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1.  Phase I Study of Induction Chemotherapy and Concomitant Chemoradiotherapy with Irinotecan, Carboplatin, and Paclitaxel for Stage III Non-small Cell Lung Cancer 
Background
The aim of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and determine the phase II dose for the combination of irinotecan-carboplatin-paclitaxel given as induction chemotherapy and with concomitant chest radiotherapy for patients with Stage III non-small cell lung cancer.
Methods
Patients with Cancer and Leukemia Group B performance status of 0 to 2, stage IIIA and IIIB NSCLC patients with resectable or unresectable disease were treated with induction chemotherapy (irinotecan 100 mg/m2, carboplatin AUC 5, and paclitaxel 175 mg/m2 days 1 and 22) followed by concomitant chemotherapy (irinotecan, carboplatin, and paclitaxel) and chest radiotherapy (66 Gy for unresectable and 50 Gy for resectable disease) beginning on week 7. The primary objective was to escalate the dose of irinotecan during chemoradiation in sequential cohorts to determine the DLT and MTD of the regimen.
Results
Thirty-eight patients were enrolled (median age 63 years, 57% male, 41% performance status 0, 30% resectable). Induction chemotherapy was tolerable and active (response rate 26%; stable disease 60%). Eight patients did not receive concurrent chemoradiotherapy because of progressive disease (5), death (1), hypersensitivity reaction to paclitaxel (1), and withdrawal of consent (1). Twenty-nine patients received concurrent chemoradiotherapy. The concomitant administration of chest radiotherapy with weekly irinotecan, carboplatin, and paclitaxel was not feasible at the first, second, and third dose levels. DLT was failure to achieve recovery to ≤ grade 1 absolute neutrophil count by the day of scheduled chemotherapy administration. Dose de-escalation to irinotecan 30 mg/m2, paclitaxel 40 mg/m2 (with omission of carboplatin) delivered on weeks 2, 3, 5, and 6 of radiotherapy was the MTD. After induction chemotherapy, partial responses, stable disease, and progressive disease was observed in 26%, 60%, and 14% of patients, respectively. After chemoradiotherapy, partial responses were attained in 16 (55%) patients, whereas 12 patients (41%) attained disease stabilization. Median overall survival was 21 months for the entire cohort. Resectable patients had a median survival of 24 months, whereas unresectable patients had a median survival of 19 months. Differences in overall and progression-free survival rates between resectable and unresectable patients was not statistically significant (p = 0.52 and p = 0.90, respectively).
Discussion
Carboplatin, paclitaxel, and irinotecan with concurrent chemoradiotherapy was poorly tolerated as a result of neutropenia. Although dose de-escalation was required for delivery of the regimen, the response rates and survival outcomes were comparable to other similar regimens.
doi:10.1097/JTO.0b013e31815e8566
PMCID: PMC3742080  PMID: 18166842
Non-small cell lung cancer; Irinotecan; Radiation therapy; Multimodality therapy
2.  Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma 
Journal of Clinical Oncology  2012;30(20):2509-2515.
Purpose
Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM.
Patients and Methods
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m2 on days 1 and 8 every 21 days, cisplatin 75 mg/m2 every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression.
Results
One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater.
Conclusion
The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.
doi:10.1200/JCO.2011.41.5869
PMCID: PMC3397785  PMID: 22665541
3.  Effects of Vascular Endothelial Growth Factor Signaling Inhibition on Human Erythropoiesis 
The Oncologist  2013;18(8):965-970.
Vascular endothelial growth factor (VEGF) signaling inhibition is associated with increased red blood cell (RBC) counts and erythropoietin production in humans. The effects of these changes are subtle at physiologic doses and are unlikely to be clinically useful biomarkers for guiding the administration of or predicting treatment responses to VEGF pathway inhibitors. We analyzed RBC measurements in patients enrolled in three studies of VEGF signaling inhibition, but we noted no significant relationships between elevations in RBCs and changes in volume status or blood pressure or between elevations in erythropoietin and smoking status.
