Chao-Hua Chiu

Predictive Factors of Gefitinib Antitumor Activity in East Asian Advanced Non-small Cell Lung Cancer Patients

Background: Gender, smoking history, adenocarcinoma histology, performance status, and East Asian ethnicity were predictive factors of gefitinib response in previous analysis. However, these factors tend to be correlated with each other; it is not clear whether gender, smoking history, and adenocarcinoma histology were all independent predictors for response in East Asian populations. Methods: Tumor response, survival and predictive factors of gefitinib response of advanced non-small cell lung cancer patients treated between May of 2002 and November of 2004 were collected retrospectively from three medical centers in Taiwan. Univariate and multivariate logistic regression models were used to test potential predictive factors associated with response to gefitinib. Overall survivals between groups with different predictive factors were compared by log-rank tests. Multivariate analyses were performed to identify factors that independently predict for survival. Results: A total of 428 patients were analyzed. The median follow-up duration for living patients was 19.5 months (range, 10.2–39.9). Objective tumor response was observed in 114 patients (26.6%, 95% confidence interval [CI]: 22.4%–30.8%) and disease stabilization in 129 patients (30.2%). Response rate was statistically significant higher in adenocarcinoma, good performance status, and chemonaive patients in multivariate analysis. The median survival was 7.4 months (95% CI: 5.8–9.0) and 1-year survival was 34.3% (95% CI: 29.0%–38.0%). Significant independent predictive factors associated with longer survival in multivariate analysis were good performance status (p < 0.001) and responsiveness to gefitinib (p < 0.001). In 286 chemotherapy-treated patients, the response rate was 22.7%. Median and 1-year survival was 7.9 months and 36.7%, respectively. Good performance status was predictive of tumor response (p < 0.001) and better survival (p < 0.001) in multivariate analysis. Response to gefitinib was predictive of better survival (p < 0.001). Conclusions: Gender and smoking status were not, but good performance status (PS), no previous chemotherapy, and adenocarcinoma histology were independent predictive factors in multivariate analysis for gefitinib response in Taiwanese advanced non-small cell lung cancer population. In patients previously treated with chemotherapy, only good PS was an independent predictor for tumor response in multivariate analysis.

Histological Subtypes of Lung Adenocarcinoma Have Differential 18F-Fluorodeoxyglucose Uptakes on the Positron Emission Tomography/Computed Tomography Scan

Introduction: Previous studies have shown that lung squamous cell carcinoma has higher 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) than adenocarcinoma. We hypothesized that histological subtypes of lung adenocarcinoma were also different in 18F-FDG uptake. Methods: Patients who had preoperative PET/computed tomography (CT) scan and had undergone complete resection for lung adenocarcinoma between April 2007 and December 2009 were enrolled in this study. Because of the limitation of spatial resolution on PET/CT, tumors less than 1 cm were excluded for analysis. Two independent classification systems were used to categorize histological subtypes of adenocarcinoma; one was modified from the current World Health Organization classification and the other used the morphological features of the terminal respiratory unit (TRU). The maximal standardized uptake value (SUVmax) on PET/CT and the glucose transporter type 1 (GLUT-1) expression of the tumors were measured and correlated to the histology of lung adenocarcinoma. Results: One hundred fifty-two patients with 153 primary lung adenocarcinomas were included. There was a significant difference in SUVmax among different histological subtypes. Namely, solid predominant adenocarcinomas had significantly higher SUVmax than those with other predominant histology (p < 0.001), and TRU-type adenocarcinomas had significantly lower SUVmax than non-TRU-type adenocarcinomas (p < 0.001). Consistently, GLUT-1 expression was higher in tumors with a solid growth pattern than those without (p < 0.001) and in tumors with non-TRU type than TRU type (p < 0.001). Conclusions: The histological subtypes of lung adenocarcinomas differ in GLUT-1 expression and 18F-FDG uptake on the PET/CT scan, suggesting that histological subtyping not only has morphological but also biological implications.

Bone scan flare phenomenon in non-small-cell lung cancer patients treated with gefitinib.

Purpose: The bone scan flare phenomenon has been evaluated in various cancers in the presence of positive response to therapy. The aim of this study was to determine whether flare phenomenon occurs in non-small-cell lung cancer patients, especially adenocarcinoma in East-Asians, who respond dramatically and promptly to gefitinib. Methods: We retrospectively evaluated the radiographic and scintigraphic images of 125 lung cancer patients who had previous gefitinib treatment between July 2003 and October 2005. Those patients who had the first post-treatment scan done within 3 months and the second scan performed after 3 months after starting the therapy were included. New lesions or increased intensity observed on the first follow-up bone scan with improvement on the second one during gefitinib treatment was defined as positive for flare phenomenon. The results were correlated with clinical disease status. Results: Thirty-three non–small-cell lung cancer patients were included. Seven (21.2%) of them showed bone scan flare phenomenon. Of these seven, 5 had adenocarcinoma and 2 had unclassified non–small-cell lung cancer. Partial response was achieved after treatment in all these cases, and flare phenomena were detected between 29 and 77 days (median: 34 days) after treatment. Conclusion: The findings show that the flare is common during the first 3 months of gefitinib initiation; hence, a repeat bone scan should be reserved for later in the treatment course.

