Alan Sandler

TRIBUTE: A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non–Small-Cell Lung Cancer

PURPOSE Erlotinib is a potent reversible HER1/epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with single-agent activity in patients with non-small-cell lung cancer (NSCLC). Erlotinib was combined with chemotherapy to determine if it could improve the outcome of patients with NSCLC. PATIENTS AND METHODS TRIBUTE randomly assigned patients with good performance status and previously untreated advanced (stage IIIB/IV) NSCLC to erlotinib 150 mg/d or placebo combined with up to six cycles of carboplatin and paclitaxel, followed by maintenance monotherapy with erlotinib. Random assignment was stratified by stage, weight loss in the previous 6 months, measurable disease, and treatment center. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response (OR), and duration of response. RESULTS There were 1,059 assessable patients (526 erlotinib; 533 placebo). Median survival for patients treated with erlotinib was 10.6 v 10.5 months for placebo (hazard ratio, 0.99; 95% CI, 0.86 to 1.16; P = .95). There was no difference in OR or median TTP. Patients who reported never smoking (72 erlotinib; 44 placebo) experienced improved OS in the erlotinib arm (22.5 v 10.1 months for placebo), though no other prespecified factors showed an advantage in OS with erlotinib. Erlotinib and placebo arms were equivalent in adverse events (except rash and diarrhea). CONCLUSION Erlotinib with concurrent carboplatin and paclitaxel did not confer a survival advantage over carboplatin and paclitaxel alone in patients with previously untreated advanced NSCLC. Never smokers treated with erlotinib and chemotherapy seemed to experience an improvement in survival and will undergo further investigation in future randomized trials.

Phase III Trial of Gemcitabine Plus Cisplatin Versus Cisplatin Alone in Patients With Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

PURPOSE The Hoosier Oncology Group has previously reported the results of its phase II trial of the combination of cisplatin plus gemcitabine. In that study of 27 assessable patients with advanced or metastatic non-small-cell lung cancer (NSCLC), the response rate was 33%, with a median survival of 8.4 months. Based on such favorable results, the Hoosier Oncology Group designed this randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS Patients were randomized to receive either cisplatin (100 mg/m(2) intravenously on day 1 of a 28-day cycle) or the combination of cisplatin (100 mg/m(2) intravenously on day 1) plus gemcitabine (1,000 mg/m(2) administered intravenously on days 1, 8, and 15 of a 28-day cycle). RESULTS From August 1995 to February 1997, 522 assessable chemotherapy-naive patients were randomized. Toxicity was predominantly hematologic and was more pronounced in the combination arm, with grade 4 neutropenia occurring in 35.3% of patients compared with 1.2% of patients on the cisplatin monotherapy arm. The incidence of neutropenic fevers was less than 5% in both arms. Grade 4 thrombocytopenia occurred in 25. 4% of patients on the combination arm compared with 0.8% of patients on the cisplatin monotherapy arm. No serious hemorrhagic events related to thrombocytopenia were reported for either arm. The combination of gemcitabine plus cisplatin demonstrated a significant improvement over single-agent cisplatin with regard to response rate (30.4% compared with 11.1%, respectively; P <.0001), median time to progressive disease (5.6 months compared with 3.7 months, respectively; P =.0013), and overall survival (9.1 months compared with 7.6 months, respectively; P =.004). CONCLUSIONS For the first-line treatment of NSCLC, the regimen of gemcitabine plus cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival.

Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.

BACKGROUND Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population. METHODS In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993. FINDINGS Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event. INTERPRETATION Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy. FUNDING F Hoffmann-La Roche/Genentech Inc.

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial

BACKGROUND Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. METHODS We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. FINDINGS Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. INTERPRETATION To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. FUNDING F. Hoffmann-La Roche Ltd, Genentech, Inc.

Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer.

