Kun Young Lim

Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations

Aims Deletion of exon 19 of the epidermal growth factor receptor (EGFR) and mutation of exon 21 are the most common EGFR mutations and predict higher response to EGFR tyrosine kinase inhibitors (TKI). Accumulating data show clinical differences in both response and survival between these two EGFR mutations. This study investigated the clinical impact of EGFR exon 19 deletion and L858R mutation by retrospectively analysing the clinical outcome of patients with advanced non-small-cell lung cancer (NSCLC) treated with EGFR TKI. Methods Patients harbouring EGFR exon 19 deletion or L858R mutations and who had received gefitinib or erlotinib treatment were identified. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were determined for the two groups. EGFR mutation was determined by PCR-based direct sequencing. Results The study indentified 87 patients harbouring EGFR exon 19 deletion (n=61) or L858R mutation (n=26) who were treated with either gefitinib (n=83) or erlotinib (n=4). Patients with exon 19 deletion had significantly longer PFS, compared with patients with L858R mutation (9.3 vs 6.9 months, p=0.02). In a multivariate Cox regression model, EGFR exon 19 deletion was independently predictive of longer PFS (p=0.02). However, no significant differences in RR (64% vs 62%, p=0.83) and OS (17.7 vs 20.5 months, p=0.65) were observed between these two mutations. Conclusions While no significant difference in OS was observed between EGFR exon 19 deletion and L858R mutation, EGFR exon 19 deletion was predictive of longer PFS following EGFR TKI treatment in patients with advanced NSCLC.

Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of lung cancer

PURPOSE We performed this study to evaluate the role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the pathologic diagnosis of lung cancer including lung masses as well as lymph nodes as targets. METHODS We retrospectively reviewed 126 patients who underwent EBUS-TBNA to diagnose radiologically suspected lung cancer. The patients had masses or lymph nodes that were highly suspicious for malignancy and accessible by EBUS-TBNA. RESULTS EBUS-TBNA was performed on 195 lesions (lymph nodes, n=151; lung masses, n=44). In 61 cases, other diagnostic methods had failed previous to EBUS-TBNA. In 118 patients, no definite endobronchial mucosal tumor invasion was observed. In eight patients with endobronchial tumor invasion, EBUS-TBNA was chosen due to tumor bleeding, necrosis, or difficult location for endobronchial biopsy. EBUS-TBNA confirmed 105 lung cancers, five other malignancies and six specific benign cases, demonstrating a diagnostic yield of 92.1% (116/126). Nine cases were diagnosed by other methods (lung cancer, n=2; other malignancies, n=2; benign cases, n=5). One case that was not confirmed by any diagnostic method was considered false negative. The sensitivity and diagnostic accuracy of EBUS-TBNA in the diagnosis of lung cancer were 97.2% (105/108) and 97.6% (123/126), respectively. CONCLUSIONS EBUS-TBNA targeting lymph nodes or masses highly suspicious for malignancy demonstrated high diagnostic value in the diagnosis of lung cancer. EBUS-TBNA is recommended for these cases, especially when other diagnostic methods have failed or are difficult.

A phase II study of sunitinib in patients with relapsed or refractory small cell lung cancer

PURPOSE This study was conducted to evaluate the efficacy and safety of sunitinib in patients with relapsed or refractory small cell lung cancer (SCLC). PATIENTS AND METHODS Eligibility included histologic or cytologic diagnosis of SCLC, ECOG PS of 0-2, cancer progression following one or two prior chemotherapy or chemo-radiotherapy (CRT) and adequate organ functions. Treatment regimen consisted of a 6-week cycle of sunitinib given as 50mg p.o. daily for 4 weeks followed by 2 weeks off. The primary end point was objective response rate (ORR). RESULTS From March 2008 to October 2010, 25 patients were enrolled and 24 received treatment. The median age was 64.5 years; 22 patients (92%) were male. Eight patients (33%) displayed sensitive relapse. Seven patients (29%) received CRT and fifteen patients (63%) had received one prior chemotherapy. A median of 1 cycle (range 1-4) of sunitinib was administered, and 23 patients were evaluable for response. Two patients displayed partial response, and seven patients presented stable disease with a ORR of 9% (95% CI, 1-28%). The median progression-free (PFS) and overall survivals were 1.4 months (95% CI, 1.1-1.7) and 5.6 months (95% CI, 3.5-7.7), respectively. The common grade 3 or 4 toxicities included thrombocytopenia (63%), asthenia (29%) and neutropenia (25%). CONCLUSIONS Although tumor response was noted in 2 patients, the median PFS was short and most patients were unable to tolerate the treatment. At the current dose schedule, sunitinib does not appear to warrant further evaluation.

