Long-term results of S-1 plus cisplatin with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer.

PURPOSE: The purpose of this phase I/II study was to evaluate the feasibility and efficacy of S-1 plus cisplatin at the recommended schedule with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: Eligible patients with LA-NSCLC were treated with cisplatin intravenously at a dose of 60 mg/m2 on day 8 plus oral S-1 at a dosage of 40 mg/m2 twice per day for two different treatment schedules for up to 4 cycles. Patients also concurrently received 60 Gy of thoracic radiation in 30 fractions. The primary endpoint of the phase II study was the proportion of patients who survived for more than 2 years. RESULTS: Between August 2005 and October 2010, a total of 45 patients were enrolled in this phase I/II study; their long-term survival was then followed for a median period of 5.8 years. Nineteen of the 39 patients in the phase II study survived for more than 2 years and met the primary endpoint of the study. The median overall survival period was 24.9 months [95% confidence interval (CI) 17.4-74.5 months], and the 2- and 5-year overall survival rates were 51.0 and 43.0%, respectively. The response rate was 85%, and the median progression-free survival period was 13.8 months (95% CI 9.5-27.1 months). Hematological toxicity was mild. Grade 3 febrile neutropenia and pneumonitis was observed in 5 and 5%, respectively. CONCLUSION: Our study indicated that S-1 plus cisplatin with concurrent thoracic radiotherapy yielded encouraging survival outcomes and an acceptable safety profile for LA-NSCLC.

Efficacy of Cell-Free and Concentrated Ascites Reinfusion Therapy for Palliative Care in a Patient with Malignant Pleural Mesothelioma: A Case Report.

Cell-free and concentrated ascites reinfusion therapy (CART) is recognized as a useful treatment to improve the symptoms caused by refractory ascites. Recently, a few clinical studies have reported the effects of CART for malignant ascites, especially in gynecological and gastrointestinal cancers. We report the case of malignant ascites in a patient with malignant pleural mesothelioma (MPM) whose symptoms were relieved by CART. A 59-year-old Japanese male with MPM who had undergone pleural decortication had pleural and peritoneal recurrence. His general status deteriorated as he developed massive ascites due to peritoneal metastases. With the initiation of CART, he recovered well enough to receive cisplatin-based systemic chemotherapy. Repeated use of CART contributed to the maintenance of his good general condition and enabled him to undergo successive systemic chemotherapy, which might have lengthened his life. This is the first report that demonstrates the efficacy of CART for palliative care in a patient with MPM. Our experience indicates that CART should be considered as a treatment option to control refractory malignant ascites regardless of the type of cancer.

Switch maintenance chemotherapy using S-1 with or without bevacizumab in patients with advanced non-small cell lung cancer: a phase II study.

OBJECTIVES: We conducted this single-institute; prospective, non-randomized parallel two-arm phase II study to evaluate the efficacy and safety of switch maintenance chemotherapy with S-1 after induction therapy with a platinum-based regimen in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients not showing disease progression after induction platinum-based chemotherapy received S-1 at the dose of 40mg/m2 twice daily for 14 consecutive days, every three weeks, with or without bevacizumab (Bev) at the dose of 15mg/kg. In cases where the induction chemotherapy regimen contained Bev, Bev was used as continuation maintenance chemotherapy where appropriate. The efficacy/toxicity of switch maintenance chemotherapy with S-1 and S-1+Bev was evaluated separately. The primary end point of this study was the treatment success rate at three months after the start of S-1 treatment. RESULTS: Between July 2010 and January 2014, 79 patients were enrolled, of which 78 were found to be eligible for inclusion in this study. The treatment success rate at three months was 28.2% (90% confidence interval (CI), 7.1-17.1%) in the S-1 group and 64.1% (90% CI, 50.0-76.8%) in the S-1+Bev group. The primary endpoint was met in the S-1+Bev group. The median PFS and OS were 2.6 months and 11.0 months in the S-1 group, and 4.6 months and 19.9 months in the S-1+Bev group, respectively. The most common grade three toxicity was neutropenia (10% incidence in the S-1+Bev group). There were no cases of febrile neutropenia. CONCLUSIONS: Switch maintenance chemotherapy with S-1 in combination with continuation maintenance chemotherapy with bevacizumab yielded modest efficacy with mild and acceptable toxicities.