Interstitial Pneumonia During Gefitinib Treatment of Non-Small-Cell Lung Cancer

Gefitinib, an orally active, selective inhibitor of epidermal growth factor-receptor tyrosine kinase, is an effective treatment for patients with advanced non-small-cell lung cancer (NSCLC). Most drug-related adverse events are mild to moderate; however, some patients may develop acute interstitial pneumonia that is sometimes fatal. In a prospective study of gefitinib in 76 patients with advanced NSCLC, 69 patients were evaluable for toxicity, and 4 cases (5.8%) of gefitinib-related interstitial pneumonia were diagnosed: 1 occurred in the second week; 2 in the second month; and 1 during the fourth month of treatment. When interstitial pneumonia occurred, the patients had stable disease (n = 2), a partial response (n = 1), or progressive disease (n = 1). All 4 patients recovered when gefitinib treatment was stopped and glucocorticosteroid therapy was started; no deaths related to gefitinib therapy were noted in this series. While treating NSCLC patients with gefitinib, it is important to carefully evaluate any new-onset respiratory symptoms and promptly arrange radiographic examinations, and to stop gefitinib treatment and begin glucocorticosteroid therapy whenever pulmonary toxicity is highly suspected.

Should EGFR mutations be tested in advanced lung squamous cell carcinomas to guide frontline treatment

There is no argument over using epidermal growth factor receptor (EGFR) mutation status to guide the frontline treatment for advanced lung adenocarcinoma (LADC); however, the role of the testing in lung squamous cell carcinoma (LSQC) remains controversial. Currently, the guidelines/consensus statements regarding EGFR mutation testing in LSQC are not consistent among different oncology societies. American Society of Clinical Oncology recommends performing EGFR mutation testing in all patients; European Society for Medical Oncology, College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology, and National Comprehensive Cancer Network suggest for some selected group. EGFR mutation is rarely found in LSQC; however, more importantly, it is not a valid predictive biomarker for EGFR tyrosine kinase inhibitors (EGFR-TKI) in LSQC as it has been shown in LADC. Available data showed that the response rate and progression-free survival in EGFR mutant LSQC patients treated with EGFR-TKI are not better than that observed in patients treated with platinum-doublet chemotherapy in the first-line setting. Therefore, in contrast to advanced LADC, EGFR mutation testing may not be necessarily performed upfront in advanced LSQC because not only the mutation rate is low, but also the predictive value is insufficient. For LSQC patients with known sensitizing-EGFR mutations, both conventional chemotherapy and EGFR-TKI are acceptable frontline treatment options.

Clinical Characteristics and Treatment Outcomes of Lung Adenocarcinomas with Discrepant EGFR Mutation Testing Results Derived from PCR-Direct Sequencing and Real-Time PCR-Based Assays

Introduction: Detection of epidermal growth factor receptor (EGFR) mutation has become the most critical molecular test in managing patients with advanced lung adenocarcinoma. Whether patients with discrepant EGFR mutation results determined by low- and high-sensitivity methods have different clinical outcomes with EGFR tyrosine kinase inhibitor (TKI) treatment needs to be further evaluated. Methods: Genomic DNA from serial lung adenocarcinoma samples that were EGFR wild-type determined by direct sequencing (DS) were reanalyzed using Scorpion/Amplification Refractory Mutation System (ARMS). The outcomes with EGFR-TKI treatment among patients with discrepant EGFR mutation results between DS and Scorpion/ARMS versus patients with EGFR mutations detected by DS were studied. Results: Of the 130 tumors studied, 28 (21.5%) were found to have EGFR mutations by Scorpion/ARMS. Discrepant EGFR mutation testing results were more common in samples from nonsmokers than in samples from smokers (30.7% versus 9.1%; p = 0.003) and in pleural than in nonpleural samples (62.5% versus 18.9%; p = 0.012). There was no significant difference in the abundance of cancer cells in region(s) selected for testing (26.2% in tumor cell percentage ⩽50 versus 16.9% in tumor cell percentage >50; p = 0.201). During EGFR-TKI treatment, the progression-free survival in patients with discrepant EGFR mutation results was similar to those with EGFR mutations detected by DS (median, 13.4 versus 10.9 months; p = 0.225). Conclusions: DS overlooked EGFR mutation in a significant number of lung adenocarcinoma patients. These patients could have obtained the same benefit from EGFR-TKI when a high-sensitivity method such as Scorpion/ARMS was applied.

Lung Adenocarcinoma with Ipsilateral Breast Metastasis: A Simple Coincidence?

