Everett E Vokes

Publications of Everett E Vokes

• Differential expression of RON in small and non-small cell lung cancers.

  Authors: Rajani Kanteti, Soundararajan Krishnaswamy, Daniel Catenacci, Yi-Hung Carol Tan, Essam El-Hashani, Gustavo Cervantes, Aliya N Husain, Maria Tretiakova, Everett E Vokes, Heather Huet, Ravi Salgia

  Genes, chromosomes & cancer. 05/2012;

  RON is a MET related receptor tyrosine kinase (RTK) and its natural ligand is macrophage stimulating protein (MSP). RON plays a very important role in the regulation of inflammation. Several studiesRON is a MET related receptor tyrosine kinase (RTK) and its natural ligand is macrophage stimulating protein (MSP). RON plays a very important role in the regulation of inflammation. Several studies have previously reported overexpression of RON in a variety of cancers including lung and identified numerous RON alternate splice forms that very likely contribute to tumor growth and metastasis. Here, we have analyzed the expression of total RON protein as well as its kinase-active form (phospho-RON) in 175 archival lung tumor FFPE (formalin fixed paraffin embedded) samples that included non-small-cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and their metastatic forms. The frequency and intensity of RON protein expression was much higher in lung tumors of neuroendocrine origin such as SCLC and in secondary tumors that metastasized to brain. In addition, the majority of the expressed RON protein was phospho-RON. We also identified 62, and 30 kDa isoforms of RON (GenBank accession numbers are JN689381 and JN689382) using RNA isolated from pooled lung cancer cell lines and RT-PCR. A majority of the NSCLC cell lines expressed a 150 kDa band that corresponded to the RON β chain and 120 kDa band in the panel of SCLC cell lines tested. RON was expressed on the cell surface in NSCLC cell lines. Finally, knock down of RON expression resulted in a significant loss in viability as well as motility in lung cancer cells suggesting that RON is a potential therapeutic target. © 2012 Wiley Periodicals, Inc.

• Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer.

  Authors: Helena J Mauceri, Harold G Sutton, Thomas E Darga, Masha Kocherginsky, Joel Kochanski, Ralph R Weichselbaum, Everett E Vokes

  Oncology reports. 05/2012; 27(5):1625-9.

  Signaling pathways that activate mTOR (mammalian target of rapamycin) are altered in many human cancers and these alterations are associated with prognosis and treatment response. mTOR inhibition canSignaling pathways that activate mTOR (mammalian target of rapamycin) are altered in many human cancers and these alterations are associated with prognosis and treatment response. mTOR inhibition can restore sensitivity to DNA damaging agents such as cisplatin. The rapamycin derivative everolimus exhibits antitumor activity and is approved for patients with renal cell cancer. Clinically, everolimus has also been evaluated in patients with advanced non-small cell lung cancer (NSCLC) that were refractory to chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors. We tested the effects of combined treatment with everolimus (RAD001) and fractionated radiation using a xenograft model of human NSCLC (A549 cells). In growth studies, mean tumor volume was reduced in the everolimus plus 30 Gy cohort with significant tumor growth suppression compared to 30 Gy alone (p=0015), or everolimus alone (p<0.001, ANOVA). everolimus (20 nM) significantly reduced protein levels of the mTOR downstream effector p70-S6K compared with radiation and vehicle (p=0.05, ANOVA) and significantly suppressed phospho-p70-S6K levels compared with all other treatments (p<0.001, ANOVA). We also evaluated everolimus and radiation effects on gene expression in A549 cells. Everolimus ± 5 Gy suppressed endothelin 1 and lactate dehydrogenase expression and increased VEGFA, p21, hypoxia-inducible factor-1α and SLC2A1 (facilitated glucose transporter 1). mTOR mRNA levels were unaffected while TNF-α levels were increased with everolimus + 5 Gy compared to either treatment alone. These findings suggest that everolimus increases the antitumor activity of radiation. Clinical trials combining everolimus with fractionated radiation in patients with NSCLC are warranted.

• 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.