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung.

PURPOSE: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. EXPERIMENTAL DESIGN: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). RESULTS: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%). CONCLUSIONS: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757-65. ©2016 AACR.

Changes in the tumor microenvironment during lymphatic metastasis of lung squamous cell carcinoma.

Metastasis and growth in neoplastic lesions requires the multistep regulation of microenvironmental factors. We aimed to elucidate the microenvironmental changes in the process of lymphatic metastasis of lung squamous cell carcinoma. We examined the morphological characteristics of 102 cases of primary tumor (PT), 50 of intralymphatic tumor (ILT), 51 of lymph node (LN) micrometastasis (LN-Mic; ≤2 mm in size), and 82 of LN macrometastasis (LN-Mac; ≥10 mm in size). Afterwards we evaluated the expression of nine molecules (epidermal growth factor receptor, fibroblast growth factor receptor 2, CD44, aldehyde dehydrogenase 1, Podoplanin, E-cadherin, S100A4, geminin, and ezrin) in matched PT, ILT, LN-Mic, and LN-Mac from 23 of these cases. The number of smooth muscle actin α-positive fibroblasts, CD34-positive microvessels and CD204-positive macrophages were also examined. As a result, the mitotic index of tumor cells was significantly lower in ILT and LN-Mic than PT and LN-Mac (P < 0.001). Moreover, stromal reaction in ILT and LN-Mic was less prominent than in PT and LN-Mac (P < 0.001). Immunohistochemical study revealed that epidermal growth factor receptor expression level and frequency of geminin-positive cells in ILT and LN-Mic were significantly lower than in PT and LN-Mac (P < 0.05). The number of stromal cells indicated by staining of CD34, CD204, and smooth muscle actin α in ILT and LN-Mic was also significantly lower than in PT and LN-Mac (P < 0.05). In lung squamous cell carcinoma, drastic microenvironmental changes (e.g., growth factor receptor expression and proliferative capacity of tumor cells and structural changes in stromal cells) occur during both the process of lymphatic permeation and the progression into macrometastases.

Successful treatment with afatinib after grade 3 hepatotoxicity induced by both gefitinib and erlotinib in EGFR mutation-positive non-small cell lung cancer.

Hepatotoxicity is a major cause of the withdrawal of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) when treating EGFR mutation-positive non-small cell lung cancer (NSCLC). We report a case in which gefitinib- and elrotinib-induced severe hepatotoxicity arose in a patient with the uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) and cytochrome p450 3A5 (CYP3A5) poor metabolizer phenotypes. Afatinib is not significantly metabolized by cytochrome p450-mediated pathways. We describe successful management of the patient's tumor by switching to afatinib. Evaluation of single nucleotide polymorphisms (SNPs) in metabolic enzymes might be useful to predict severe hepatotoxicity induced by EGFR-TKIs.

A phase I dose-escalation study of LY2875358, a bivalent MET antibody, given as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.

Background MET is a tyrosine kinase receptor involved in the regulation of cell proliferation and migration. Reported here are the phase I dose-escalation results for LY2875358, a monoclonal antibody against MET, in Japanese patients with advanced malignancies. Methods The study comprised a 3 + 3 dose-escalation part for LY2875358 monotherapy in patients with advanced malignancies (Part A) followed by an assessment of LY2875358 in combination with erlotinib or gefitinib in patients with non-small cell lung cancer (Part B). LY2875358 was administered once every 2 weeks. The primary objective was to evaluate the safety and tolerability of LY2875358; secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and antitumor activity. Results Eleven patients received LY2875358 monotherapy at 3 dose levels (700 mg, N = 3; 1400 mg, N = 3; 2000 mg, N = 5) and 6 patients received LY2875358 2000 mg in combination with erlotinib (N = 3) or gefitinib (N = 3). No dose-limiting toxicities or serious adverse events related to LY2875358 were observed. The most frequently reported drug-related adverse events were hypoalbuminemia (2 patients) in Part A and dermatitis acneiform (4 patients) in Part B. LY2875358 area under the curve (AUC) and maximum concentration (Cmax) increased with dose over the dose range of 700 mg to 2000 mg. A best response of stable disease was achieved by 2/11 patients in Part A and 4/6 patients in Part B (disease control rate: 35 %). Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.

