Soo-Hyun Lee

Transbronchial and Transesophageal Fine-Needle Aspiration Using an Ultrasound Bronchoscope in Mediastinal Staging of Potentially Operable Lung Cancer

OBJECTIVEnWe performed this study to evaluate the role of transesophageal endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) following endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the mediastinal staging of lung cancer.nnnMETHODSnIn this prospective study, we applied transbronchial and transesophageal ultrasonography using an ultrasound bronchoscope on patients with confirmed or strongly suspected potentially operable non-small cell lung cancer. Following EBUS-TBNA, EUS-B-FNA was used for mediastinal nodes that were inaccessible or difficult to access by EBUS-TBNA. The accessibility by EBUS-TBNA and EUS-B-FNA to mediastinal nodal stations having at least one node ≥ 5 mm was also checked.nnnRESULTSnIn 150 patients, we performed EBUS-TBNA and EUS-B-FNA on 299 and 64 mediastinal nodal stations, respectively. Among 143 evaluable patients, EBUS-TBNA diagnosed mediastinal metastasis in 38 patients. EUS-B-FNA identified mediastinal metastasis in three additional patients. Surgery diagnosed mediastinal metastasis in four more patients. The sensitivity, negative predictive value, and diagnostic accuracy of EBUS-TBNA in the detection of mediastinal metastasis were 84.4%, 93.3%, and 95.1%, respectively. These values for the combined approach of EBUS-TBNA and EUS-B-FNA increased to 91.1%, 96.1%, and 97.2%, respectively, although the differences were not statistically significant (P = .332, P = .379, and P = .360, respectively). Among 473 mediastinal nodal stations having at least one node ≥ 5 mm that were evaluated, the proportion of accessible mediastinal nodal stations by EBUS-TBNA was 78.6%, and the proportion increased to 84.8% by combining EUS-B-FNA with EBUS-TBNA (P = .015).nnnCONCLUSIONnFollowing EBUS-TBNA in the mediastinal staging of potentially operable lung cancer, the accessibility to mediastinal nodal stations increased by adding EUS-B-FNA and an additional diagnostic gain might be obtained by EUS-B-FNA.nnnTRIAL REGISTRATIONnclinicaltrials.gov, NCT00741247.

A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer.

Purpose: To evaluate the efficacy and safety of gefitinib plus simvastatin (GS) versus gefitinib alone (G) in previously treated patients with advanced non–small cell lung cancer (NSCLC). Experimental Design: Between May 2006 and September 2008, 106 patients (51% men, 75% adenocarcinoma, 50% never smoker) were randomly assigned to G alone (250 mg/d, n = 54) or GS (250 and 40 mg/d, respectively, n = 52). One cycle was 4 weeks of treatment. Therapy was continued until disease progression or intolerable toxicity was observed. The primary endpoint was response rate (RR). Secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). Results: The RR was 38.5% (95% CI, 25.3–51.7) for GS and 31.5% (95% CI, 19.1–43.9) for G. The median PFS was 3.3 months [M] (95% CI, 1.4–5.2M) for GS and 1.9M (95% CI, 1.0–2.8M) for G. The median OS was 13.6M (95% CI, 7.1–20.1M) for GS and 12.0M (95% CI, 7.8–16.2M) for G. In exploratory subgroup analysis, GS showed higher RR (40% vs. 0%, P = 0.043) and longer PFS (3.6M vs. 1.7M, P = 0.027) compared with G alone in patients with wild-type epidermal growth factor receptor (EGFR) nonadenocarcinomas. Adverse events in both arms were generally mild and mainly consisted of skin rashes. Conclusions: Although no superiority of GS to G was demonstrated in this unselected NSCLC population, GS showed higher RR and longer PFS compared with G alone in patients with wild-type EGFR nonadenocarcinomas. Simvastatin may improve the efficacy of gefitinib in that subgroup of gefitinib-resistant NSCLC patients. Clin Cancer Res; 17(6); 1553–60. ©2011 AACR.