  Authors: Pasi A Jänne, Xiaofei Wang, Mark A Socinski, Jeffrey Crawford, Thomas E Stinchcombe, Lin Gu, Marzia Capelletti, Martin J Edelman, Miguel A Villalona-Calero, Robert Kratzke, Everett E Vokes, Vincent A Miller

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 04/2012;

  PURPOSEErlotinib 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 investigatedPURPOSEErlotinib 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 METHODSPatients 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.ResultsPFS 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. CONCLUSIONErlotinib and erlotinib plus chemotherapy have similar efficacy in clinically selected populations of patients with advanced NSCLC. EGFR mutations identify patients most likely to benefit.

• Phase II study of gefitinib adaptive dose escalation to skin toxicity in recurrent or metastatic squamous cell carcinoma of the head and neck.

  Authors: Cesar A Perez, Hunho Song, Luis E Raez, Mark Agulnik, Tatyana A Grushko, Allison Dekker, Kerstin Stenson, Elizabeth A Blair, Olufunmilayo I Olopade, Tanguy Y Seiwert, Everett E Vokes, Ezra E W Cohen

  Oral oncology. 04/2012;

  BACKGROUND: Gefitinib has activity in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) and skin toxicity has been postulated to be a predictor of response and improvedBACKGROUND: Gefitinib has activity in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) and skin toxicity has been postulated to be a predictor of response and improved outcome. METHODS: This open-label, multi-institution, phase II study evaluated the activity of gefitinib at individually escalated doses up to 750mg to achieve the skin toxicity grade ⩾2. RESULTS: Forty four patients were enrolled. Only twenty-three (52%) experienced skin rash grade ⩾2. Of 44 patients, partial responses were noted in 3 (7%), stable disease in 8 (18%) and progressive disease in 33patients. Median progression-free survival was 1.9months (95% CI 1.6-2.2) and median overall survival was 5.1months (95% CI 2.4-7.8). Grade of skin rash was not associated with response rate (p=0.169) nor tumor control rate (p=0.284); however, higher gefitinib trough levels were associated with disease control. Of the 11 tissue samples analyzed for EGFR gene copy by FISH, 7 were EGFR FISH positive, but this was not associated with improved tumor control or survival. CONCLUSIONS: Gefitinib has clinical activity as monotherapy in SCCHN. Dose escalation of gefitinib is feasible and may increase skin toxicity, but our data do not support increased activity.

• Cyclooxygenase-2 (COX-2) As a Predictive Marker for the Use of COX-2 Inhibitors in Advanced Non-Small-Cell Lung Cancer.

  Authors: Martin J Edelman, Lydia Hodgson, Xiaofei Wang, Robert A Kratzke, Everett E Vokes

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 04/2012;

• CYFRA 21-1 as a Prognostic and Predictive Marker in Advanced Non-Small-Cell Lung Cancer in a Prospective Trial: CALGB 150304.

  Authors: Martin J Edelman, Lydia Hodgson, Paula Y Rosenblatt, Robert H Christenson, Everett E Vokes, Xiaofei Wang, Robert Kratzke

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 04/2012; 7(4):649-54.

  : Cytokeratin 19 and its soluble fragment CYFRA have been studied as markers that may be associated with response to therapy and survival in non-small-cell lung cancer (NSCLC). As a prospective: Cytokeratin 19 and its soluble fragment CYFRA have been studied as markers that may be associated with response to therapy and survival in non-small-cell lung cancer (NSCLC). As a prospective correlative study of Cancer and Leukemia Group B 30203, a randomized phase II trial of carboplatin/gemcitabine with eicosanoid modulators (celecoxib, zileuton, or both) in advanced NSCLC, serum CYFRA levels were obtained before and during treatment. : Serum CYFRA levels were measured at baseline and after the first cycle of treatment using an electrochemoluminescent assay. Paired specimens were available from 88 patients. The logarithms of the initial concentration and of the difference in concentrations were analyzed for association with overall survival (OS) and failure-free survival (FFS). : Lower baseline CYFRA levels were associated with both longer OS and FFS (p < 0.0001 and p = 0.0003). In addition, larger reductions in CYFRA levels correlated with longer OS and FFS (p = 0.0255 and p = 0.0068). : CYFRA and change in CYFRA were found to be reliable markers for response to chemotherapy for NSCLC; however, a precise threshold to mark response has yet to be determined.