Prognostic Factor Analysis in Patients With Small-Cell Lung Cancer Treated With Third-Line Chemotherapy.

BACKGROUND: There is little information on the clinical outcome of patients with small-cell lung cancer (SCLC) treated with third-line chemotherapy. The purpose of this study was to clarify the prognostic factors of SCLC patients receiving third-line chemotherapy. PATIENTS AND METHODS: Between November 2001 and October 2011, 202 of 648 consecutive SCLC patients at the National Cancer Center Hospital East received third-line chemotherapy. Multivariate Cox regression analysis was performed to identify the prognostic factors for overall survival after third-line chemotherapy. RESULTS: The demographics of the 202 patients were as follows: median age 66 years, 83% male, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2, and 3 values of 22, 122, 49, and 9, respectively. Median time to treatment failure after second-line chemotherapy (TTF2) was 4.5 months (TTF2 ≥ 5/< 5 months, 82/120). The median overall survival after third-line chemotherapy was 5.1 months. Multivariate Cox regression analysis showed that PS 0-1 (hazard ratio, 0.38; 95% confidence interval, 0.27-0.54; P < .001) and TTF2 ≥ 5 months (hazard ratio, 0.57; 95% confidence interval, 0.41-0.79; P < .001) were independent prognostic factors. TTF2 threshold of 5 months was determined on the basis of concordance probability adjusted by PS. CONCLUSION: PS 0-1 and TTF2 ≥ 5 months were associated with a favorable prognosis among SCLC patients receiving third-line chemotherapy. These 2 factors might be helpful for the selection of candidates for third-line chemotherapy and for patient stratification when conducting future clinical trials in the third-line setting.

Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study.

INTRODUCTION: The purpose of this study was to evaluate the natural course of the progression of pulmonary subsolid nodules (SSNs). MATERIALS AND METHODS: Eight facilities participated in this study. A total of 795 patients with 1229 SSNs were assessed for the frequency of invasive adenocarcinomas. SSNs were classified into three categories: pure ground-glass nodules (PGGNs), heterogeneous GGNs (HGGNs) (solid component detected only in lung windows), and part-solid nodules. RESULTS: The mean prospective follow-up period was 4.3 ± 2.5 years. SSNs were classified at baseline as follows: 1046 PGGNs, 81 HGGNs, and 102 part-solid nodules. Among the 1046 PGGNs, 13 (1.2%) developed into HGGNs and 56 (5.4%) developed into part-solid nodules. Among the 81 HGGNs, 16 (19.8%) developed into part-solid nodules. Thus, the SSNs at the final follow-up were classified as follows: 977 PGGNs, 78 HGGNs, and 174 part-solid nodules. Of the 977 PGGNs, 35 were resected (nine minimally invasive adenocarcinomas [MIAs], 21 adenocarcinomas in situ [AIS], and five atypical adenomatous hyperplasias). Of the 78 HGGNs, seven were resected (five MIAs and two AIS). Of the 174 part-solid nodules, 49 were resected (12 invasive adenocarcinomas, 26 MIAs, 10 AIS, and one adenomatous hyperplasia). For the PGGNs, the mean period until their development into part-solid nodules was 3.8 ± 2.0 years, whereas the mean period for the HGGNs was 2.1 ± 2.3 years (p = 0.0004). CONCLUSION: This study revealed the frequencies and periods of development from PGGNs and HGGNs into part-solid nodules. Invasive adenocarcinomas were diagnosed only among the part-solid nodules, corresponding to 1% of all 1229 SSNs.

Factors influencing the concordance of histological subtype diagnosis from biopsy and resected specimens of lung adenocarcinoma.