PURPOSE Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody. Erlotinib HCl (Tarceva, OSI-774; OSI Pharmaceuticals, New York, NY) is a potent, reversible, highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor. Preclinical data in various xenograft models produced greater growth inhibition than with either agent alone. Additionally, both agents have demonstrated benefit in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS A phase I/II study in two centers examined erlotinib and bevacizumab (A+T) in patients with nonsquamous stage IIIB/IV NSCLC with > or = one prior chemotherapy. In phase I, erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose, although no dose-limiting toxicities were observed. Phase II assessed the efficacy and tolerability of A+T at this dose. Pharmacokinetic parameters were evaluated. ResultsForty patients were enrolled and treated in this study (34 patients at phase II dose); the median age was 59 years (range, 36 to 72 years), 21 were female, 30 had adenocarcinoma histology, nine were never-smokers, and 22 had > or = two prior regimens (three patients had > or = four prior regimens). The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between A + T. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. CONCLUSION Encouraging antitumor activity and safety of A + T support further development of this combination for patients with advanced NSCLC and other solid tumors.

Randomized Phase III Trial Comparing Irinotecan/Cisplatin With Etoposide/Cisplatin in Patients With Previously Untreated Extensive-Stage Disease Small-Cell Lung Cancer

PURPOSE Etoposide and cisplatin (EP) has been a standard treatment for extensive-disease small-cell lung cancer (SCLC). An earlier phase III trial reported improved survival for patients receiving irinotecan plus cisplatin (IP) versus EP. Our trial was designed to determine if a modified weekly regimen of IP would provide superior survival with less toxicity than EP. PATIENTS AND METHODS The primary objective was to compare overall survival in extensive-disease SCLC patients randomly assigned to receive IP (n = 221) or EP (n = 110). Patients were randomly assigned in 2:1 ratio to cisplatin 30 mg/m2 intravenously (IV) + irinotecan 65 mg/m2 IV on days 1 and 8 every 21 days, or cisplatin 60 mg/m2 IV on day 1, and etoposide 120 mg/m2 IV on days 1 to 3 every 21 days for at least four cycles, until progressive disease, or until intolerable toxicity resulted. RESULTS Selected grade 3/4 toxicities for IP/EP were: neutropenia (36.2% v 86.5%; P < .01), febrile neutropenia (3.7% v 10.4%; P = .06), anemia (4.8% v 11.5%; P = .02), thrombocytopenia (4.3% v 19.2%; P < .01), vomiting (12.5% v 3.8%; P = .04), and diarrhea (21.3% v 0%; P < .01). There was no significant difference in response rates (48% v 43.6%), median time to progression (4.1 v 4.6 months), or overall survival (median survival time, 9.3 months v 10.2 months; P = .74). CONCLUSION Treatment with this dose and schedule of IP did not result in improved survival when compared with EP. Fewer patients receiving IP had grade 3/4 anemia, thrombocytopenia, neutropenia, and febrile neutropenia compared with patients receiving EP, but more had grade 3/4 diarrhea and vomiting.

Phase II Study of Efficacy and Safety of Bevacizumab in Combination With Chemotherapy or Erlotinib Compared With Chemotherapy Alone for Treatment of Recurrent or Refractory Non–Small-Cell Lung Cancer

PURPOSE Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, and erlotinib, a reversible, orally available epidermal growth factor receptor tyrosine kinase inhibitor, have demonstrated evidence of a survival benefit in the treatment of non-small-cell lung cancer (NSCLC). A single-arm phase I and II study of bevacizumab plus erlotinib demonstrated encouraging efficacy, with a favorable safety profile. PATIENTS AND METHODS A multicenter, randomized phase II trial evaluated the safety of combining bevacizumab with either chemotherapy (docetaxel or pemetrexed) or erlotinib and preliminarily assessed these combinations versus chemotherapy alone, as measured by progression-free survival (PFS). All patients had histologically confirmed nonsquamous NSCLC that had progressed during or after one platinum-based regimen. RESULTS One hundred twenty patients were randomly assigned and treated. No unexpected adverse events were noted. Fewer patients (13%) in the bevacizumab-erlotinib arm discontinued treatment as a result of adverse events than in the chemotherapy alone (24%) or bevacizumab-chemotherapy (28%) arms. The incidence of grade 5 hemorrhage in patients receiving bevacizumab was 5.1%. Although not statistically significant, relative to chemotherapy alone, the risk of disease progression or death was 0.66 (95% CI, 0.38 to 1.16) among patients treated with bevacizumab-chemotherapy and 0.72 (95% CI, 0.42 to 1.23) among patients treated with bevacizumab-erlotinib. One-year survival rate was 57.4% for bevacizumab-erlotinib and 53.8% for bevacizumab-chemotherapy compared with 33.1% for chemotherapy alone. CONCLUSION Results for PFS and overall survival favor combination of bevacizumab with either chemotherapy or erlotinib over chemotherapy alone in the second-line setting. No unexpected safety signals were noted. The rate of fatal pulmonary hemorrhage was consistent with previous bevacizumab trials. The toxicity profile of the bevacizumab-erlotinib combination is favorable compared with either chemotherapy-containing group.