• Phase II Study of Dasatinib in Patients with Previously Treated Malignant Mesothelioma (Cancer and Leukemia Group B 30601): A Brief Report.

  Authors: Arkadiusz Z Dudek, Herbert Pang, Robert A Kratzke, Gregory A Otterson, Lydia Hodgson, Everett E Vokes, Hedy L Kindler

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 04/2012; 7(4):755-9.

  : We conducted a phase II trial of dasatinib in malignant mesothelioma (MM) patients to evaluate its toxicity and efficacy as a second-line treatment. : Patients with unresectable MM and no: We conducted a phase II trial of dasatinib in malignant mesothelioma (MM) patients to evaluate its toxicity and efficacy as a second-line treatment. : 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 vascular endothelial growth factor and platelet-derived growth factor b and colony stimulating factor 1 (CSF-1) and mesothelin-related protein at baseline and during therapy. : 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 progression-free survival at 24 weeks was 23% (95% confidence interval: 13.5-40.0%). Survival was markedly longer in patients with lower pretreatment CSF-1 levels and in patients whose CSF-1 levels decreased from baseline during therapy. : Single-agent dasatinib has no activity in MM and is associated with pulmonary toxicities that prohibit its use in an unselected MM population.

• A Phase II Study of Lapatinib in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck.

  Authors: Jonas A de Souza, Darren W Davis, Yujian Zhang, Arun Khattri, Tanguy Y Seiwert, Serdal Aktolga, Stuart Wong, Mark F Kozloff, Sreenivasa Nattam, Mark W Lingen, Rangesh Kunnavakkam, Kerstin M Stenson, Elizabeth A Blair, Jeffrey Bozeman, Janet E Dancey, Everett E Vokes, Ezra Ew Cohen

  Clinical cancer research : an official journal of the American Association for Cancer Research. 02/2012;

  PurposeThis study sought to determine the efficacy and safety profile of lapatinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).Experimental DesignThisPurposeThis study sought to determine the efficacy and safety profile of lapatinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).Experimental DesignThis phase II multi-institutional study enrolled patients with recurrent/metastatic SCCHN into 2 cohorts: those without (arm A) and those with (arm B) prior exposure to an epidermal growth factor receptor (EGFR) inhibitor. All subjects were treated with lapatinib 1500 mg daily. Primary endpoints were response rate (arm A) and progression-free survival (arm B). The biologic effects of lapatinib on tumor growth and survival pathways were assessed in paired tumor biopsies obtained before and after therapy.ResultsForty-five patients were enrolled, 27 in arm A and 18 in arm B. Diarrhea was the most frequent toxicity occurring in 49% of patients. Seven patients experienced related grade 3 toxicity (3 fatigue, 2 hyponatremia, 1 vomiting, 1 diarrhea). In an intent-to-treat analysis, no complete or partial responses were observed and stable disease was the best response observed in 41% of arm A (median duration 50 days, range 34 - 159) and 17% of arm B subjects (median 163 days, range 135 - 195). Median PFS was 52 days in both arms. Median OS was 288 (95% CI, 62-374) and 155 (95% CI, 75-242) days for arms A and B, respectively. Correlative analyses revealed an absence of EGFR inhibition in tumor tissue.ConclusionLapatinib as a single agent in recurrent/metastatic SCCHN, although well tolerated, appears to be inactive in either EGFR inhibitor naive or refractory subjects.

• Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium.

  Authors: Hedy Lee Kindler, Kristen Wroblewski, James A Wallace, Michael J Hall, Gershon Locker, Sreenivasa Nattam, Edem Agamah, Walter M Stadler, Everett E Vokes

  Investigational new drugs. 02/2012; 30(1):382-6.