OBJECTIVES: Lung adenocarcinoma is heterogeneous, characterized by various histological subtypes. Determination of the predominant histological subtype (lepidic, papillary, acinar or solid-predominant) has been shown to correlate with genetic abnormalities and clinicopathological features. Although subtyping using small biopsy samples is important for tailored approaches to clinical management, limited data exist on the concordance of predominant subtype between resected specimens and biopsy specimens. MATERIALS AND METHODS: We compared the diagnosed predominant subtypes in resected specimens and matched biopsy specimens in a series of 327 lung adenocarcinomas. The accuracy of preoperative diagnosis by biopsy and the factors that influence concordance with resected specimen analysis were examined. RESULTS: In 211 of the 326 patients (66.0%), the predominant adenocarcinoma subtype diagnosed from biopsy matched the findings of resection analysis. Overall, the concordance rate in biopsy samples with larger tumor areas (≥ 0.7 mm(2)) was significantly higher than in those with smaller tumor area (<0.7 mm(2); 71.2% vs 60.7%, respectively; p=0.015). In the biopsy samples with smaller tumor areas, the concordance rate was 77% in lepidic subtype, 71% in papillary subtype, 60% in solid subtype, and 40% in acinar subtype. Concordance rate in the biopsy samples with larger tumor area was higher in papillary and solid subtypes (88% and 76%, respectively), but remained low in acinar subtype (37%). CONCLUSION: The current results indicate that accuracy of adenocarcinoma subtyping based on small biopsy samples is influenced by tumor area. Our study also suggests that subtyping of acinar histology using biopsy specimen is particularly error-prone.

Clinical Impact of Gastric Acid-Suppressing Medication Use on the Efficacy of Erlotinib and Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations.

BACKGROUND: Gastric acid-suppressing medications (AS), namely, proton pump inhibitors and histamine-2 receptor antagonists, increase gastric pH, which may reduce the absorption of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors-erlotinib and gefitinib. PATIENTS AND METHODS: From 2008 to 2011, 130 consecutive patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations were treated with either erlotinib or gefitinib at our institution. The clinical characteristics of the patients were reviewed, and the efficacy and toxicity of erlotinib and gefitinib were compared for patients receiving and not receiving AS. RESULTS: Among the 130 patients, 47 received AS (AS users group), while the remaining 83 patients did not (AS non-users group). The overall response rate (ORR) and median progression-free survival (PFS) in the subject population was 60% and 10 months, respectively. In the AS users and non-users groups, the ORR was 64% and 63% (P = .92), while the median PFS was 8.7 and 10.7 months (P = .13), respectively. No significant difference in either ORR or PFS was observed between the 2 groups. With regard to the toxicity, the frequencies of rash (83% vs. 86%; P = .60) and diarrhea (34% vs. 29%; P = .55) were similar for both groups. A multivariate analysis identified that AS use was not a significant factor for either PFS or OS. CONCLUSION: Concurrent use of AS did not affect the efficacy or toxicity of erlotinib and gefitinib in patients with advanced NSCLC harboring EGFR mutations.

Aggressive tumor microenvironment of solid predominant lung adenocarcinoma subtype harboring with epidermal growth factor receptor mutations.

INTRODUCTION: Tumor microenvironment critically affects cancer progression. This study aimed to identify differences in microenvironments of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations by histological subtypes. METHODS: The study cohort included 214 lung adenocarcinomas harboring EGFR mutations. We analyzed clinicopathological characteristics of lepidic (LPA), papillary (PPA), acinar (APA), and solid-predominant adenocarcinoma (SPA) subtypes, and examined expression levels of EGFR, E-cadherin, ezrin, laminin-5, ALDH1, and PD-L1 in cancer cells, and of CD34, CD204, podoplanin (PDPN), and FoxP3 in stromal cells in 4 subtypes (n=20 each). RESULTS: SPA displayed significantly more frequent lymph node metastasis, lymphovascular invasion, and worse prognosis than the other subtypes. Ezrin expression levels in SPA were also significantly higher than in LPA, PPA, or APA (P<0.05, all). Laminin-5 and PD-L1 expression levels in SPA were significantly higher than in LPA (P<0.01 for both) and PPA (P<0.01 for both) and tended to be higher than in APA (laminin-5: P=0.096, PD-L1: P=0.081). Furthermore, SPA displayed higher levels of PDPN (+) cancer-associated fibroblasts (P<0.01) and CD204 (+) tumor-associated macrophages (P<0.05) than the other subtypes. CONCLUSION: Compared with other predominant subtypes with EGFR mutations, the microenvironment of SPA with EGFR mutations is characterized by cancer cells with higher invasive and immune evasion potential and more abundant stromal cells with tumor-promoting functions, which would contribute to the more aggressive behavior of SPA.

