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.

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.

Docetaxel for platinum-refractory advanced thymic carcinoma.

OBJECTIVE: Thymic carcinoma is a rare mediastinal neoplasm. While platinum-based chemotherapy has been reported to be effective for advanced thymic carcinoma in a first-line setting, little information is available regarding the benefits of salvage chemotherapy for platinum-refractory thymic carcinoma. This study assessed the efficacy and safety profiles of docetaxel monotherapy for platinum-refractory thymic carcinoma. METHODS: A total of 13 thymic carcinoma patients treated with docetaxel monotherapy in a second- or later-line setting between January 2003 and April 2014 were retrospectively reviewed. The median age was 61 years (range, 41-75 years). RESULTS: The overall response rate and disease control rate were 31% [95% confidence interval (CI), 6-56%] and 77% (95% CI, 54-100%), respectively. The median progression-free survival and overall survival after docetaxel monotherapy were 5.5 months (95% CI, 2.3-6.5 months) and 24.0 months (95% CI, 9.4-31.2 months), respectively. The most common Grade ≥3 toxicity was neutropenia (62%). No incidents of febrile neutropenia and no treatment-related deaths were recorded. CONCLUSIONS: This retrospective analysis demonstrated that docetaxel was active against platinum-refractory thymic carcinoma with acceptable toxicities. Docetaxel monotherapy might be a promising therapeutic option for patients with platinum-refractory thymic carcinoma.

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.

Low-dose irinotecan as a second-line chemotherapy for recurrent small cell lung cancer.

OBJECTIVE: Irinotecan is a potent inhibitor of deoxyribonucleic acid topoisomerase 1 and the weekly schedule of 100-125 or 350 mg/m(2) administration on Day 1 every 3 weeks is recommended for recurrent small cell lung cancer. However, severe gastrointestinal toxic effects and myelosuppression are often observed in this dose setting. We conducted a retrospective study to evaluate the efficacy and safety of low-dose irinotecan monotherapy (60 mg/m(2) on Days 1, 8 and 15 every 4 weeks) as second-line chemotherapy for small cell lung cancer. METHODS: The medical charts of small cell lung cancer patients who had received second-line chemotherapy at the National Cancer Center Hospital East between April 2003 and June 2012 were reviewed. Consecutive 57 patients who were treated with low dose of irinotecan (60 mg/m(2) on Days 1, 8 and 15 every 4 weeks) were analyzed in this study. RESULTS: Median age was 70 years (range, 51-83). Fifty-two (91%) were male, 36 (63%) had an Eastern Cooperative Oncology Group performance status 0-1 and 26 (46%) were sensitive relapse. The median number of chemotherapy cycles was 2. The objective response rate was 32% (95% confidence interval: 20-45%).The median progression-free survival and the median overall survival were 2.9 months (95% confidence interval: 1.9-3.4 months) and 5.3 months (95% confidence interval: 3.6-7.6 months), respectively. The incidence of Grade 3/4 neutropenia, diarrhea and nausea/vomiting was 21, 4 and 5%, respectively. CONCLUSIONS: Low-dose irinotecan monotherapy for recurrent small cell lung cancer might be effective with favorable toxicity. Randomized trial of 60 mg/m(2) versus standard dose of irinotecan is warranted.

Protective effect of magnesium preloading on cisplatin-induced nephrotoxicity: a retrospective study.

