mean (SD) 3D relative displacements of PT-C, LN-C and PT-LN were each 6 (2) mm. Variations of displacements >3 mm/5 mm were observed in 28 %/6 % of scans for PT-LN, 20 %/9 % for PT-C, and 20 %/8 % for LN-C. CONCLUSIONS: Motion reassessment is recommended in patients with large initial motion range. Relative motion-related displacements between PT and LN were larger than PT and LN motion alone. Both PT and C appear to be comparable surrogates for LN respiratory motion.

Clinical Application of Recombinant Human Endostatin in Postoperative Early Complementary Therapy on Patients with Non-small Cell Lung Cancer in Chinese Mainland.

OBJECTIVE: To explore the clinical application of recombinant human endostatin (Endostar) in the treatment of patients with non-small cell lung cancer (NSCLC) in Chinese mainland. MATERIALS AND METHODS: A total of 75 patients diagnosed as NSCLC were randomly divided into control group (37 cases) and treatment group (38 cases). Control group was treated with postoperative complementary chemotherapy containing two-agent platinum protocol on postoperative d21, 3 weeks as a cycle, for totally 4~6 cycles. On this basis, treatment group was added with Endostar 7.5 mg/m2 on postoperative d8~9, 3~4 h/time, qd, 14 weeks as a cycle, for totally 4 cycles. The interval between every two cycles was 7 d. The 5-year progression-free survival (PFS), 5-year survival time and complications in both groups were observed. RESULTS: Compared with control group, the average PFS increased evidently in treatment group by 9.8 months (41.6 months vs. 31.8 months), and there was significant difference (P<0.05). And the median PFS was 42.5 months in treatment group, obviously longer than that in control group (33.7 months) by 8.8 months (P<0.05). Additionally, the 5-year overall survival rate (OS), average survival time and median survival time (MST) were 47.4%, 50.1 months and 59.3 months in treatment group, significantly higher than the 29.7%, 42.1 months and 43.5 months in control group (P<0.05). Only 1 patient showed poor healing of surgical wound in treatment group, but no surgery-associated complication was found in control group. Moreover, the postoperative complementary therapy-connected complication rates were 63.2% (24/38) and 59.5% (22/37) in treatment group and control group respectively, but there was no significant difference (P>0.05). CONCLUSIONS: The application of Endostar combined with sensitive platinum-contained chemotherapeutic agents in the postoperative complementary chemotherapy can be widely used in clinic because it can significantly prolong the long-term survival time of patients with NSCLC.

Nodal stage of surgically resected non-small cell lung cancer and its effect on recurrence patterns and overall survival.

PURPOSE: Current National Comprehensive Cancer Network guidelines recommend postoperative radiation therapy (PORT) for patients with resected non-small cell lung cancer (NSCLC) with N2 involvement. We investigated the relationship between nodal stage and local-regional recurrence (LR), distant recurrence (DR) and overall survival (OS) for patients having an R0 resection. METHODS AND MATERIALS: A multi-institutional database of consecutive patients undergoing R0 resection for stage I-IIIA NSCLC from 1995 to 2008 was used. Patients receiving any radiation therapy before relapse were excluded. A total of 1241, 202, and 125 patients were identified with N0, N1, and N2 involvement, respectively; 161 patients received chemotherapy. Cumulative incidence rates were calculated for LR and DR as first sites of failure, and Kaplan-Meier estimates were made for OS. Competing risk analysis and proportional hazards models were used to examine LR, DR, and OS. Independent variables included age, sex, surgical procedure, extent of lymph node sampling, histology, lymphatic or vascular invasion, tumor size, tumor grade, chemotherapy, nodal stage, and visceral pleural invasion. RESULTS: The median follow-up time was 28.7 months. Patients with N1 or N2 nodal stage had rates of LR similar to those of patients with N0 disease, but were at significantly increased risk for both DR (N1, hazard ratio [HR] = 1.84, 95% confidence interval [CI]: 1.30-2.59; P=.001; N2, HR = 2.32, 95% CI: 1.55-3.48; P<.001) and death (N1, HR = 1.46, 95% CI: 1.18-1.81; P<.001; N2, HR = 2.33, 95% CI: 1.78-3.04; P<.001). LR was associated with squamous histology, visceral pleural involvement, tumor size, age, wedge resection, and segmentectomy. The most frequent site of LR was the mediastinum. CONCLUSIONS: Our investigation demonstrated that nodal stage is directly associated with DR and OS but not with LR. Thus, even some patients with, N0-N1 disease are at relatively high risk of local recurrence. Prospective identification of risk factors for local recurrence may aid in selecting an appropriate population for further study of postoperative radiation therapy.

Combined treatment modalities in Pancoast tumor: results of a monocentric retrospective study.