  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 cancerSorafenib, 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. We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naïve patients with histologically-confirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15 of a 28 day cycle. 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%. Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.

• Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer.

  Authors: Michael D Hasselle, Daniel J Haraf, Kyle E Rusthoven, Daniel W Golden, Ravi Salgia, Victoria M Villaflor, Niket Shah, Philip C Hoffman, Steven J Chmura, Philip P Connell, Everett E Vokes, Ralph R Weichselbaum, Joseph K Salama

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 12/2011; 7(2):376-81.

  Outcomes data treating patients with oligometastatic (≤ 5 metastases) non-small cell lung carcinoma (NSCLC) with hypofractionated image-guided radiotherapy (HIGRT) are limited. ConsecutiveOutcomes data treating patients with oligometastatic (≤ 5 metastases) non-small cell lung carcinoma (NSCLC) with hypofractionated image-guided radiotherapy (HIGRT) are limited. Consecutive oligometastatic NSCLC patients were reviewed from a prospective database. Patients were included if all active diseases were treated with HIGRT. Lesions that had received prior radiation or had radiographic/metabolic resolution after chemotherapy were not treated with HIGRT. Local control of all treated lesions, distant control, progression-free survival (PFS), overall survival (OS), and control of individual lesions (LeC) were calculated. Twenty-five patients with median of 2 treated oligometastatic lesions were included. Median follow-up was 14 months. Median age was 66 years. Nineteen patients received systemic therapy before HIGRT and 11 had progressive disease after their most recent systemic therapy before HIGRT. Median OS and PFS were 22.7 and 7.6 months. The 18 months local control, distant control, OS, and PFS were 66.1%, 31.7%, 52.9%, and 28.0%. Greater than two sites treated with HIGRT, nonadenocarcinoma histology, prior systemic therapy, and progression after systemic therapy were associated with worse PFS. Sixty-two individual lesions of median size 2.7 cm were treated. For extracranial lesions, median total and fraction dose were 50 and 5 Gy. Median standard equivalent dose in 2 Gy fractions for extracranial lesions was 64.6 Gy yielding 18 months LeC of 70.7%. Standard equivalent dose ≥64.6 Gy increased LeC (p = 0.04). Two patients experienced grade 3 toxicity. HIGRT for oligometastatic NSCLC provides durable LeC and may provide long-term PFS in some patients. Future HIGRT studies should optimize patient selection and integration with systemic therapy.

• Vatalanib in malignant mesothelioma: A phase II trial by the Cancer and Leukemia Group B (CALGB 30107).

  Authors: Thierry Jahan, Lin Gu, Robert Kratzke, Arkadiusz Dudek, Gregory A Otterson, Xiaofei Wang, Mark Green, Everett E Vokes, Hedy Lee Kindler

  Lung cancer (Amsterdam, Netherlands). 12/2011;

  INTRODUCTION: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the efficacy and safety of vatalanib in previously untreated patients with malignantINTRODUCTION: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the efficacy and safety of vatalanib in previously untreated patients with malignant mesothelioma and to evaluate potential biomarkers of disease response (CALGB 30107). METHODS: Treatment consisted of vatalanib 1250mg given orally once daily. CT scans were obtained at baseline and every 6 weeks thereafter. Baseline serum levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), thrombospondin-1 (TSP-1), and mesothelin were obtained. The primary endpoint was 3-month progression-free survival (PFS). RESULTS: Forty-seven patients enrolled at 19 centers. The median age was 75 years, and the majority of patients (79%) had an ECOG performance status of 1. Tumors were classified as epithelial (77%), sarcomatoid (10%), or mixed (9%) histology. Toxicity was mild; the most common grade 3/4 adverse events were neutropenia (2%), nausea (15%), elevated alanine aminotransferase (11%), hypertension (2%), and gastrointestinal bleeding (2%). Partial responses were observed in 6% of patients and stable disease in 72% of patients. The 3-month PFS rate was 55% (95% CI: 40%, 68%). The median PFS was 4.1 months. Median overall survival was 10.0 months. There was no correlation between serum levels of VEGF, PDGF, TSP-1, or mesothelin and treatment response, PFS, or survival. CONCLUSIONS: Vatalanib as a single agent with this dose and schedule does not warrant further study in this disease.