Dose-Escalation Study of Thoracic Radiotherapy in Combination With Pemetrexed Plus Cisplatin in Japanese Patients With Locally Advanced Nonsquamous Non-Small Cell Lung Cancer: A Post Hoc Analysis of Survival and Recurrent Sites.

OBJECTIVES: We performed a post hoc analysis of progression-free survival (PFS), overall survival (OS), and recurrent sites in patients with locally advanced nonsquamous non-small cell lung cancer who were enrolled in a phase I trial of combination chemotherapy consisting of pemetrexed plus cisplatin with concurrent thoracic radiotherapy. METHODS: Patients received pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) on day 1 every 3 weeks for 3 cycles plus concurrent thoracic radiotherapy consisting of 60 Gy (n=6) or 66 Gy (n=12); 4 to 6 weeks thereafter, patients received consolidation treatment with pemetrexed (500 mg/m) every 3 weeks for up to 3 cycles. We reviewed the medial records to collect data on progression, recurrent sites, late toxicity, and survival. RESULTS: No late radiation morbidity was observed. Thirteen patients (72%) exhibited disease progression: 8 patients had distant metastases, 8 patients had local recurrence (within the radiation field [n=6], outside the radiation field [n=2], and both [n=1]), and 3 patients had local recurrence plus distant metastases. The median PFS was 10.5 months (95% confidence interval [CI], 8.8-12.3), and the 3-year PFS rate was 28% (95% CI, 7.0-48.6). Ten of the 18 patients died of lung cancer. The median follow-up time for the censored cases was 42.8 months (range, 38.1 to 52.9 mo). The median OS was 27.3 months (95% CI, 13.1-41.6), and the 3-year OS rate was 50% (95% CI, 26.9-73.1). CONCLUSIONS: The median PFS and OS in our study were comparable to those of historical chemoradiotherapy controls.

Unique intravascular tumor microenvironment predicting recurrence of lung squamous cell carcinoma.

PURPOSE: Histological vascular invasion (VI) by tumors is a risk factor for recurrence after surgical resection. However, VI features vary histologically. The aim of this study was to identify characteristic VI features that are associated with recurrence in squamous cell carcinoma (SCC) of the lung. METHODS: We enrolled 149 patients with pathological stage I primary lung SCC in this study and examined whether the presence, frequency, and size of VI were associated with recurrence. We also evaluated immunophenotypes of carcinoma cells and stromal cells within VI areas. RESULTS: Of the 149 patients, 58 had tumors with VI. The presence of VI was significantly correlated with shorter recurrence-free survival (RFS) (P = 0.018). Although VI frequency was not associated with RFS, larger VI size (>425 µm) was significantly correlated with shorter RFS (P = 0.003). Carcinoma cells within larger VI areas expressed significantly higher levels of podoplanin, cancer stem cell marker (P = 0.039); higher numbers of CD34(+) microvessels (P = 0.009), CD204(+) macrophages (P = 0.026), and α-SMA(+) myofibroblasts (P = 0.056) were present within larger VI areas than within smaller VI ones. CONCLUSIONS: Our results indicate that larger VI areas are a predictor for recurrence in lung SCC; also, within the larger blood vessel, cancer stem cells and abundant stromal cells can create a more favorable microenvironment for tumor metastasis.

RECIST progression patterns during EGFR tyrosine kinase inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation.