Inhibition of vascular endothelial growth factor (VEGF) signaling increases red blood cell (RBC) counts, and erythropoiesis markers have been proposed to guide antiangiogenic therapy in humans. We analyzed RBC measurements in patients enrolled in three studies: a phase II trial of axitinib in thyroid cancer; a study of sorafenib in advanced solid tumors; and a randomized trial of fluorouracil, hydroxyurea, and radiation with and without bevacizumab for head and neck cancer. In the sorafenib trial, plasma erythropoietin concentrations were measured at baseline, day 8, and day 35. Over the first 84 days of treatment, RBC counts increased for each day on sorafenib (2.7 M/μL [95% confidence interval (CI), 1.5–3.9]) and axitinib (4.3 M/μL [95% CI, 2.2–6.5]). RBCs declined over the first 68 days of cytotoxic chemoradiotherapy alone (−12.8 M/μL per day [95% CI, −15.7 to −9.8]) but less so with added bevacizumab (−7.2 M/μL per day [95% CI, −9.5 to −4.9]). Erythropoietin levels increased, on average, by 9.5 mIU/mL between day 8 and day 35 of sorafenib exposure. No significant relationships between elevations in RBCs and changes in volume status or blood pressure or between elevations in erythropoietin and smoking status were found. VEGF signaling inhibition is associated with increased RBC and erythropoietin production in humans. The effects of these changes are subtle at physiologic doses and are unlikely to be clinically useful biomarkers for guiding the administration of or predicting treatment responses to VEGF pathway inhibitors.
doi:10.1634/theoncologist.2013-0006
PMCID: PMC3755935  PMID: 23900000
Vascular endothelial growth factor A; Biological markers; Erythrocyte count; Erythropoietin; Axitinib; Bevacizumab; Sorafenib
4.  Randomized Phase II Trial of Erlotinib Alone or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers With Advanced Lung Adenocarcinoma: CALGB 30406 Trial 
Journal of Clinical Oncology  2012;30(17):2063-2069.
Purpose
Erlotinib is clinically effective in patients with non–small-cell lung cancer (NSCLC) who have adenocarcinoma, are never or limited former smokers, or have EGFR mutant tumors. We investigated the efficacy of erlotinib alone or in combination with chemotherapy in patients with these characteristics.
Patients and Methods
Patients with advanced NSCLC (adenocarcinoma) who were epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy naive never or light former smokers (smokers of > 100 cigarettes and ≤ 10 pack years and quit ≥ 1 year ago) were randomly assigned to continuous erlotinib or in combination with carboplatin and paclitaxel (ECP) for six cycles followed by erlotinib alone. The primary end point was progression-free survival (PFS). Tissue collection was mandatory.
Results
PFS was similar (5.0 v 6.6 months; P = .1988) in patients randomly assigned to erlotinib alone (arm A; n = 81) or to ECP (arm B; n = 100). EGFR mutation analysis was possible in 91% (164 of 181) of patients, and EGFR mutations were detected in 40% (51 of 128) of never smokers and in 42% (15 of 36) of light former smokers. In arm A, response rate (70% v 9%), PFS (14.1 v 2.6 months), and overall survival (OS; 31.3 v 18.1 month) favored EGFR-mutant patients. In arm B, response rate (73% v 30%), PFS (17.2 v 4.8 months), and OS (38.1 v 14.4 months) favored EGFR-mutant patients. Incidence of grades 3 to 4 hematologic (2% v 49%; P < .001) and nonhematologic (24% v 52%; P < .001) toxicity was greater in patients treated with ECP.
Conclusion
Erlotinib and erlotinib plus chemotherapy have similar efficacy in clinically selected populations of patients with advanced NSCLC. EGFR mutations identify patients most likely to benefit.
doi:10.1200/JCO.2011.40.1315
PMCID: PMC3397694  PMID: 22547605
5.  Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium 
Investigational new drugs  2010;30(1):382-386.
Summary
Background
Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease.
Patients and methods
We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naïve patients with histologicallyconfirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2 on days 1, 8 and 15 of a 28 day cycle.
Results
Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%.
Conclusion
Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.
doi:10.1007/s10637-010-9526-z
PMCID: PMC4319645  PMID: 20803052
Pancreatic cancer; Phase II trial; Gemcitabine; Sorafenib
6.  Cediranib in patients with malignant mesothelioma: A phase II trial of the University of Chicago Phase II Consortium 
Introduction
Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors -1, -2, and -3.
Methods
We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily.
Results
Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR + SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed ≥ grade 3 hypertension (8.5 vs. 4.1 months, p=0.024).
Conclusion
This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated.
doi:10.1016/j.lungcan.2012.06.011
PMCID: PMC4319647  PMID: 22831987
Mesothelioma; cediranib; vascular endothelial growth factor; hypertension
7.  Dasatinib in previously treated metastatic colorectal cancer: a phase II trial of the University of Chicago Phase II Consortium 
Investigational new drugs  2011;30(3):1211-1215.
Summary
Background
Treatment options for metastatic colorectal cancer (CRC) are limited after a fluoropyrimi-dine, oxaliplatin and irinotecan; novel agents need to be explored in this setting. Dasatinib, an oral inhibitor of Src family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models.