• A Phase II Study of Halichondrin B Analog Eribulin Mesylate (E7389) in Patients with Advanced Non-small Cell Lung Cancer Previously Treated with a Taxane: A California Cancer Consortium Trial.

  Authors: Barbara J Gitlitz, Denice D Tsao-Wei, Susan Groshen, Angela Davies, Marianna Koczywas, Chandra P Belani, Athanassios Argiris, Suresh Ramalingam, Everett E Vokes, Martin Edelman, Philip Hoffman, Marc S Ballas, Stephen V Liu, David R Gandara

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 12/2011; 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 advancedINTRODUCTION:: 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/m on days 1 and 8 every 21 days. The primary end point was objective response rate and secondary end points included progression-free survival and overall survival. RESULTS:: Sixty-six patients were accrued. The objective response rate was 5% with a median duration of response of 7.8 months. In the TS arm, 3 of 45 patients (7%) achieved a partial response and another 11 of 45 (24%) achieved stable disease for at least 3 months, whereas in the TR arm, no patients achieved a partial response and 4 of 21 (19%) achieved stable disease for at least 3 months. Median progression-free survival was 2.9 months in the TS subgroup and 1.2 months in the TR subgroup. The median overall survival 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 pretreated, TS NSCLC.

• Long-term outcome of a phase II study of docetaxel-based multimodality chemoradiotherapy for locally advanced carcinoma of the esophagus or gastroesophageal junction.

  Authors: Nicholas W Choong, Ann M Mauer, Daniel C Haraf, Mark K Ferguson, Alan B Sandler, Kenneth A Kesler, Paul A S Fishkin, Rafat H Ansari, James Wade, Stuart A Krauss, David F Sciortino, Mitchell C Posner, Masha Kocherginsky, Philip C Hoffman, Livia Szeto, Everett E Vokes

  Medical oncology (Northwood, London, England). 12/2011; 28 Suppl 1:S152-61.

  We performed a phase II trial to evaluate a docetaxel-based regimen in locoregionally advanced esophageal cancer. Untreated stage II-IVa esophageal cancer patients with performance status 0-2 wereWe performed a phase II trial to evaluate a docetaxel-based regimen in locoregionally advanced esophageal cancer. Untreated stage II-IVa esophageal cancer patients with performance status 0-2 were included. Tumor resectability was determined prior to initiation of study. Induction docetaxel (75 mg/m(2)) and cisplatin (75 mg/m(2)) day 1 with prophylactic filgrastim was delivered every 21 days for 3 cycles. Subsequent concomitant chemoradiotherapy (CRT) utilized weekly docetaxel (20 mg/m(2)) and concurrent radiotherapy (2 Gy/day) in resectable/resected patients (50 Gy) and in unresectable patients (66 Gy). A total of 78 patients (15 squamous cell carcinoma, 60 adenocarcinoma, 3 mixed/undifferentiated; 68 men, 10 women; median age 61 years) were accrued. The regimen was administered to 59 (76%) potentially resectable patients and 13 (17%) unresectable patients; 6 patients (8%) received the regimen post-operatively. Response rate in 66 evaluable patients following induction chemotherapy was 30%. Sixty-nine patients underwent CRT. Ten patients had disease progression during CRT. Forty-five out of 59 potentially resectable patients underwent esophagectomy after CRT, and 42 patients had complete tumor resection with negative margins. Eighteen out of 59 patients who were potentially resectable patients had pathologic complete response (pCR-31%). Grade 3/4 toxicity during induction chemotherapy included leucopenia, neutropenia, vomiting, and neuropathy. Esophagitis was the predominant toxicity during CRT. Median overall survival was 11.4 months for unresectable patients, 14.3 months for resectable patients and 10.4 months for patients who received the regimen post-operatively (log-rank P = 0.2492). Docetaxel-based CRT regimen is active and tolerable in esophageal cancer. The observed pCR in the potentially resectable group indicates good local control.