Introduction: Lung cancer with breast metastasis is rare. However, differentiating between primary breast cancer and metastatic lung adenocarcinoma is of clinical importance. The metastasis cascade of how cancer cells migrate from the primary lung tumor to the breast is not clear yet. Methods: Pathology and cytology databases were searched for patients diagnosed to have lung adenocarcinoma with breast metastasis. Their medical records, chest computed tomography images, and pathology slides were reviewed independently. Results: We identified six lung adenocarcinoma patients with breast metastases in a 10-year period from a tertiary medical center. Interestingly, all breast metastases affected the same side as the primary lung cancers. In addition, all our cases shared other clinical manifestations, namely, ipsilateral pleural effusion/thickness and axillary lymph node enlargement. Conclusion: Because this distinctive feature could not be explained by simple coincidence, we consider that lung adenocarcinoma may preferentially metastasize to the ipsilateral breast through a stepwise mechanism, involving pleural seeding, axillary lymph node metastasis, and retrograde lymphatic spreading into the breast.

Erlotinib in patients with advanced lung squamous cell carcinoma

PurposeErlotinib had proved efficacy in patients with advanced non-small cell lung cancer, especially adenocarcinoma. The aim of this study was to evaluate the efficacy of erlotinib in patients with advanced lung squamous cell carcinoma (LSQC).MethodsWe retrospectively reviewed medical records and serial chest images of consecutive patients who were diagnosed with advanced LSQC and had been treated with erlotinib monotherapy. The primary objective was to evaluate the treatment efficacy and to correlate with patients’ clinical characteristics.ResultsTotally 55 patients were analyzed (42 men and 13 women, median age of 71xa0years). In 37 patients who had measurable lesions, 6 had partial response and 13 had stable disease, yielding an overall response rate of 16.2xa0% and disease control rate of 51.4xa0%. In all patients, the median progression-free survival (PFS) and overall survival (OS) were 2.0xa0months (95xa0% confidence interval, 1.5–2.4xa0months) and 10.4xa0months (95xa0% confidence interval, 0.6–20.2xa0months), respectively. The PFS and OS were significantly longer in patients who had good clinical response (either the tumor achieved partial response or the patients had disease controlled for more than 6xa0months) than those who did not (median PFS, 13.0 vs. 1.6xa0months; median OS, 28.3 vs. 4.9xa0months; both P values <0.01). Patients who never smoked seemed to have better clinical response and longer survival than those who had smoking history (Pxa0=xa00.077 and 0.086, respectively).ConclusionsErlotinib could provide some clinical benefit to patients with advanced LSQC.

Idiopathic Acute Eosinophilic Pneumonia

Idiopathic acute eosinophilic pneumonia (IAEP) is a rare disease but of clinical importance because of its good prognosis if treated promptly and appropriately. The etiology remains unknown and the temporal relationship between IAEP and a history of resent onset of cigarette smoking has been described. We report a typical case of a 21-year-old male with recent onset of smoking, who presented with acute febrile hypoxemic respiratory failure. High-resolution chest computed tomography scan revealed patchy ground glass opacity and ill-defined nodules, diffuse interlobar and interlobular septal thickening, and bilateral small amount of pleural effusion, which mimicked congestive heart failure except that the heart size was within normal limits. Bronchoalveolar lavage (BAL) was performed soon after the patient was admitted and remarkable eosinophilia was noted in BAL fluid. Clinical condition and chest radiographs improved dramatically after corticosteroid treatment. Because effective treatment and prompt institution of therapy can obviate unnecessary morbidity and mortality, IAEP should be kept in mind when treating patients presenting with diffuse parenchymal lung disease and acute respiratory failure. In that case, BAL is valuable and should be performed as soon as possible.

Radiation recall pneumonitis induced by epidermal growth factor receptor-tyrosine kinase inhibitor in patients with advanced nonsmall-cell lung cancer.

Background Radiation recall pneumonitis (RRP) is a special form of radiation pneumonitis precipitated by certain pharmacological agents. Epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) is an effective treatment for advanced nonsmall‐cell lung cancer (NSCLC) and has been reported as a potent radiation sensitizer. The incidence and general characteristics of EGFR‐TKI‐related RRP in patients with NSCLC remain unclear. Methods Clinical records and serial chest images of consecutive patients with advanced NSCLC who had received thoracic radiotherapy (TRT) and EGFR‐TKI treatment were retrospectively reviewed. EGFR‐TKI‐related RRP was diagnosed according to history, clinical manifestations, and radiographic characteristics. Potential risk factors were analyzed. Results In total, 160 patients with NSCLC who received EGFR‐TKI after TRT were identified. Of these patients, seven (4.4%) developed EGFR‐TKI‐related RRP. The median time interval between the end of radiotherapy and RRP was 124 days (range, 80–635 days) and that between the initiation of EGFR‐TKI and RRP was 43 days (range, 18–65 days). No risk factor for the development of RRP was identified except that patients in whom EGFR‐TKI was initiated within 90 days after the completion of radiotherapy had significantly higher rates of RRP than those of patients who began receiving EGFR‐TKI treatment after 90 days (21% vs. 2.1%, p = 0.005). Conclusion In patients with NSCLC who have a history of TRT, treatment with EGFR‐TKI may induce not only interstitial lung disease but also RRP. Physicians should be aware of both unexpected adverse events when using EGFR‐TKI.