Patients and methods
We conducted a multi-center phase II trial of dasatinib in unresectable, previously-treated metastatic CRC patients. No more than 2 prior chemotherapy regimens were permitted, which must have contained a fluoropyrimidine, oxaliplatin and irinotecan. The primary endpoint was progression-free survival (PFS) at 4 months. The Simon two-stage design required that at least 5 of the first 19 patients be progression-free at 4 months to expand to a second stage.
Results
Nineteen patients enrolled at 9 centers. The study was terminated after the first stage due to lack of efficacy. There were no objective responses; 1 patient (5%) had stable disease for 7.3 months. The PFS rate at 4 months was 5.3% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Grade 3/4 toxicities included fatigue in 16% of patients, and anemia, anorexia, nausea/vomiting and dyspnea in 11%.
Conclusion
Dasatinib is inactive as a single agent in previously treated metastatic CRC patients.
doi:10.1007/s10637-011-9681-x
PMCID: PMC4317401  PMID: 21552992
Colorectal cancer; Phase II trial; Dasatinib
8.  Cisplatin, Irinotecan, and Bevacizumab for Untreated Extensive-Stage Small-Cell Lung Cancer: CALGB 30306, a Phase II Study 
Journal of Clinical Oncology  2011;29(33):4436-4441.
Purpose
The efficacy of cisplatin, irinotecan, and bevacizumab was evaluated in patients with extensive-stage small-cell lung cancer (ES-SCLC).
Patients and Methods
Patients with ES-SCLC received cisplatin 30 mg/m2 and irinotecan 65 mg/m2 on days 1 and 8 plus bevacizumab 15 mg/kg on day 1 every 21 days for six cycles on this phase II study. The primary end point was to differentiate between 50% and 65% 12-month survival rates.
Results
Seventy-two patients were enrolled between March 2005 and April 2006; four patients canceled, and four were ineligible. Grade 3 or 4 toxicities included neutropenia (25%), all electrolyte (23%), diarrhea (16%), thrombocytopenia (10%), fatigue (10%), nausea (10%), hypertension (9%), anemia (9%), infection (7%), vascular access thrombosis (2%), stroke (2%), and bowel perforation (1%). Three deaths (5%) occurred on therapy as a result of pneumonitis (n = 1), stroke (n =1), and heart failure (n = 1). Complete response, partial response, and stable disease occurred in three (5%), 45 (70%), and 11 patients (17%), respectively. Progressive disease occurred in one patient (2%). Overall response rate was 75%. Median progression-free survival (PFS) was 7.0 months (95% CI, 6.4 to 8.4 months). Median overall survival (OS) was 11.6 months (95% CI, 10.5 to 15.1 months). Hypertension ≥ grade 1 was associated with improved OS after adjusting for performance status (PS) and age (hazard ratio [HR], 0.55; 95% CI, 0.31 to 0.97; P = .04). Lower vascular endothelial growth factor levels correlated with worse PFS after adjusting for age and PS (HR, 0.90; 95% CI, 0.83 to 0.99; P = .03).
Conclusion
PFS and OS times were higher compared with US trials in ES-SCLC with the same chemotherapy. However, the primary end point of the trial was not met. Hypertension was associated with improved survival after adjusting for age and PS.
doi:10.1200/JCO.2011.35.6923
PMCID: PMC3221525  PMID: 21969504
9.  Combination MET inhibition and Topoisomerase I inhibition block cell growth of Small Cell Lung Cancer 
Molecular cancer therapeutics  2013;13(3):576-584.
Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)–induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC.
doi:10.1158/1535-7163.MCT-13-0109
PMCID: PMC4286701  PMID: 24327519
small cell lung cancer; MET; topoisomerase-I; SU11274; SN-38
10.  A Randomized Phase II Study to Assess the Efficacy of Pemetrexed or Sunitinib or Pemetrexed Plus Sunitinib in the Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer 
Background
Second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) improves survival modestly but new strategies are needed. This trial was designed to evaluate an antivascular endothelial growth factor strategy with or without standard chemotherapy in previously treated NSCLC.
Methods
Patients with stage IIIB/IV NSCLC with performance status 0 to 1 progressive after first-line chemotherapy were eligible for randomization to pemetrexed, sunitinib, or the combination. Patients were stratified by performance status, stage, and sex. Primary objective was 18-week progression-free survival (PFS) rate; secondary objectives included response, overall survival (OS), and toxicity. Target accrual was 225. The study was terminated early because of decreasing accrual rates.