• Cisplatin, irinotecan, and bevacizumab for untreated extensive-stage small-cell lung cancer: CALGB 30306, a phase II study.

  Authors: Neal E Ready, Arkadiusz Z Dudek, Herbert H Pang, Lydia D Hodgson, Stephen L Graziano, Mark R Green, Everett E Vokes

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 11/2011; 29(33):4436-41.

  The efficacy of cisplatin, irinotecan, and bevacizumab was evaluated in patients with extensive-stage small-cell lung cancer (ES-SCLC). Patients with ES-SCLC received cisplatin 30 mg/m(2) andThe efficacy of cisplatin, irinotecan, and bevacizumab was evaluated in patients with extensive-stage small-cell lung cancer (ES-SCLC). Patients with ES-SCLC received cisplatin 30 mg/m(2) and irinotecan 65 mg/m(2) 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. 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). 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.

• Targeted and Cytotoxic Therapy in Coordinated Sequence (TACTICS): Erlotinib, Bevacizumab, and Standard Chemotherapy for Non-Small-Cell Lung Cancer, A Phase II Trial.

  Authors: Ezra E W Cohen, Janakiraman Subramanian, Feng Gao, Livia Szeto, Mark Kozloff, Leonardo Faoro, Theodore Karrison, Ravi Salgia, Ramaswamy Govindan, Everett E Vokes

  Clinical lung cancer. 11/2011; 13(2):123-8.

  This trial focused on optimally combining existing targeted therapies and cytotoxic chemotherapy in the treatment of unselected patients with advanced non-small-cell lung cancer (NSCLC). PatientsThis trial focused on optimally combining existing targeted therapies and cytotoxic chemotherapy in the treatment of unselected patients with advanced non-small-cell lung cancer (NSCLC). Patients with previously untreated advanced-stage nonsquamous NSCLC were eligible for this trial. In module A, patients received up to 4 cycles of erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients then received carboplatin (AUC = 6), paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg for 4 cycles in module B. Patients who did not have progressive disease in module A received maintenance erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks in module C. Forty-eight patients were enrolled in this multicenter phase II trial. Most patients were male (62.5%) and white (77.1%) with stage IV disease (93.8%) and adenocarcinoma histologic type (66.7%). The overall response rate in module A was 10.4%, in module B it was 15.1%, and in module C it was 5.5%. The study achieved its primary endpoint, with a nonprogression rate of 45.8% in module A. The median overall survival (OS) was 12.6 months. The novel systemic therapy regimen is feasible in patients with advanced NSCLC. However there is no further role for developing this regimen in unselected patients with NSCLC.

• Chemoradiation for patients with large-volume laryngeal cancers.

  Authors: Kerstin M Stenson, Ellen Maccracken, Rangesh Kunnavakkam, Ezra E W Cohen, Louis D Portugal, Victoria Villaflor, Tanguy Seiwert, Elizabeth Blair, Daniel J Haraf, Joseph K Salama, Everett E Vokes

  Head & neck. 11/2011;