Outcomes for Elderly, Advanced-Stage Non–Small-Cell Lung Cancer Patients Treated With Bevacizumab in Combination With Carboplatin and Paclitaxel: Analysis of Eastern Cooperative Oncology Group Trial 4599

PURPOSE Fit elderly patients with advanced non-small-cell lung cancer (NSCLC) benefit from platinum-based, two-drug chemotherapy. Bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P) improves survival for advanced, nonsquamous NSCLC, as evidenced in Eastern Cooperative Oncology Group (ECOG) 4599. We conducted a subset analysis of ECOG 4599 to determine the outcome for elderly patients. PATIENTS AND METHODS ECOG 4599 randomly assigned patients with advanced nonsquamous NSCLC to PC or to PCB. We analyzed outcome in patients who were at least 70 years of age at the time of study entry. Patient characteristics, efficacy, and toxicity data were compared between PC and PCB for the elderly. Outcomes for elderly and younger patients (< 70 years) treated with PCB were also compared. RESULTS Among elderly patients (n = 224; 26%), there was a trend towards higher response rate (29% v 17%; P = .067) and progression-free survival (5.9 v 4.9 months; P = .063) with PCB compared with PC, although overall survival (PCB = 11.3 months; PC = 12.1 months; P = .4) was similar. Grade 3 to 5 toxicities occurred in 87% of elderly patients with PCB versus 61% with PC (P < .001), with seven treatment-related deaths in the PCB arm compared with two with PC. Elderly patients had higher incidence of grade 3 to 5 neutropenia, bleeding, and proteinuria with PCB compared with younger patients. CONCLUSION In elderly NSCLC patients, PCB was associated with a higher degree of toxicity, but no obvious improvement in survival compared with PC. Data from this unplanned, retrospective analysis justify prospective evaluation of the therapeutic index of PCB regimen in elderly patients.

Endoscopic Ultrasonography, Fine-Needle Aspiration Biopsy Guided by Endoscopic Ultrasonography, and Computed Tomography in the Preoperative Staging of Non-Small-Cell Lung Cancer: A Comparison Study