BACKGROUND: A retrospective monocentric study of consecutive patients with superior sulcus tumor non-small cell lung cancer (SS-NSCLC), treated by induction concurrent chemoradiotherapy (CRT), article management. METHODS: From 1994 to 2005, 36 patients (15 T3, 21 T4 tumors, including N2-N3 node involvement) received induction CRT with cisplatin/vinorelbine/fluorouracil combined with 44 Gy radiotherapy (5 daily 2 Gy fractions/week). After CRT completion, RECIST evaluation and operability were assessed. In resectable patients, surgery was performed one month after CRT. Patients with unresectable disease followed CRT up to 66 Gy. The median of follow-up period was 38.6 months [2-206]. RESULTS: Induction CRT was completed for 94.4% with 71% radiological objective response (OR). Sixteen patients (44%) underwent surgical resection, and pathologic complete resection was performed in 93.8%. There were 7 patients (44%) with pathologic complete response. The median disease-free survival (DFS) time was 12.9 months with DFS rates at 1 and 2 years 53.6% and 39.1% respectively. The median overall survival (OS) was 46.4 months. The OS rates at 2 and 5 years were 68.8% and 37.5% respectively with no difference between T3 and T4 tumors. In unresectable disease, the median DFS time was 8.1 months. The DFS rate at 1 year was 25.2%. The median OS was 9.1 months. The OS rates at 1 and 2 years were 45% and 16.9% respectively. Recurrences were found in 72% of patients. Brain metastasis was the most common site of recurrence. Prognostic factors for OS were the response to induction treatment, the possibility of surgery, and pathologic complete response. CONCLUSIONS: This trimodality treatment regimen confers a survival outcome in agreement with previous studies. Patients with pretreatment N3 lymph node should be included in trimodality treatment.

Membrane carbonic anhydrase IX expression and relapse risk in resected stage I-II non-small-cell lung cancer.

BACKGROUND: Adjuvant chemotherapy reduces recurrences of non-small-cell lung cancer (NSCLC). To determine which patients need adjuvant chemotherapy, we assessed factors associated with time to relapse (TTR). METHODS: In 230 resected stage I-II NSCLCs, we correlated immunohistochemistry scores for factors associated with cell growth rate, growth regulation, hypoxia, cell survival, and cell death with TTR. RESULTS: With a median follow-up of 82 months (1-158) for those alive and relapse free at last follow-up, median time to recurrence was not reached. The 2- and 5-year probabilities of maintaining freedom from recurrence were 80.7% (95% confidence interval, 75.3%, 86.4%) and 74.6% (95% confidence interval, 68.6%, 81.2%), respectively. TTR curves flattened at an apparent cure rate of 70%. In multicovariate Cox models, factors correlating with shorter TTR were membranous carbonic anhydrase IX (mCAIX) staining (any versus none, hazard ratio = 2.083, p = 0.023) and node stage (N1 versus N0, hazard ratio = 2.591, p = 0.002). mCAIX scores correlated positively with tumor size, grade, squamous histology, necrosis, mitoses, Ki67, p53, nuclear DNA methyltransferase 1, and cytoplasmic enhancer-of-split-and-hairy-related protein, and they correlated inversely with papillary histology, epidermal growth factor receptor mutation (trend), copper transporter-1, and cytoplasmic hypoxia-inducible factor-1α, vascular endothelial growth factor, DNA methyltransferase 1, and excision repair cross-complementing rodent repair deficiency, complementation group 1. CONCLUSION: Nodal stage and mCAIX immunohistochemistry were the strongest independent predictors of shorter TTR in resected NSCLCs. mCAIX correlated with tumor size, markers of tumor proliferation and necrosis, and tumor genetic characteristics, and it paradoxically correlated inversely with the hypoxia markers, hypoxia-inducible factor-1α and vascular endothelial growth factor. Presence of mCAIX could help determine patients with high risk of recurrence who might require adjuvant chemotherapy.

Zoledronic acid in patients with stage IIIA/B NSCLC: results of a randomized, phase III study.

BACKGROUND: Bone metastases are common in patients with advanced non-small-cell lung cancer (NSCLC) and can have devastating consequences. Preventing or delaying bone metastases may improve outcomes. PATIENTS AND METHODS: This study evaluated whether zoledronic acid (ZOL) delayed disease progression or recurrence in patients with controlled stage IIIA/B NSCLC after first-line therapy. Patients received vitamin D and calcium supplementation and were randomized to i.v. ZOL (every 3-4 weeks) or no treatment (control). The primary end point was progression-free survival (PFS). RESULTS: No significant intergroup differences were observed in PFS or overall survival (OS). Median PFS was 9.0 months with ZOL versus 11.3 months for control. Fifteen ZOL-treated (6.6%) and 19 control patients (9.0%) developed bone metastases. Estimated 1-year OS was 81.8% for each group. ZOL safety profile was consistent with previous clinical data, but with higher discontinuations versus control. Fifteen ZOL-treated (6.6%) and five control patients (2.3%) had renal adverse events. Two cases of osteonecrosis of the jaw were reported. CONCLUSIONS: ZOL did not significantly affect PFS or OS in stage IIIA/B NSCLC patients with controlled disease, with a trend toward worsening PFS in the longer-term follow-up. Few patients experienced bone metastases, possibly limiting the potential ZOL impact on disease course.