OBJECTIVE: Magnesium supplementation has been reported to have a nephroprotective effect on cisplatin-induced renal dysfunction, but little evidence exists regarding the effect of magnesium preloading before cisplatin administration. We started to include magnesium preloading (8 mEq) in cisplatin-containing treatment regimens in January 2011. The aim of the present study was to evaluate whether magnesium preloading reduces cisplatin-induced nephrotoxicity. METHODS: We retrospectively reviewed 496 thoracic malignancy patients treated with cisplatin (≥60 mg/m²)-containing regimens as a first-time chemotherapy between January 2009 and December 2011. We compared the incidence of Grade ≥2 serum creatinine elevation according to the Common Terminology Criteria for Adverse Events, version 4.0, between magnesium preloading group (n = 161 [32%]) and non-magnesium preloading group (n = 335 [68%]) during the first cycle and all cycles. RESULTS: The median number of administered cycles was four in both groups. The incidence of Grade ≥2 serum creatinine elevation in magnesium preloading group was significantly lower during both the first cycle and all cycles than in the non-magnesium preloading group (4.9 versus 19.1% during the first cycle, and 14.2 versus 39.7% during all the cycles). A multivariate analysis indicated that magnesium preloading significantly reduced cisplatin-induced nephrotoxicity throughout the entire period from after the first administration (odds ratio: 0.262, 95% confidence interval: 0.106-0.596 during the first cycle, and odds ratio: 0.234, 95% confidence interval: 0.129-0.414 during all cycles). CONCLUSIONS: Magnesium preloading before cisplatin administration significantly reduced cisplatin-induced nephrotoxicity.

Meta-analysis of epoetin beta and darbepoetin alfa treatment for chemotherapy-induced anemia and mortality: Individual patient data from Japanese randomized, placebo-controlled trials.

Erythropoiesis-stimulating agents (ESA) reduce the need for transfusions and improve the quality of life in patients receiving chemotherapy, but several clinical trials have suggested that ESA might have a negative impact on survival. To evaluate the efficacy and safety of ESA, epoetin beta and darbepoetin alfa, including their impact on overall survival and thromboembolic events, we conducted an individual data-based meta-analysis of three randomized, placebo-controlled trials studying Japanese patients with chemotherapy-induced anemia. All trials were conducted in compliance with Good Clinical Practice. A total of 511 patients with solid tumor or lymphoma (epoetin beta or darbepoetin alfa, n = 273; placebo, n = 238) were included. The ESA significantly reduced the risk of transfusion (relative risk, 0.47; 95% confidence interval, 0.29-0.76). No significant effect of the ESA on overall survival was observed (unadjusted hazard ratio, 1.00; 95% confidence interval, 0.75-1.34). A prespecified subgroup analysis showed no strong interaction between the baseline hemoglobin concentration and the effect of ESA on overall survival. Among the ESA-treated patients, the highest hemoglobin achieved during the treatment period in each patient had no impact on mortality. No increase in thromboembolic events was observed in the ESA-treated patients (0.7% vs 1.7% placebo). The ESA reduced the risk of transfusion without a negative impact on the survival of patients with chemotherapy-induced anemia.

Renal toxicity caused by brand-name versus generic cisplatin: a comparative analysis.

OBJECTIVE: A generic cisplatin formulation has replaced the brand-name formulation since November 2003 in our hospital. We retrospectively assessed the renal toxicity caused by the brand-name and generic cisplatin formulations. METHODS: The medical records of patients with thoracic malignancy who were treated at our hospital between November 2000 and April 2008 were reviewed. In total, 1296 eligible patients received 80 mg/m(2) of cisplatin: 499 patients were treated with the brand-name cisplatin formulation before November 2003 (Group 1) and 797 patients were treated with the generic formulation after November 2003 (Group 2). We compared the maximum serum creatinine level after chemotherapy in the two groups. RESULTS: The patient characteristics, including age, sex and performance status, and pretreatment serum creatinine levels were well balanced between the two groups. More patients received four cycles of chemotherapy in Group 2 (P < 0.0001). The median (range) of the maximum serum creatinine levels during all the chemotherapy cycles were 1.1 (0.5-4.1) mg/dl and 1.1 (0.5-4.4) mg/dl in Groups 1 and 2, respectively (P = 0.0237). The incidence of grade 0 serum creatinine elevations decreased from 47% to 39%, while that of grade 1 serum creatinine elevations increased from 32% to 41% (P = 0.0094). The incidence rates of grade 2 or 3 serum creatinine elevations were similar (21 vs. 20%). The time to serum creatinine elevation was also similar in Groups 1 and 2 (P = 0.161). CONCLUSION: Although grade 1 maximum serum creatinine level was more common in the generic cisplatin formulation group, this was attributed to the larger number of patients receiving four cycles of chemotherapy in this group.