Accurate staging of non-small-cell lung cancer plays a crucial role in determining the treatment options available to patients with this disease. The preoperative documentation of metastasis to the mediastinal lymph nodes has therapeutic implications that have traditionally focused on palliation but more recently have included neoadjuvant strategies [1, 2]. Metastasis to the mediastinal lymph nodes occurs in nearly half of all patients with non-small-cell lung cancer. The development of mediastinal metastasis is probably the most frequent deterrent to cure, even when the presentation is localized. If metastasis involves contralateral or large, bulky (>1.5 to 2.0 cm) subcarinal lymph nodes, surgery alone may not be curative [3-9]. As a result of recent revisions to the staging systems for lung cancer, ipsilateral mediastinal and subcarinal lymph node involvement is now classified as potentially resectable, N2 disease; contralateral mediastinal lymph node involvement (N3 disease) precludes resection [10-12]. Computed tomography of the chest is the current method by which mediastinal lymphadenopathy is detected in non-small-cell lung cancer. However, its sensitivity for detection of metastasis to the lymph nodes varies; accuracy in previous studies has ranged from 52% to 88% [13-23]. This inconsistency has been attributed to the variable correlation of lymph node size with the presence of malignancy. When enlarged contralateral or ipsilateral mediastinal lymph nodes are seen on computed tomography of the chest, standard practice is to determine more accurate staging by performing aspiration biopsy of the lymph node with computed tomographic guidance; bronchoscopy; or, less commonly, a transthoracic approach. If these procedures are unsuccessful, open biopsy is performed by using mediastinoscopy or limited thoracotomy [24-26]. If contralateral lymph nodes are positive for malignancy, surgical resection of the primary tumor is contraindicated. The development of endoscopic ultrasonography has now made it possible to visualize, with high resolution, not only the gastrointestinal tract but also surrounding structures. Endoscopic ultrasonography has been shown to be superior to computed tomography in evaluating lymph nodes for metastases in esophageal, gastric, and pancreatic cancer [27-29]. Promising results for detecting posterior mediastinal lymph nodes in patients with lung cancer suggest a possible role for endoscopic ultrasonography in staging lymph nodes in patients with non-small-cell lung cancer [30-36]. Fine-needle aspiration biopsy guided by endoscopic ultrasonography was recently reported to further improve the accuracy of endoscopic ultrasonography in predicting malignancy of gastrointestinal masses, with rates as high as 87% to 91% [37-42]. We previously reported the results of endoscopic ultrasonography in 17 patients with lung cancer. This method was very accurate for detecting mediastinal lymphadenopathy; the overall accuracy was 71% compared with 41% for computed tomography (P = 0.032) [43]. During the initial study, however, fine-needle aspiration biopsy guided by endoscopic ultrasonography was not available. The goal of the present study was to prospectively evaluate the accuracy of endoscopic ultrasonography alone, endoscopic ultrasonography-guided fine-needle aspiration biopsy, and computed tomography of the chest in detecting mediastinal lymph node metastasis in patients with non-small-cell lung cancer. Methods Patient Selection The study sample consisted of all patients presenting to the Indiana University Thoracic Oncology Program between July 1993 and June 1995 with a diagnosis of non-small-cell lung cancer. The study was approved by the institutional review board, and all enrolled patients gave informed consent. Patients were excluded if they had documented unresectable disease (that is, distant metastasis or locally advanced staged disease [stage III b]) as shown on computed tomography of the chest or if they had a serious medical illness and a life expectancy of less than 1 year. All patients underwent initial preoperative intravenous contrast-enhanced computed tomography of the chest; the axial technique was used in 60% of patients, and the spiral technique was used in 40%. Computed tomography was done at the referring hospital or Indiana University Medical Center; the scans were read at Indiana University Medical Center by a senior attending radiologist who has recognized expertise in this area and used currently accepted radiographic techniques to stage the tumor. The radiologists determination of the benign or malignant nature of each lymph node was recorded on a preoperative computed tomography lymph node map; the American Thoracic Society mediastinal staging map (Figure 1) was used to describe the location of each node [12]. Any patient who had a questionably enlarged mediastinal lymph node (>1 cm in diameter) and was considered a surgical candidate was then scheduled for endoscopic ultrasonography. Figure 1. American Thoracic Society scheme for mapping mediastinal lymphadenopathy by anatomic location, as seen from behind with endoscopic ultrasonography. Endoscopic Ultrasonography Endoscopic ultrasonography was performed in an outpatient setting on all patients by one of three experienced endosonographers; the radial scanning echoendoscope (GFUM-20, Olympus America, Melville, New York) or the linear-array scanning echoendoscope (FG32UA, Pentax, Orangeburg, New York) was used for all procedures. When done by an experienced operator, endoscopic ultrasonography is similar to standard upper endoscopy both in technique and duration of the procedure. When fine-needle aspiration biopsy is performed, the procedure is slightly prolonged. Patients were sedated with meperidine and midazolam, the doses of which were titrated to achieve adequate conscious sedation. The instrument was advanced into the stomach, and the celiac axis was imaged. The probe was then withdrawn to the gastroesophageal junction and slowly withdrawn at 1-cm intervals. Images were obtained with 7.5- and 12-MHz frequencies at each interval. All imaged mediastinal lymph nodes were mapped by location according to the American Thoracic Society classification scheme [12]. From these data, an objective assessment was made as to whether the mediastinal lymphadenopathy detected by endoscopic ultrasonography was benign or possibly malignant according to the following previously reported criteria for malignancy: round shape; sharp, distinct borders; hypoechoic texture; and a short-axis diameter greater than 5 mm [36-39]. Malignancy was suspected if all of these criteria were present. All patients who were studied before the availability of endoscopic ultrasonography-guided fine-needle aspiration biopsy underwent surgical resection, and endoscopic ultrasonographic findings were correlated to surgical pathologic findings. Patients who were studied after the advent of fine-needle aspiration biopsy and were found to have no suspicious lymph nodes by endoscopic ultrasonography were directly referred for surgery because there was no indication for aspiration biopsy. Endoscopic Ultrasonography-Guided Fine-Needle Aspiration Biopsy Endoscopic ultrasonography-guided aspiration biopsy became available after the first 17 patients were enrolled in our pilot study. All posterior mediastinal lymph nodes that were suspicious for malignant involvement according to the endoscopic ultrasonographic criteria were noted; selected nodes underwent biopsy during the same procedure. Many of the patients had more than one suspicious lymph node. We performed biopsy only on the most suspicious lymph node, which would have the greatest effect on clinical staging (that is, determination of whether the metastasis was contralateral or subcarinal). This technique for ultrasonography-guided aspiration biopsy was initially developed for use with the linear-array instrument (Figure 2) and is described elsewhere [40-42]. We recently reported a similar technique that uses a radial scanning echoendoscope (Figure 3) [37]. Ultrasonography-guided aspiration biopsy involves the insertion of an aspiration catheter needle device through the accessory channel port of the echoendoscope; the needle is then deployed into the lymph node to be sampled under endoscopic ultrasonographic guidance. Aspiration biopsy is done by introducing a specially designed fine-needle aspiration catheter system that consists of a 4-cm long, 23-gauge needle attached to a 180-cm long, 5-French aspiration catheter (Wilson-Cook, Winston-Salem, North Carolina); in and out movements of the catheter are used while the operator firmly grasps the catheter at the point at which it enters the accessory port. Figure 2. A mediastinal lymph node as imaged with the linear-array endoscopic ultrasonography system. arrow Figure 3. Endoscopic ultrasonographic image obtained from the radial scanning instrument showing a large hypoechoic, oval subcarinal lymph node (LN) suspicious for metastatic involvement. Preliminary cytologic findings were obtained during fine-needle aspiration biopsy by a cytopathologist who was present during the procedure. Before the sample was reviewed, Diff-Quik stain (Harleco, Gibbstown, New Jersey) was applied to the slide that contained the deposited specimen. Additional passes were made until a positive cytologic result or a negative result on an adequate tissue sample was obtained [37]. Patients who were considered eligible for surgical resection after staging by computed tomography and endoscopic ultrasonography (that is, patients with a negative result on aspiration biopsy of contralateral or bulky subcarinal lymph nodes or those with nodes that seemed to be benign according to endoscopic ultrasonographic criteria) underwent thoracotomy for pulmonary resection with ipsilateral mediastinal and subcarinal lymph node dissection. During mediastinal dissection, each lymph node was placed in th