Transoesophageal needle aspiration using a convex probe ultrasonic bronchoscope

Background and objective:u2003 Although endoscopic ultrasound‐guided fine needle aspiration can be helpful when combined with bronchoscopic procedures, endoscopic ultrasound‐guided fine needle aspiration is not available as a conjunctive procedure with bronchoscopy at many institutions. This study evaluated the feasibility and the additional role of transoesophageal fine needle aspiration using a convex probe ultrasonic bronchoscope (EUS‐B‐FNA).

Complex renal cysts associated with crizotinib treatment

An apparent causal association between crizotinib treatment and renal cyst development emerged during clinical trials in anaplastic lymphoma kinase (ALK)‐positive non–small cell lung cancer (NSCLC). Serious adverse event (SAE) reports of renal cysts from a safety database of 1375 patients from four clinical trials were reviewed. A blinded, retrospective, independent radiologic review (IRR) was performed using scans from patients on study for ≥6 months in three clinical trials; risk factors for renal cyst development were assessed. Among 17 patients with renal cysts reported as SAEs, evidence of invasion into adjacent structures was noted in seven patients, with no evidence of malignancy found. These patients generally did not require dose reductions, none required permanent crizotinib discontinuation due to this AE, and most continued treatment with clinical benefit. In the blinded IRR, among 255 crizotinib‐treated patients, 22%, 3%, and 2% had preexisting simple cysts, complex cysts, or both, respectively. At the 6‐month tumor assessment, 9% of all patients had acquired new cysts, and 2% of patients with preexisting cysts had developed new cysts and enlargements (>50%) of preexisting simple cysts. Asians appeared to have an increased risk of developing new cysts on treatment; Koreans in particular had 5.18 times higher odds of developing cysts than non‐Asians (95% confidence interval, 1.51–17.78; P = 0.05). Crizotinib treatment appears to be associated with an increased risk of development and progression of renal cysts in patients with ALK‐positive NSCLC. While close monitoring is recommended, dosing modification was not generally necessary, allowing patients to remain on crizotinib treatment.

Clinical Significance of Heterogeneity in Response to Retreatment With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Lung Cancer Acquiring Secondary Resistance to the Drug

BACKGROUNDnIn patients with lung cancer acquiring resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), an intrapatient heterogeneity in response to retreatment with EGFR-TKIs remains to be elucidated.nnnPATIENTS AND METHODSnRecords were retrospectively reviewed for 68 patients with advanced non-small-cell lung cancer who received second EGFR-TKIs after systemic progression that followed durable response to the first EGFR-TKIs. All tumor lesions identified on radiologic images before second EGFR-TKIs were categorized into organs. Tumor response to EGFR-TKIs was assessed per patient and per organ. Mixed response (MR) was defined as the coexistence of at least 2 responsive and progressive organs.nnnRESULTSnTumor lesions were detected in 244 organs. The response rate (RR) and median time to progression (TTP) to second EGFR-TKIs for patients were 26.5% and 11.6 weeks (95% CI, 8.5-14.7 weeks), and the RR and median TTP for organs were 38.8% and 17.3 weeks (95% CI, 14.8-19.8 weeks). Of 35 patients categorized to progressive disease, 22 (62.8%) showed MR. Among organs, the RR was highest for the central nervous system (CNS) and lowest for the liver (CNS vs. others vs. liver: 77.8%, 36.9%, 17.6%; P < .001). Multivariate analysis confirmed the organ type and prior drug sensitivity at the time of stopping first EGFR-TKIs as predictors for the risk of progression to second EGFR-TKIs in organs.nnnCONCLUSIONSnIntrapatient heterogeneity in response to second EGFR-TKIs is not a rare event. The organ type and prior drug sensitivity at the failure time of first EGFR-TKIs may predict the efficacy of second EGFR-TKIs in individual organs.

Transient pulmonary eosinophilia incidentally found on low-dose computed tomography: findings in 40 individuals.