Results
Between April 2008 and September 2011, 130 patients were registered and randomized; of this, 125 patients were treated. Baseline characteristics in the three arms were well balanced. Toxicity was higher in the sunitinib-containing arms. The 18-week PFS rate in the pemetrexed, sunitinib, and combination arms was 54% (95% confidence interval [CI], 40–71), 37% (95% CI, 25–54), and 48% (95% CI, 35–66), respectively (p= 0.25). Median PFS in the pemetrexed, sunitinib, and combination arms in months was 4.9 (2.1–8.8), 3.3 (2.3–4.2), and 3.7 (2.5–5.8), respectively (p= 0.18). There was an overall statistically significant difference in OS between the three arms: median OS in months was 10.5 (8.3–20.2) for pemetrexed, 8.0 (6.8–13.5) for sunitinib, and 6.7 (4.1–10.1) for the combination (p= 0.03).
Conclusion
Pemetrexed had a superior toxicity profile to either sunitinib or the combination of pemetrexed and sunitinib. The 18-week PFS rate was not significantly different between the arms. OS was significantly better with pemetrexed alone compared with the two sunitinib-containing arms, with the doublet performing worst for OS.
doi:10.1097/JTO.0000000000000071
PMCID: PMC4284815  PMID: 24419419
CALGB 30704; Lung cancer
11.  Randomized Phase II Study of Pemetrexed, Carboplatin, and Thoracic Radiation With or Without Cetuximab in Patients With Locally Advanced Unresectable Non–Small-Cell Lung Cancer: Cancer and Leukemia Group B Trial 30407 
Journal of Clinical Oncology  2011;29(23):3120-3125.
Purpose
Cancer and Leukemia Group B conducted a randomized phase II trial to investigate two novel chemotherapy regimens in combination with concurrent thoracic radiation therapy (TRT).
Patients and Methods
Patients with unresectable stage III non–small-cell lung cancer (NSCLC) were randomly assigned to carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2) every 21 days for four cycles and TRT (70 Gy; arm A) or the same treatment with cetuximab administered concurrent only with TRT (arm B). Patients in both arms received up to four cycles of pemetrexed as consolidation therapy. The primary end point was the 18-month overall survival (OS) rate; if the 18-month OS rate was ≥ 55%, the regimen(s) would be considered for further study.
Results
Of the 101 eligible patients enrolled (48 in arm A and 53 in arm B), 60% were male; the median age was 66 years (range, 32 to 81 years); 44% and 35% had adenocarcinoma and squamous carcinoma, respectively; and more patients enrolled onto arm A compared with arm B had a performance status of 0 (58% v 34%, respectively; P = .04). The 18-month OS rate was 58% (95% CI, 46% to 74%) in arm A and 54% (95% CI, 42% to 70%) in arm B. No significant difference in OS between patients with squamous and nonsquamous NSCLC was observed (P = .667). The toxicities observed were consistent with toxicities associated with concurrent chemoradiotherapy.
Conclusion
The combination of pemetrexed, carboplatin, and TRT met the prespecified criteria for further evaluation. This regimen should be studied further in patients with locally advanced unresectable nonsquamous NSCLC.
doi:10.1200/JCO.2010.33.4979
PMCID: PMC3157978  PMID: 21747084
12.  Predictors of pulmonary toxicity in limited stage small cell lung cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70 Gy daily radiotherapy: CALGB 30904 
Introduction
Standard therapy for limited stage small cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy followed by prophylactic cranial radiotherapy. Predictors of post chemoradiotherapy pulmonary toxicity in limited stage (LS) small cell lung cancer (SCLC) patients are not well defined. Current guidelines are derived from non-small cell lung cancer regimens, and do not account for the unique biology of this disease. Therefore, we analyzed patients on three consecutive CALGB LS-SCLC trials treated with concurrent chemotherapy and daily high dose radiotherapy (70 Gy) to determine patient and treatment related factors predicting for post-treatment pulmonary toxicity.
Methods
Patients treated on CALGB protocols 39808, 30002, 30206 investigating two cycles of chemotherapy followed by concurrent chemotherapy and 70 Gy daily thoracic radiation therapy were pooled. Patient, tumor, and treatment related factors were evaluated to determine predictors of grade 3–5 pulmonary toxicities after concurrent chemoradiotherapy.
Results
100 patients were included. No patient experienced grade 4–5 post-treatment pulmonary toxicity. Patients who experienced post-treatment pulmonary toxicity were more likely to be older (median age 69 vs 60, p=0.09) and have smaller total lung volumes (2565 cc vs 3530 cc, p=0.05).). Furthermore, exposure of larger volumes of lung to lower (median V5=70%, p=0.09, median V10=63%, p=0.07), intermediate (median V20=50, p=0.04) and high (median V60=25%, p=0.01) doses of radiation were all associated with post-treatment grade 3 pulmonary toxicity, as was a larger mean lung radiation dose (median 31 Gy) p=0.019.