Aldehyde dehydrogenase 1 expression in cancer cells could have prognostic value for patients with non-small cell lung cancer who are treated with neoadjuvant therapy: identification of prognostic microenvironmental factors after chemoradiation.

Prognostic factors for patients with non-small cell lung cancer (NSCLC) who have been treated with neoadjuvant therapy have not been fully assessed. The purpose of this study was to analyze prognostic biomarkers in NSCLC after treatment with neoadjuvant therapy, with special reference to the immunophenotypes of both the cancer cells and stromal cells. A total of 52 patients with NSCLC who were treated with neoadjuvant therapy followed by complete resection were included. We examined the expressions of nine markers in the cancer cells and stromal cells. The 5-year disease-free survival rate of patients with high aldehyde dehydrogenase 1 (ALDH1) expression levels in their cancer cells was significantly lower than those with a low ALDH1 level (47.3% vs. 21.5%, respectively; P = 0.023). The other molecules expressed in cancer cells did not exhibit any prognostic value. In NSCLC without neoadjuvant therapy (case control, n = 104), expression of ALDH1 in cancer cells was not correlated with prognosis (P = 0.507). A multivariate analysis identified ALDH1 expression in cancer cells as significantly independent prognostic factors for disease-free survival (P = 0.045). The current study indicated that the immunophenotypes of ALDH1 in cancer cells could have prognostic value for patients with NSCLC who are treated with neoadjuvant therapy.

Risk factors associated with fatal pulmonary hemorrhage in locally advanced non-small cell lung cancer treated with chemoradiotherapy.

BACKGROUND: The purpose of this study was to identify the risk factors associated with fatal pulmonary hemorrhage (PH) in patients with locally advanced non-small cell lung cancer (NSCLC), treated with chemoradiotherapy. METHODS: The medical records of 583 patients with locally advanced NSCLC, who were treated with chemoradiotherapy between July 1992 and December 2009 were reviewed. Fatal PH was defined as PH leading to death within 24 h of its onset. Tumor cavitation size was defined by the cavitation diameter/tumor diameter ratio and was classified as minimum (< 0.25), minor (≥ 0.25, but < 0.5), and major (≥ 0.5). RESULTS: Of the 583 patients, 2.1% suffered a fatal PH. The numbers of patients with minimum, minor, and major cavitations were 13, 11, and 14, respectively. Among the 38 patients with tumor cavitation, all 3 patients who developed fatal PH had major cavitations. On multivariate analysis, the presence of baseline major cavitation (odds ratio, 17.878), and a squamous cell histology (odds ratio, 5.491) proved to be independent significant risk factors for fatal PH. Interestingly, all patients with fatal PH and baseline major cavitation were found to have tumors with squamous cell histology, and the occurrence of fatal PH in patients having both risk factors was 33.3%. CONCLUSIONS: Patients at high risk of fatal PH could be identified using a combination of independent risk factors.

A method for determining the modulation transfer function from thick microwire profiles measured with x-ray microcomputed tomography.