Purpose: To describe computed tomography (CT) findings of transient pulmonary eosinophilia (TPE) incidentally found on low-dose CT (LDCT) and to identify suggestive CT features helpful in initial diagnosis. Materials and Methods: We retrospectively reviewed LDCT scans in 40 individuals who met criteria for having TPE. There were 35 men and 5 women (age range, 32-62 years; mean, 48.5 ± 9 years). Initial LDCT scans were assessed as either (a) nodules, further characterized as either solid, solid associated with a halo of ground-glass attenuation, or pure ground-glass lesions as well as by number, size, and location or (b) ill-defined foci of parenchymal consolidation. Results: A range of focal parenchymal abnormalities (n = 78) were identified-both single (48%) and multiple (52%). Most of these proved to be either solid nodules with discrete ground-glass halos (72%), or poorly defined solid nodules exhibiting a variety of differing morphologies (24%). Ill-defined foci of consolidation were noted in 3 cases (4%). The lesions were predominantly located in the lower lung zone (73%) with peripheral distribution (92%). Conclusions: Transient pulmonary eosinophilia most often manifests as solid nodules with associated ground-glass halos. Awareness of TPE should serve to limit the number of mistaken diagnoses of early lung cancer.

A Phase II Study of Poziotinib in Patients with Epidermal Growth Factor Receptor ( EGFR )-Mutant Lung Adenocarcinoma Who Have Acquired Resistance to EGFR–Tyrosine Kinase Inhibitors

Purpose We examined the efficacy of poziotinib, a second-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with activating EGFR mutations, who developed acquired resistance (AR) to EGFR-TKIs. Materials and Methods This single-arm phase II study included EGFR-mutant lung adenocarcinoma with AR to erlotinib or gefitinib based on the Jackman criteria. Patients received poziotinib 16 mg orally once daily in a 28-day cycle. The primary endpoint was progression-free survival (PFS). Prestudy tumor biopsies and blood samples were obtained to determine resistance mechanisms. Results Thirty-nine patients were treated. Tumor genotyping was determined in 37 patients; 19 EGFR T790M mutations and two PIK3CA mutations were detected in the prestudy tumors, and seven T790M mutations were detected in the plasma assay. Three (8%; 95% confidence interval [CI], 2 to 21) and 17 (44%; 95% CI, 28 to 60) patients had partial response and stable disease, respectively. The median PFS and overall survival were 2.7 months (95% CI, 1.8 to 3.7) and 15.0 months (95% CI, 9.5 to not estimable), respectively. A longer PFS was observed for patients without T790M or PIK3CA mutations in tumor or plasma compared to those with these mutations (5.5 months vs. 1.8 months, p=0.003). The most frequent grade 3 adverse events were rash (59%), mucosal inflammation (26%), and stomatitis (18%). Most patients required one (n=15) or two (n=15) dose reductions. Conclusion Low activity of poziotinib was detected in patients with EGFR-mutant non-small cell lung cancer who developed AR to gefitinib or erlotinib, potentially because of severe-toxicityimposed dose limitation.

Randomized Phase II Study of Afatinib Plus Simvastatin Versus Afatinib Alone in Previously Treated Patients with Advanced Nonadenocarcinomatous Non-small Cell Lung Cancer

Purpose This phase II study examined whether the addition of simvastatin to afatinib provides a clinical benefit compared with afatinib monotherapy in previously treated patients with nonadenocarcinomatous non-small cell lung cancer (NA-NSCLC). Materials and Methods Patients with advanced NA-NSCLC who progressed after one or two chemotherapy regimens were randomly assigned to a simvastatin (40 mg/day) plus afatinib (40 mg/day) (AS) arm or to an afatinib (A) arm. The primary endpoint was response rate (RR). Results Sixty-eight patients were enrolled (36 in the AS arm and 32 in the A arm). The RR was 5.7% (95% confidence interval [CI], 0.7 to 19.2) for AS and 9.4% (95% CI, 2.0 to 25.0) for A (p=0.440). In arms AS and A, the median progression-free survival (PFS) was 1.0 versus 3.6 months (p=0.240) and the overall survival was 10.0 months versus 7.0 months (p=0.930), respectively. Skin rash, stomatitis, and diarrhea were the most common adverse events in both arms. More grade 3 or 4 diarrhea was observed in arm A (18.8% vs. 5.6% in arm AS). In all patients, the median PFS for treatment including afatinib was not correlated with the status of epidermal growth factor receptor (EGFR) mutation (p=0.122), EGFR fluorescence in situ hybridization (p=0.944), or EGFR immunohistochemistry (p=0.976). However, skin rash severity was significantly related to the risk of progression for afatinib (hazard ratio for skin rash grade ≥ 2 vs. grade < 2, 0.44; 95% CI, 0.25 to 0.78; p=0.005). Conclusion There were no significant differences in the efficacy between AS and A arms in patients with NA-NSCLC.