Conclusion
Post-treatment pulmonary toxicity following the completion of 2 cycles of chemotherapy followed by concurrent chemotherapy and high dose daily radiation therapy was uncommon. Care should be taken to minimize mean lung radiation exposure, as well as volumes of low, intermediate and high doses of radiation.
PMCID: PMC4098705  PMID: 24396884
limited stage; small cell lung cancer; high dose chemoradiotherapy; toxicity predictors; pneumonitis; lung toxicity radiation
14.  A Pooled Analysis of Limited Stage Small Cell Lung Cancer Patients Treated with Induction Chemotherapy Followed by Concurrent Platinum-based Chemotherapy and 70 Gy Daily Radiotherapy: CALGB 30904 
Introduction
Standard therapy for limited stage small cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy followed by prophylactic cranial radiotherapy. Although many consider the standard radiotherapy regimen to be 45 Gray (Gy) in 1.5 Gy twice-daily fractions, this has failed to gain widespread acceptance. We pooled data for patients assigned to receive daily radiotherapy to 70 Gy on three consecutive prospective CALGB L-SCLC cancer trials and report the results here.
Methods
All patients on consecutive CALGB L-SCLC trials (39808, 30002, and 30206) utilizing high dose daily radiotherapy with concurrent chemotherapy were included, and analyzed for toxicity, disease control and survival. Overall survival (OS) and Progression-free survival (PFS) were modeled using Cox proportional hazards models. Prognostic variables for OS-rate and PFS-rate were assessed using logistic regression model.
Results
200 patients were included. The median follow-up was 78 months. Grade 3 or greater esophagitis was 23%. The median OS for pooled population was 19.9 months (95% CI: 16.7-22.3), and 5-year OS rate was 20% (95% CI: 16-27%). The 2 year progression free survival was 26% (95% CI: 21-32%). Multivariate analysis found younger age p=0.02 (HR: 1.023, 95% CI: (1.00,1.04), and female sex p=0.02 (HR:0.69, 95% CI: 0.50-0.94) independently associated with improved overall survival.
Conclusion
2 Gy daily radiotherapy to a total dose of 70 Gy was well tolerated with similar survival to 45 Gy (1.5 Gy twice daily). This experience may aid practitioners decide whether high dose daily radiotherapy with platinum based chemotherapy is appropriate outside of a clinical trial.
doi:10.1097/JTO.0b013e318293d8a4
PMCID: PMC3822578  PMID: 23715301
15.  DNA Repair Biomarkers XPF and Phospho-MAPKAP Kinase 2 Correlate with Clinical Outcome in Advanced Head and Neck Cancer 
PLoS ONE  2014;9(7):e102112.
Background
Induction chemotherapy is a common therapeutic option for patients with locoregionally-advanced head and neck cancer (HNC), but it remains unclear which patients will benefit. In this study, we searched for biomarkers predicting the response of patients with locoregionally-advanced HNC to induction chemotherapy by evaluating the expression pattern of DNA repair proteins.
Methods
Expression of a panel of DNA-repair proteins in formalin-fixed paraffin embedded specimens from a cohort of 37 HNC patients undergoing platinum-based induction chemotherapy prior to definitive chemoradiation were analyzed using quantitative immunohistochemistry.
Results
We found that XPF (an ERCC1 binding partner) and phospho-MAPKAP Kinase 2 (pMK2) are novel biomarkers for HNSCC patients undergoing platinum-based induction chemotherapy. Low XPF expression in HNSCC patients is associated with better response to induction chemoradiotherapy, while high XPF expression correlates with a worse response (p = 0.02). Furthermore, low pMK2 expression was found to correlate significantly with overall survival after induction plus chemoradiation therapy (p = 0.01), suggesting that pMK2 may relate to chemoradiation therapy.
Conclusions
We identified XPF and pMK2 as novel DNA-repair biomarkers for locoregionally-advanced HNC patients undergoing platinum-based induction chemotherapy prior to definitive chemoradiation. Our study provides insights for the use of DNA repair biomarkers in personalized diagnostics strategies. Further validation in a larger cohort is indicated.
doi:10.1371/journal.pone.0102112
PMCID: PMC4096922  PMID: 25019640
16.  Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer 
BMC Cancer  2014;14:185.
Background
Non-small cell lung cancers (NSCLC) are highly heterogeneous at the molecular level and comprise 75% of all lung tumors. We have previously shown that the receptor tyrosine kinase (RTK) MET frequently suffers gain-of-function mutations that significantly promote lung tumorigenesis. Subsequent studies from our lab also revealed that PAX5 transcription factor is preferentially expressed in small cell lung cancer (SCLC) and promotes MET transcription. PAX8, however, is also expressed in NSCLC cell lines. We therefore investigated the role of PAX8 in NSCLC.