BACKGROUND: Progression patterns at the response evaluation criteria in solid tumors-progressive disease (RECIST-PD) during treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for advanced non-small cell lung cancer (NSCLC) in patients harboring an EGFR mutation are clinically heterogeneous. We evaluated the association between progression patterns during EGFR-TKI treatment and prognosis after treatment in such patients. METHODS: From 2008 to 2012, 160 consecutive patients with advanced NSCLC harboring an EGFR mutation were treated with EGFR-TKIs (erlotinib or gefitinib). Among these, 104 who experienced RECIST-PD were retrospectively evaluated for initial response to EGFR-TKIs, progression sites, focus of progression (solitary lesion or multiple lesions), symptom status at RECIST-PD evaluation, and post-progression survival (PPS). RESULTS: Of 104 patients, 96 (92%) had an EGFR major mutation, and 50 (48%) received EGFR-TKIs as first-line treatment. Overall response rate and median time to RECIST-PD on EGFR-TKIs were 68% and 8.2 months, respectively. At the time of attaining RECIST-PD status, 44 (42%) patients were symptomatic, and 60 (58%) were asymptomatic. Progression sites at RECIST-PD were isolated brain in 17 (16%) patients and systemic in 87 (84%): 24 (23%) had a solitary lesion, and 80 (77%) had multiple lesions. After RECIST-PD assessment, 40 (38%) patients continued EGFR-TKIs, and 25 (24%) switched to cytotoxic agents; 10 (10%) received local radiotherapy for an isolated progression site (brain 6; bone 3; lung 1). Median PPS was 10.8 months. Multivariate analysis revealed that asymptomatic or solitary lesion status was associated with significantly longer PPS (asymptomatic: HR 0.36, 95% CI 0.21-0.62, P<0.01; solitary progression lesion: HR 0.45, 95% CI 0.18-99, P=0.04). CONCLUSIONS: Progression patterns at the RECIST-PD during EGFR-TKI treatment of advanced NSCLC in patients harboring an EGFR mutation are widely diverse, and might be associated with clinical outcome after treatment failure.

Impact of single nucleotide polymorphisms on severe hepatotoxicity induced by EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring EGFR mutations.

BACKGROUND: Many patients are forced to discontinue treatment with EGFR tyrosine kinase inhibitors (TKIs), particularly gefitinib, due to severe hepatotoxicity. Here, we investigated the association between the rate of severe hepatotoxicity and single nucleotide polymorphisms (SNPs) in metabolic enzymes. MATERIALS AND METHODS: Multi-SNP analyses were performed in 60 patients with EGFR-mutated non-small cell lung cancer using blood samples obtained prior to starting treatment with gefitinib. The poor metabolizer (PM) phenotype was defined as homozygosity or double heterozygosity for variant alleles that confer reduced enzyme activities. Associated enzymes were screened using univariate logistic regression analyses adjusted for multiplicity and were further evaluated using multivariate logistic regression analyses to determine the influence of these enzymes on severe hepatotoxicity. RESULTS: Severe hepatotoxicity was detected in 19 (32%) of the 60 patients. Patient phenotypes consisted of CYP3A5, PM/non-PM (31/29) and CYP2D6, PM/non-PM (5/55). In multivariate logistic regression analyses, the rate of severe hepatotoxicity was significantly higher among patients with PM phenotypes than those without (CYP3A5 PM vs. non-PM: 48.4% vs. 13.8%, P=0.0069; CYP2D6 PM vs. non-PM: 80.0% vs. 27.3%, P=0.0364). Of the 9 patients switched from gefitinib to erlotinib due to severe hepatotoxicity, 8 had a PM phenotype for CYP2D6 or CYP3A5. All cases were successfully managed without exacerbation of severe hepatotoxicity. CONCLUSIONS: Evaluation of SNPs in CYP3A5 and CYP2D6 can effectively predict severe hepatotoxicity induced by gefitinib. Erlotinib can be used as an alternative treatment for patients who develop gefitinib-induced severe hepatotoxicity.

Phase II study of amrubicin at a dose of 45 mg/m2 in patients with previously treated small-cell lung cancer.