PURPOSE: This study describes a model-dependent method to determine the modulation transfer function (MTF) in the transversal plane, obtained by a microcomputed tomography (micro-CT) system from profiles of a thick wire phantom instead of a thin wire phantom, and the study evaluates the feasibility of the proposed method in the MTF determination of micro-CT systems. METHODS: The MTF is generally calculated as the absolute value of the normalized Fourier transform from the point spread function obtained by scanning a thin wire phantom. Since the wire is not a point source, the raw MTF is corrected for the finite size of the wire phantom; a wire with too large a diameter introduces inaccuracies in the MTF values. Therefore, we solved the MTF determination from profiles of a thick wire phantom via MTF modeling on the basis of the symmetric Lévy function that generalizes Gaussian and Lorentzian functions. We then applied the method to profiles of wire phantoms (1 mm, 2 mm, and 3 mm in diameter) measured by a clinical CT system to evaluate the applicable diameter range of the thick wire phantom. Two types of reconstruction kernels (standard and sharp) were used in the clinical CT. The performance of the method was evaluated using microwire phantoms (10 and 30 µm in diameter) measured by a synchrotron radiation micro-CT (SRµCT) system, in which the Shepp-Logan filter and Ramachandran-Lakshminarayanan filter were used as the reconstruction kernel. The MTFs obtained using thin wire phantoms of 0.1 mm and 3 µm in diameter were regarded as the gold standard MTFs for the clinical CT and SRµCT, respectively. The root-mean-square error (RMSE) and relative error (RE) of the 10% value of the MTF were used to measure the difference between the MTF determined by the method and the gold standard. RESULTS: The mean RMSEs for two types of reconstruction kernels of three wire phantoms (1, 2, and 3 mm in diameter) were 0.0085, 0.012, and 0.021, respectively. The mean REs for the 1-, 2-, and 3-mm wire phantoms gave the same values of 2.0%, 3.5%, and 3.5%, respectively, for two types of reconstruction kernel. The MTFs determined from thick wire phantoms reveal the spatial resolution for the two kernels. The mean RMSEs for two types of reconstruction kernels of the microwire phantoms of 10 and 30 µm in diameter were 0.0045 and 0.0035, respectively. The mean REs of the two wire phantoms of 10 and 30 µm diameter had 4.0% and 3.1%, respectively, for two types of reconstruction kernel. CONCLUSIONS: Experimental data presented in this paper support the effectiveness of the model-dependent method based on the symmetric Lévy function. We conclude that the method is a useful approach for measuring the spatial resolution in the x∕y-scan plane (transversal orientation) of micro-CT systems by substituting a thick wire phantom for a thin wire phantom.

Quantitative classification based on CT histogram analysis of non-small cell lung cancer: correlation with histopathological characteristics and recurrence-free survival.

PURPOSE: Quantification of the CT appearance of non-small cell lung cancer (NSCLC) is of interest in a number of clinical and investigational applications. The purpose of this work is to present a quantitative five-category (α, ß, γ, δ, and ɛ) classification method based on CT histogram analysis of NSCLC and to determine the prognostic value of this quantitative classification. METHODS: Institutional review board approval and informed consent were obtained at the National Cancer Center Hospital. A total of 454 patients with NSCLC (maximum lesion size of 3 cm) were enrolled. Each lesion was measured using multidetector CT at the same tube voltage, reconstruction interval, beam collimation, and reconstructed slice thickness. Two observers segmented NSCLC nodules from the CT images by using a semi-automated three-dimensional technique. The two observers classified NSCLCs into one of five categories from the visual assessment of CT histograms obtained from each nodule segmentation result. Interobserver variability in the classification was computed with Cohen's κ statistic. Any disagreements were resolved by consensus between the two observers to define the gold standard of the classification. Using a classification and regression tree (CART), the authors obtained a decision tree for a quantitative five-category classification. To assess the impact of the nodule segmentation on the classification, the variability in classifications obtained by two decision trees for the nodule segmentation results was also calculated with the Cohen's κ statistic. The authors calculated the association of recurrence with prognostic factors including classification, sex, age, tumor diameter, smoking status, disease stage, histological type, lymphatic permeation, and vascular invasion using both univariate and multivariate Cox regression analyses. RESULTS: The κ values for interobserver agreement of the classification using two nodule segmentation results were 0.921 (P < 0.001) and 0.903 (P < 0.001), respectively. The κ values for the variability in the classification task using two decision trees were 0.981 (P < 0.001) and 0.981 (P < 0.001), respectively. All the NSCLCs were classified into one of five categories (type α, n = 8; type ß, n = 38; type γ, n = 103; type δ, n = 112; type ɛ, n = 193) by using a decision tree. Using a multivariate Cox regression analysis, the classification (hazard ratio 5.64; P = 0.008) and disease stage (hazard ratio 8.33; P < 0.001) were identified as being associated with an increased recurrence risk. CONCLUSIONS: The quantitative five-category classifier presented here has the potential to provide an objective classification of NSCLC nodules that is strongly correlated with prognostic factors.