Methods
Using IHC analysis, PAX8 protein expression was determined in archival NSCLC tumor tissues (n = 254). In order to study the effects of PAX8 knockdown on NSCLC cellular functions such as apoptosis and motility, siRNA against PAX8 was used. Confocal fluorescence microscopy was used to monitor the localization of MET, RON and PAX8. The combinatorial effect of PAX8 knockdown and MET inhibition using SU11274 was investigated in NSCLC cell viability assay.
Results
Relative levels of PAX8 protein were elevated (≥ + 2 on a scale of 0–3) in adenocarcinoma (58/94), large cell carcinoma (50/85), squamous cell carcinoma (28/47), and metastatic NSCLC (17/28; lymph node). Utilizing early progenitors isolated from NSCLC cell lines and fresh tumor tissues, we observed robust overexpression of PAX8, MET, and RON. PAX8 knockdown A549 cells revealed abrogated PAX8 expression with a concomitant loss in MET and the related RON kinase expression. A dramatic colocalization between the active form of MET (also RON) and PAX8 upon challenging A549 cells with HGF was visualized. A similar colocalization of MET and EGL5 (PAX8 ortholog) proteins was found in embryos of C. elegans. Most importantly, knockdown of PAX8 in A549 cells resulted in enhanced apoptosis (~6 fold) and decreased cell motility (~45%), thereby making PAX8 a potential therapeutic target. However, the combinatorial approach of PAX8 knockdown and treatment with MET inhibitor, SU11274, had marginal additive effect on loss of NSCLC cell viability.
Conclusion
PAX8 provides signals for growth and motility of NSCLC cells and is necessary for MET and RON expression. Further investigations are necessary to investigate the therapeutic potential of PA8 in NSCLC.
doi:10.1186/1471-2407-14-185
PMCID: PMC3995599  PMID: 24628993
PAX8; MET; RON; NSCLC
17.  Evaluation of a novel rash scale and a serum proteomic predictor in a randomized phase II trial of sequential or concurrent cetuximab and pemetrexed in previously treated non-small cell lung cancer 
BMC Cancer  2014;14:5.
Background
Candidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC). In a phase II trial that was closed to accrual because of changes in clinical practice we examined the relationships among candidate biomarkers, quantitative changes in tumor size, progression-free and overall survival.
Methods
55 patients with progressive NSCLC after platinum therapy were randomized to receive (Arm A) cetuximab, followed by pemetrexed at progression, or (Arm B) concurrent cetuximab and pemetrexed. All received cetuximab monotherapy for the first 14 days. Pre-treatment serum and weekly rash assessments by standard and EGFRi-induced rash (EIR) scales were collected.
Results
43 patients (20-Arm A, 23-Arm B) completed the 14-day run-in. Median survival was 9.1 months. Arm B had better median overall (Arm B = 10.3 [95% CI 7.5, 16.8]; Arm A = 3.5 [2.8, 11.7] months P = 0.046) and progression-free survival (Arm B = 2.3 [1.6, 3.1]; Arm A = 1.6 [0.9, 1.9] months P = 0.11). The EIR scale distributed ratings among 6 rather than 3 categories but ordinal scale rash severity did not predict outcomes. The serum proteomic classifier and absence of rash after 21 days of cetuximab did.
Conclusions
Absence of rash after 21 days of cetuximab therapy and the serum proteomic classifier, but not ordinal rash severity, were associated with NSCLC outcomes. Although in a small study, these observations were consistent with results from larger retrospective analyses.
Trial registration
Clinicaltrials.gov Identifier NCT00203931
doi:10.1186/1471-2407-14-5
PMCID: PMC3893521  PMID: 24386952
Pemetrexed; Lung Cancer; Cetuximab; Rash; EGFR; Proteomics
18.  Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited stage small cell lung cancer: CALGB 30206 
Introduction
We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens sequentially for patients with untreated limited stage small cell lung cancer (LS-SCLC).
Methods
Patients with untreated, measurable LS-SCLC, performance status 0–2, and adequate organ function were eligible. Treatment consisted of induction with cisplatin 30 mg/m2 and irinotecan 65 mg/m2 intravenously on day 1 and 8 every 21 days for two cycles. Beginning day 43, daily chest irradiation to 70 Gy was administered concurrently with carboplatin AUC 5 day 1 and etoposide 100 mg/m2 days 1 to 3 every 21 days for 3 cycles. The primary objective was to differentiate between 45% and 60% 2-year survival.