Molecular Characteristics of Bronchioloalveolar Carcinoma and Adenocarcinoma, Bronchioloalveolar Carcinoma Subtype, Predict Response to Erlotinib

PURPOSE We conducted this phase II trial to determine the efficacy of erlotinib in patients with bronchioloalveolar carcinoma (BAC) and adenocarcinoma, BAC subtype, and to determine molecular characteristics associated with response. PATIENTS AND METHODS Patients (n = 101) with BAC (n = 12) or adenocarcinoma, BAC subtype (n = 89), were enrolled. All patients received erlotinib 150 mg daily. Epidermal growth factor receptor (EGFR) mutation, EGFR copy number, EGFR immunohistochemistry (IHC), and KRAS mutation status were analyzed in available tumors. The primary end point was response rate (RR). RESULTS Overall RR was 22% (95% CI, 14% to 31%). In patients with pure BAC, the RR and median survival were 20% and 4 months, as compared with 23% and 19 months in those with adenocarcinoma, BAC subtype. No patient (zero of 18; 95% CI, 0% to 19%) whose tumor harbored a KRAS mutation responded to erlotinib. Patients with EGFR mutations had an 83% RR (15 of 18; 95% CI, 65% to 94%) and 23-month median OS. On univariate analysis, EGFR mutation and copy number were associated with RR and PFS. EGFR IHC was not associated with RR or progression-free survival (PFS). After multivariate analysis, only EGFR mutation was associated with RR and PFS. No molecular factors were associated with overall survival. CONCLUSION Erlotinib is active in BAC and adenocarcinoma, mixed subtype, BAC. Testing for EGFR and KRAS mutations can predict RR and PFS after treatment with erlotinib in this histologically enriched subset of patients with non-small-cell lung cancer (NSCLC). These data suggest that histologic subtype and molecular characteristics should be reported in clinical trials in NSCLC using EGFR-directed therapy.