  BACKGROUND: Patients with T4 laryngeal cancers, including those with large-volume (cartilage or tongue-base invasion) lesions, are often excluded from organ-preservation trials due to expectations ofBACKGROUND: Patients with T4 laryngeal cancers, including those with large-volume (cartilage or tongue-base invasion) lesions, are often excluded from organ-preservation trials due to expectations of inferior outcome in terms of survival and function. We hypothesize that such patients indeed have acceptable survival and function when treated with organ-preservation strategies. METHODS: Retrospective analysis of prospectively collected data of a cohort of patients with T4 laryngeal cancer was carried out. Follow-up ranged from 0.18 to 15.6 years. All T4 laryngeal cancer patients who were enrolled in the University of Chicago concomitant chemoradiotherapy protocols from 1994 to the present were reviewed. This study was composed of 80 newly diagnosed T4 laryngeal cancer patients. Efficacy of treatment was determined through evaluations of survival and function. Survival was evaluated via Kaplan-Meier methods. Swallowing function was evaluated by an oropharyngeal motility (OPM) study and swallowing scores were assigned. Higher scores reflected increasing swallowing dysfunction. RESULTS: Fifty-five of 80 patients (∼69%) had documented large-volume tumor. Two- and 5-year overall survivals were 60.0% and 48.7%, respectively. Disease-specific 2- and 5-year survivals for the group were 80.1% and 71.3%, and 79.4 and 74.3%, respectively, for the 55 patients with large volume status. Progression-free survival rates were 52.6% and 47.6%. Forty-four of 65 patients (∼68%) with OPM data had a Swallowing Performance Status Scale (SPSS) score of ≤5, indicating various degrees of swallowing abnormalities not requiring a gastrostomy tube. This is a functional-preservation rate of 67.7%. CONCLUSIONS: Chemoradiation for patients with T4 laryngeal cancer appears to be an effective and reasonable option, particularly in light of the satisfactory survival and function-preservation rates. © 2011 Wiley Periodicals, Inc. Head Neck, 2011.

• Stereotactic body radiotherapy for multisite extracranial oligometastases: Final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease.

  Authors: Joseph K Salama, Michael D Hasselle, Steven J Chmura, Renuka Malik, Neil Mehta, Kamil M Yenice, Victoria M Villaflor, Walter M Stadler, Philip C Hoffman, Ezra E W Cohen, Philip P Connell, Daniel J Haraf, Everett E Vokes, Samuel Hellman, Ralph R Weichselbaum

  Cancer. 10/2011;

  BACKGROUND: A subset of patients with metastatic cancer in limited organs may benefit from metastasis-directed therapy. The authors investigated whether patients with limited metastases could beBACKGROUND: A subset of patients with metastatic cancer in limited organs may benefit from metastasis-directed therapy. The authors investigated whether patients with limited metastases could be safely treated with metastasis-directed radiotherapy. METHODS: Patients with 1 to 5 metastatic cancer sites with a life expectancy of >3 months received escalating stereotactic body radiotherapy (SBRT) doses to all known cancer sites. Patients were followed radiographically with CT scans of the chest, abdomen, and pelvis and metabolically with fluorodeoxyglucose-positron emission tomography, 1 month after treatment, and then every 3 months. Acute toxicities were scored using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0, and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system. RESULTS: Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 on a prospective radiation dose escalation study. Median follow-up was 20.9 months. Patients tolerated treatment well; the maximal tolerated dose was not reached in any cohort. Eleven patients (18.3%) have not progressed. One and 2-year progression-free survival are 33.3% (95% confidence interval [CI], 22.8-46.1) and 22.0% (95% CI, 12.8-34.4); 1-year and 2-year overall survival are 81.5% (95% CI, 71.1-91.1) and 56.7% (95% CI, 43.9-68.9). Seventy-two percent of patients whose tumors progressed did so in limited (1-3) metastatic sites. CONCLUSIONS: Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT. Further investigation should focus on patient selection. Cancer 2011;. © 2011 American Cancer Society.

• 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.

  Authors: Ramaswamy Govindan, Jeffrey Bogart, Thomas Stinchcombe, Xiaofei Wang, Lydia Hodgson, Robert Kratzke, Jennifer Garst, Timothy Brotherton, Everett E Vokes

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 08/2011; 29(23):3120-5.

  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 withCancer 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 with unresectable stage III non-small-cell lung cancer (NSCLC) were randomly assigned to carboplatin (area under the curve, 5) and pemetrexed (500 mg/m(2)) 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. 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. 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.

• Adjuvant chemoradiotherapy for locoregionally advanced and high-risk salivary gland malignancies.

  Authors: Aaron W Pederson, Joseph K Salama, Daniel J Haraf, Mary Ellen Witt, Kerstin M Stenson, Louis Portugal, Tanguy Seiwert, Victoria M Villaflor, Ezra E W Cohen, Everett E Vokes, Elizabeth A Blair

  Head & neck oncology. 07/2011; 3:31.