Results
Two induction cycles were delivered to 72 of 75 (96%) eligible patients and all planned treatment was delivered to 59 patients (79%). Cisplatin and irinotecan induction chemotherapy resulted in complete responses in 7% and partial responses 64% (response rate 71%; 95% CI 59–81%). The best response to all therapy included 88% complete or partial responses (95% CI for 78–94%). With median follow-up of 57 months, the median progression-free survival and overall survival are 12.6 (95% CI 9.4–14.7) and 18.1 months (15.8–22.9), respectively. The 1- and 2-year survival was 69% and 31%, respectively. Frequent (>20%) grade 3 and 4 toxicities were neutropenia 84%, hemoglobin 36%, platelets 51%, esophagitis (22%) and dehydration in 24%. There were no fatal toxicities.
Conclusions
This treatment regimen of irinotecan-cisplatin induction chemotherapy followed by 70 Gy concurrent radiation and etoposide-carboplatin has tolerable toxicity but did not meet the pre-planned 2-year survival target for further development.
doi:10.1097/JTO.0b013e31827628e1
PMCID: PMC3524334  PMID: 23196276
small cell lung cancer; chemotherapy; radiotherapy; topoisomerase inhibitor
19.  O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer 
Background:
World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer.
Methods:
We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo, a mouse flank xenograft tumor model was utilized.
Results:
Nearly 71% (12/17) of adenocarcinoma and 38% (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC50 of 52-420 μM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60%.
Conclusion:
MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.
doi:10.4103/1477-3163.120632
PMCID: PMC3853796  PMID: 24319345
Alkylating agents; deoxyribonucleic acid repair genes; in vivo pre-clinical; esophageal cancer; O-6-methylguanine-deoxyribonucleic acid methyltransferase hypermethylation; response to treatment; temozolomide
20.  Randomized Phase II Study of Carboplatin and Etoposide With or Without the bcl-2 Antisense Oligonucleotide Oblimersen for Extensive-Stage Small-Cell Lung Cancer: CALGB 30103 
Purpose
To assess the efficacy and toxicity of carboplatin, etoposide, and the bcl-2 antisense oligonucleotide oblimersen as initial therapy for extensive-stage small-cell lung cancer (ES-SCLC). bcl-2 has been implicated as a key factor in SCLC oncogenesis and chemotherapeutic resistance.
Patients and Methods
A 3:1 randomized phase II study was performed to evaluate carboplatin and etoposide with (arm A) or without oblimersen (arm B) in 56 assessable patients with chemotherapy-naïve ES-SCLC. Outcome measures including toxicity, objective response rate, complete response rate, failure-free survival, overall survival, and 1-year survival rate.
Results
Oblimersen was associated with slightly more grade 3 to 4 hematologic toxicity (88% v 60%; P = .05). Response rates were 61% (95% CI, 45% to 76%) for arm A and 60% (95% CI, 32% to 84%) for arm B. The percentage of patients alive at 1 year was 24% (95% CI, 12% to 40%) with oblimersen, and 47% (95% CI, 21% to 73%) without oblimersen. Hazard ratios for failure-free survival (1.79; P = .07) and overall survival (2.13; P = .02) suggested worse outcome for patients receiving oblimersen. These results hold when adjusted for other prognostic factors, such as weight loss, in multivariate regression analysis.
Conclusion
Despite extensive data supporting a critical role for Bcl-2 in chemoresistance in SCLC, addition of oblimersen to a standard regimen for this disease did not improve any clinical outcome measure. Emerging data from several groups suggest that this lack of efficacy may be due to insufficient suppression of Bcl-2 in vivo. Additional evaluation of this agent in SCLC is not warranted.
doi:10.1200/JCO.2007.14.3461
PMCID: PMC3715075  PMID: 18281659
21.  The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target 
PLoS ONE  2013;8(7):e67668.
Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.
doi:10.1371/journal.pone.0067668
PMCID: PMC3699624  PMID: 23844053
23.  Paxillin mutations affect focal adhesions and lead to altered mitochondrial dynamics 
Cancer Biology & Therapy  2013;14(7):679-691.