Lung Cancer Screening with Low-Dose CT in Female Never Smokers: Retrospective Cohort Study with Long-term National Data Follow-up

Purpose Because of growing concerns about lung cancer in female never smokers, chest low-dose computed tomography (LDCT) screening is often performed although it has never shown clinical benefits. We examinewhether or not female never smokers really need annual LDCT screening when the initial LDCT showed negative findings. Materials and Methods This retrospective cohort study included 4,365 female never smokers aged 40 to 79 years who performed initial LDCT from Aug 2002 to Dec 2007. Lung cancer diagnosis was identified from the Korea Central Cancer Registry Database registered until December 31, 2013. We calculated the incidence, cumulative probability, and standardized incidence ratio (SIR) of lung cancer by Lung Imaging Reporting and Data System (Lung-RADS) categories showed on initial LDCT. Results After median follow-up of 9.69 years, 22 (0.5%) had lung cancer. Lung cancer incidence for Lung-RADS category 4 was 1,848.4 (95% confidence interval [CI], 1,132.4 to 3,017.2) per 100,000 person-years and 16.4 (95% CI, 7.4 to 36.4) for categories 1, 2, and 3 combined. The cumulative probability of lung cancer for category 4 was 10.6% at 5 years and 14.8% at 10 years while they were 0.07% and 0.17% when categories 1, 2, and 3 were combined. The SIR for subjects with category 4 was 43.80 (95% CI, 25.03 to 71.14), which was much higher than 0.47 (95% CI, 0.17 to 1.02) for categories 1, 2, and 3 combined. Conclusion Considering the low risk of lung cancer development in female never smokers, it seems unnecessary to repeat annual LDCT screening for at least 5 years or even longer unless the initial LDCT showed Lung-RADS category 4 findings.

Abstract 4119: Association of plasma hepatocyte growth factor (HGF) and insulin-like growth factor binding protein (IGFBP)-3 with gefitinib resistance in patients with advanced non-small cell lung cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FLnnPurpose: It has been suggested that hepatocyte growth factor (HGF) and insulin-like growth factor binding protein (IGFBP)-3 are associated with gefitinib resistance in non-small cell lung cancer (NSCLC). We investigated the predictive and prognostic roles of these proteins in NSCLC patients treated with gefitinib.nnMethods: Of 106 patients enrolled in the randomized phase II study of gefitinib, 97 had plasma samples available for ELISA testing. Of these samples, seven and eight, respectively, had HGF and IGFBP-3 values that could not be measured. Therefore, the correlations between clinical outcomes and plasma levels of HGF and IGFBP-3 were evaluated in 90 and 89 patients, respectively.nnResults: Plasma HGF levels were significantly higher in older patients, male patients, patients with squamous cell carcinoma, current smokers, and patients with EGFR wild-type tumors. Low HGF levels were significantly associated with higher response rate (RR), and longer progression-free survival (PFS) and overall survival (OS) irrespective of EGFR mutation status. In a multivariate analysis, the presence of EGFR mutations (HR, 0.42; 95% CI, 0.24 to 0.73; P=0.002) and low HGF levels (HR, 0.58; 95% CI, 0.35 to 0.95; P=0.031) were independently predictive of longer PFS, and an ECOG PS of 0 (HR, 2.95; 95% CI, 1.57-5.54; P=0.001) and low HGF levels (HR, 0.40; 95% CI, 0.22-0.72; P=0.002) were independently predictive of longer OS. No statistically significant differences were found for IGFBP-3.nnConclusion: High HGF levels are significantly associated with resistance to gefitinib and can be used as a predictive marker for the differential outcome of gefitinib treatment in NSCLC irrespective of EGFR mutation status.nnCitation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4119. doi:10.1158/1538-7445.AM2011-4119