OBJECTIVE: Most of the previous studies of amrubicin in patients with previously treated small-cell lung cancer were conducted at a dose of 40 mg/m(2). The aim of this study was to assess the efficacy and safety of amrubicin at a dose of 45 mg/m(2) in patients with relapsed or refractory small-cell lung cancer. METHODS: Previously treated small-cell lung cancer patients were eligible. Amrubicin at a dose of 45 mg/m(2) was administered on Days 1-3 every 3 weeks. The primary endpoint was the response rate. RESULTS: From June 2003 to January 2005, 35 patients were enrolled, of whom 34 received this study treatment. Four cycles or more could be administered in 21 patients (62%). Dose reduction was required in 15 (52%) of the 29 patients who had received two cycles or more. Three complete responses and 15 partial responses were observed among the 34 treated patients, yielding a response rate of 53% (95% confidence interval, 35-71%). Median progression-free survival of the patients was 4.4 months (95% confidence interval, 2.4-5.1 months). Median survival time was 8.2 months (95% confidence interval, 6.6-10.0 months) and 1-year survival rate was 24% (95% confidence interval, 9-39%). Grade 3/4 leukopenia, neutropenia and thrombocytopenia were observed in 76, 97 and 38% of the patients, respectively. Febrile neutropenia occurred in 12 patients (35%), and one patient died from pneumonia. CONCLUSIONS: While amrubicin at a dose of 45 mg/m(2) showed high response rate for both sensitive and refractory relapse, the incidence of febrile neutropenia was also high. The utility of amrubicin at 45 mg/m(2) might accordingly be limited.

Second-line docetaxel for patients with platinum-refractory advanced non-small cell lung cancer and interstitial pneumonia.

PURPOSE: The role of second-line chemotherapy in patients with non-small cell lung cancer (NSCLC) and preexisting interstitial pneumonia (IP) previously treated with platinum-based chemotherapy remains uncertain. This study was conducted to elucidate the efficacy and tolerability of second-line docetaxel monotherapy for patients with platinum-refractory advanced (stage IIIB, IV, or relapse) NSCLC and preexisting IP. METHODS: A total of 35 patients (median age, 67 years) treated with docetaxel monotherapy in a second-line setting following first-line platinum-based chemotherapy between January 2002 and December 2013 were retrospectively reviewed. RESULTS: The overall response rate and disease control rate were 8.6 % [95 % confidence interval (CI) 0-17.9 %] and 37.1 % (95 % CI 21.1-53.1 %), respectively. The median progression-free survival and median overall survival periods were 1.6 months (95 % CI 1.2-2.0 months) and 5.1 months (95 % CI 3.2-6.7 months), respectively. The incidence of acute exacerbation (AE) of IP following docetaxel monotherapy was 14.3 % (5/35 patients). Of the five patients who developed AE of IP, three patients died. The toxicity of this regimen was substantial, with treatment-related deaths occurring in 5 (14.3 %) patients (AE of IP: 3, sepsis: 2). CONCLUSIONS: Docetaxel monotherapy has a poor activity and substantial risks when used for the treatment of platinum-resistant NSCLC with IP. Novel therapeutic approaches should be explored in this setting.

Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth.

Cancer-associated fibroblasts (CAFs) expressing podoplanin (PDPN) are a favorable prognosticator in surgically resected small cell lung cancer (SCLC). Here we explore whether CAFs expressing PDPN influence proliferation of SCLC cells. Compared with control group (SCLC cells co-cultured with CAFs-Ctrl), numbers of SCLC cells co-cultured with CAFs overexpressing PDPN were decreased. Suppression of PDPN expression by shRNA in CAFs resulted in increased numbers of SCLC cells. In surgically resected human SCLC specimens, the frequency of Geminin-positive cancer cells was significantly higher in the cases with PDPN-positive CAFs than in the cases with PDPN-negative CAFs. Thus CAFs expressing PDPN inhibit growth of SCLC cells, suggesting that CAFs expressing PDPN represent a tumor inhibitory stromal cell component in SCLC.