Cytoskeletal and focal adhesion abnormalities are observed in several types of cancer, including lung cancer. We have previously reported that paxillin (PXN) was mutated, amplified, and overexpressed in a significant number of lung cancer patient samples, that PXN protein was upregulated in more advanced stages of lung cancer compared with lower stages, and that the PXN gene was also amplified in some pre-neoplastic lung lesions. Among the mutations investigated, we previously found that PXN variant A127T in lung cancer cells enhanced cell proliferation and focal adhesion formation and colocalized with the anti-apoptotic protein B Cell Lymphoma 2 (BCL-2), which is known to localize to the mitochondria, among other sites. To further explore the effects of activating mutations of PXN on mitochondrial function, we cloned and expressed wild-type PXN and variants containing the most commonly occurring PXN mutations (P46S, P52L, G105D, A127T, P233L, T255I, D399N, E423K, P487L, and K506R) in a GFP-tagged vector using HEK-293 human embryonic kidney cells. Utilizing live-cell imaging to systematically study the effects of wild-type PXN vs. mutants, we created a model that recapitulates the salient features of the measured dynamics and conclude that compared with wild-type, some mutant clones confer enhanced focal adhesion and lamellipodia formation (A127T, P233L, and P487L) and some confer increased association with BCL-2, Dynamin-related Protein-1 (DRP-1), and Mitofusion-2 (MFN-2) proteins (P233L and D399N). Further, PXN mutants, through their interactions with BCL-2 and DRP-1, could regulate cisplatin drug resistance in human lung cancer cells. The data reported herein suggest that mutant PXN variants play a prominent role in mitochondrial dynamics with direct implications on lung cancer progression and hence, deserve further exploration as therapeutic targets.
doi:10.4161/cbt.25091
PMCID: PMC3742497  PMID: 23792636
mitochondria; paxillin; gene mutation; cell motility; fission; fusion; mitochondrial dynamics
24.  Phase II study of dasatinib in patients with previously treated malignant mesothelioma (Cancer and Leukemia Group B 30601): a brief report 
Journal of Thoracic Oncology  2012;7(4):755-759.
Introduction
We conducted a phase II trial of dasatinib in malignant mesothelioma (MM) patients to evaluate its toxicity and efficacy as a second-line treatment.
Material and Methods
Patients with unresectable MM and no symptomatic effusions were given dasatinib 70 mg twice daily as part of a 28-day cycle. We also measured plasma VEGF and PDGFβ and serum CSF-1 and mesothelin-related protein at baseline and during therapy.
Results
Forty-six patients were enrolled in this study. Fifty percent of the first 12 patients enrolled experienced ≥ grade 3 treatment-related adverse events, and therefore, the starting dose was reduced to 50 mg twice daily. Grade 3 and 4 toxicities included fatigue (11%) and pleural effusion (9%). The overall disease control rate was 32.6%, and PFS at 24 weeks was 23% (95% CI: 13.5%, 40.0%). Survival was markedly longer in patients with lower pre-treatment CSF-1 levels and in patients whose CSF-1 levels decreased from baseline during therapy.
Discussion
Single-agent dasatinib has no activity in MM and is associated with pulmonary toxicities that prohibit its use in an unselected MM population.
doi:10.1097/JTO.0b013e318248242c
PMCID: PMC3308128  PMID: 22425926
dasatinib; mesothelioma; SRC kinase
25.  A phase II study of halichondrin B analogue eribulin mesylate (E7389) in patients with advanced non-small cell lung cancer previously treated with a taxane: a California Cancer Consortium trial 
Journal of Thoracic Oncology  2012;7(3):574-578.
Introduction
Eribulin mesylate (E7389) is an analog of halichondrin B with a unique mechanism of microtubule binding. The activity and toxicity of eribulin were assessed in patients with advanced non-small cell lung cancer (NSCLC) previously treated with a taxane.
Methods
An open-label phase II study included patients with NSCLC previously treated with platinum and taxane-based therapy, with up to two prior cytotoxic regimens, given for metastatic disease or as adjuvant therapy. Patients were stratified by taxane-sensitivity: taxane-sensitive (TS, progression > 90 days after taxane) or taxane-resistant (TR, progression ≤ 90 days after taxane). Patients received an intravenous infusion of eribulin at 1.4 mg/m2 on days 1 and 8 every 21 days. The primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS) and overall survival (OS).
Results
Sixty-six patients were accrued. The ORR was 5% with a median duration of response of 7.8 months. In the TS arm, 3 out of 45 patients (7%) achieved a partial response (PR) and another 11 out of 45 (24%) achieved stable disease (SD) for at least 3 months, whereas in the TR arm, no patients achieved a PR and 4 out of 21 (19%) achieved SD for at least 3 months. Median PFS was 2.9 months in the TS subgroup and 1.2 months in the TR subgroup. The median OS was 12.6 months in the TS subgroup and 8.9 months in the TR subgroup. Toxicities were primarily hematologic; only two patients developed grade 3 neuropathy.
Conclusions
Eribulin mesylate is well tolerated and demonstrates activity in pre-treated, taxane-sensitive NSCLC.
doi:10.1097/JTO.0b013e31823f43ca
PMCID: PMC3288403  PMID: 22198425
Halichondrin B; Eribulin Mesylate; Non-Small Cell Lung Cancer; Taxane-Refractory; Taxane-Sensitive

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