  To report the outcomes of patients with locoregionally advanced and high- risk salivary gland malignancies treated with surgery followed by adjuvant chemoradiotherapy. From 09/1991 - 06/2007, 24To report the outcomes of patients with locoregionally advanced and high- risk salivary gland malignancies treated with surgery followed by adjuvant chemoradiotherapy. From 09/1991 - 06/2007, 24 high-risk salivary gland cancer patients were treated with surgery, followed by adjuvant chemoradiotherapy for high-risk pathologic features including, perineural involvement, nodal involvement, positive margins, or T3/T4 tumors. Chemoradiotherapy was delivered for 4-6 alternating week cycles: the most common regimen, TFHX, consisted of 5 days paclitaxel (100 mg/m² on d1), infusional 5-fluorouracil (600 mg/m²/d × 5d), hydroxyurea (500 mg PO BID), and 1.5 Gy twice daily irradiation followed by a 9-day break without treatment. Median follow-up was 42 months. The parotid gland was more frequently involved (n = 17) than minor (n = 4) or submandibular (n = 3) glands. The median radiation dose was 65 Gy (range 55-68 Gy). Acute treatment related toxicity included 46% grade 3 mucositis and 33% grade 3 hematologic toxicity. Six patients required feeding tubes during treatment. One patient progressed locally, 8 patients progressed distantly, and none progressed regionally. Five-year locoregional progression free survival was 96%. The 3 and 5 year overall survival was 79% and 59%, respectively. Long-term complications included persistent xerostomia (n = 5), esophageal stricture requiring dilatation (n = 1), and tempromandibular joint syndrome (n = 1). Surgical resection followed by adjuvant chemoradiotherapy results in promising locoregional control for high-risk salivary malignancy patients.

• Bortezomib for patients with advanced-stage bronchioloalveolar carcinoma: a California Cancer Consortium Phase II study (NCI 7003).

  Authors: Suresh S Ramalingam, Angela M Davies, Jeffrey Longmate, Martin J Edelman, Primo N Lara, Everett E Vokes, Miguel Villalona-Calero, Barbara Gitlitz, Karen Reckamp, Ravi Salgia, John J Wright, Chandra P Belani, David R Gandara

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 06/2011; 6(10):1741-5.

  Bronchioloalveolar carcinoma (BAC), a subtype of non-small cell lung cancer, is a difficult disease to treat with low response rates with cytotoxic chemotherapy. Bortezomib, a proteasome inhibitor,Bronchioloalveolar carcinoma (BAC), a subtype of non-small cell lung cancer, is a difficult disease to treat with low response rates with cytotoxic chemotherapy. Bortezomib, a proteasome inhibitor, has demonstrated objective responses in patients with BAC in early-phase clinical trials. We conducted a phase II study of bortezomib in patients with advanced-stage BAC. Patients with advanced BAC, adenocarcinoma with BAC features or BAC with adenocarcinoma features, and less than two prior regimens were eligible. Prior epidermal growth factor receptor (EGFR) inhibitor therapy was allowed. Bortezomib was administered intravenously at 1.6 mg/m on days 1 and 8 of every 21-day cycle until disease progression or unacceptable toxicity. The primary end point was response rate. The Simon two-stage design was used. Forty-two patients were enrolled, and the study was halted early for slow accrual. Patient characteristics were female 55%, median age 68 years, and Eastern Cooperative Oncology Group performance status of 0 and 1 in 31 and 11 patients, respectively. Twenty-six (62%) patients had received prior therapy with an EGFR inhibitor. A median of four cycles of therapy were administered. Objective responses were noted in 5%, whereas 57% had disease stabilization. The median progression-free survival and overall survival were 5.5 and 13.6 months, respectively. Grade 3 diarrhea and fatigue were noted in three and five patients, respectively. Bortezomib is tolerated well and is associated with modest anticancer activity in patients with advanced BAC, including patients who progressed on EGFR inhibitor therapy.