Cystic tumors in the anterior mediastinum: Radiologic-pathological correlation

Anterior mediastinal neoplasms comprise a diverse group of tumors and occasionally manifest as a cystic lesion. We retrospectively reviewed computed tomography (CT) scans in 46 patients with pathologically proved cystic anterior mediastinal tumors. We categorize them into a pure cystic mass and a cystic tumor with a solid portion. In this pictorial essay, the radiologic appearances of cystic anterior mediastinal tumors are described with CT and illustrated with their gross and histopathological findings on resected specimen.

A phase 2 study of irinotecan, cisplatin, and simvastatin for untreated extensive-disease small cell lung cancer.

The objective of this study was to investigate the efficacy of simvastatin in combination with irinotecan and cisplatin in chemotherapy‐naive patients with extensive‐disease small‐cell lung cancer (ED‐SCLC).

Randomized phase II study of maintenance irinotecan therapy versus observation following induction chemotherapy with irinotecan and cisplatin in extensive disease small cell lung cancer.

Introduction: To determine whether irinotecan maintenance therapy in extensive disease-small cell lung cancer can improve survival of patients who responded to irinotecan plus cisplatin (IP) induction therapy. Methods: A total of 120 chemo-naive patients with adequate organ functions and Eastern Cooperative Oncology Group performance status of 0 to 2 were enrolled from March 2003 through April 2006. After IP induction therapy, with either schedule A (I: 60 mg/m2 intravenously (IV) on days 1, 8, and 15; P: 30 mg/m2 IV on days 1 and 8, every 4 weeks for six cycles) or schedule B (I: 60 mg/m2 and P: 30 mg/m2 IV on days 1, and 8, every 3 weeks for eight cycles), responding patients were randomized to either maintenance with irinotecan 100 mg/m2 IV on days 1, 8, and 15, every 4 weeks up to six cycles, or observation. Results: Overall, 100 (83%) of 120 patients achieved objective tumor responses (12 complete responses, 88 partial responses) after IP induction therapy. Of those patients who remained in remission upon completion of planned cycles of induction therapy, 45 were randomized to maintenance (n = 21) or observation (n = 24). Median progression-free survival (PFS) and overall survival (OS) for all patients were 7.2 and 14.0 months, respectively. For the maintenance arm, median PFS and OS were 12.0 and 17.6 months, respectively. For the observation arm, median PFS and OS were 9.9 and 20.5 months, respectively, which was not significantly different from the maintenance arm. Conclusions: IP chemotherapy is very useful for the treatment of small cell lung cancer. However, maintenance irinotecan therapy did not seem to further affect the clinical outcome of patients who had responded to IP induction therapy.

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

BACKGROUND In 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. PATIENTS AND METHODS Records 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. RESULTS Tumor 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. CONCLUSIONS Intrapatient 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.

A phase II study of nintedanib in patients with relapsed small cell lung cancer

OBJECTIVES Nintedanib is an oral triple angiokinase inhibitor. This study was conducted to evaluate the efficacy and safety of nintedanib in patients (pts) with relapsed/refractory small cell lung cancer (SCLC). PATIENTS AND METHODS Pts with an ECOG PS from 0 to 2 who exhibited progression after one or two prior chemotherapy or chemo/radiotherapy were enrolled. Pts received nintedanib 200mg BID daily in a 4-week cycle until progression or intolerable toxicity. The primary end point was the objective response rate (ORR). A two-stage design was employed. To continue to stage 2, ≥2 responders out of 22 pts were required. RESULTS From Dec 2011 to June 2014, 24 pts were enrolled. Twenty-two pts completed treatment and were evaluable for response. The median follow-up was 9.7 (0.5-19.8) months. The median age was 64 (46-77) years. Twenty-two pts were male. Six pts had sensitive relapse. Eight pts received one prior chemotherapy. A median of one (range 1-5) cycle was administered. One pt had a partial response, and seven pts exhibited stable disease. The ORR was 5% (95% confidence interval [CI], 0.1-22.8). Median progression-free survival was 1.0 (95% CI, 0.9-1.1) month, and overall survival was 9.8 (95% CI, 8.4-11.2) months. The response criteria to proceed to full accrual were not met. The most frequent drug-related adverse events (AE) included hepatic enzyme elevation (86%), anemia (73%), anorexia (59%), and nausea (50%). Most AEs were mild and manageable. Grade 3 hepatic enzyme elevation occurred in 5 pts (23%). CONCLUSIONS Nintedanib exhibited only limited activity with a manageable AE profile in relapsed or refractory SCLC (NCT01441297).

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.

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.