A phase I study of gemcitabine and carboplatin in patients with advanced non-small cell lung cancer and a performance status of 2.

OBJECTIVE: The aim of this study was to determine the maximum-tolerated dose (MTD) and the recommended dose of combination chemotherapy with gemcitabine (GEM) and carboplatin (CBDCA) in non-small cell lung cancer (NSCLC) patients with a performance status (PS) of 2. METHODS: Chemotherapy-naïve NSCLC patients with PS 2 were enrolled. Chemotherapy consisted of an escalated dose of GEM on days 1 and 8 and CBDCA on day 1 every 3 weeks. Patients were scheduled to receive GEM (mg/m(2))/CBDCA (area under the curve: AUC) at four dose levels: 800/4 (level 1), 1000/4 (level 2), 1000/4.5 (level 3) and 1000/5 (level 4), respectively. RESULTS: Between February 2004 and August 2006, 13 patients were enrolled in this study. Dose-limiting toxicities (DLTs) were thrombocytopenia, febrile neutropenia and hyponatremia. DLTs were observed in two of six patients at dose level 1 and in three of six patients at dose level 2. Dose level 2 was thus determined to be the MTD. Among 12 evaluable patients, 7 patients had stable diseases and 5 patients had progressive diseases, and the median survival time was 3.8 months. CONCLUSIONS: The MTD and the recommended dose for Phase II studies of this regimen were determined to be GEM 1000 mg/m(2) and CBDCA AUC of 4. Additional objective measures are needed to evaluate patients' risk and benefit in future clinical trials for PS 2 patients.

Mutational status of EGFR and KIT in thymoma and thymic carcinoma.

This study was conducted to evaluate the prevalence of EGFR and KIT mutations in thymomas and thymic carcinomas as a means of exploring the potential for molecularly targeted therapy with tyrosine kinase inhibitors. Genomic DNA was isolated from 41 paraffin-embedded tumor samples obtained from 24 thymomas and 17 thymic carcinomas. EGFR exons 18, 19, and 21, and KIT exons 9, 11, 13, and 17, were analyzed for mutations by PCR and direct sequencing. Protein expression of EGFR and KIT was evaluated immunohistochemically. EGFR mutations were detected in 2 of 20 thymomas, but not in any of the thymic carcinomas. All of the EGFR mutations detected were missense mutations (L858R and G863D) in exon 21. EGFR protein was expressed in 71% of the thymomas and 53% of the thymic carcinomas. The mutational analysis of KIT revealed only a missense mutation (L576P) in exon 11 of one thymic carcinoma. KIT protein was expressed in 88% of the thymic carcinomas and 0% of the thymomas. The results of this study indicate that EGFR and KIT mutations in thymomas and thymic carcinomas are rare, but that many of the tumors express EGFR or KIT protein.

Performance evaluation of 4 measuring methods of ground-glass opacities for predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer: a multicenter study.

OBJECTIVE: To evaluate the performance of 4 methods of measuring the extent of ground-glass opacities as a means of predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer (NSLC). METHODS: Ground-glass opacities on thin-section computed tomographic images of 120 peripheral NSLCs were measured at 7 medical institutions by the length, area, modified length, and vanishing ratio (VR) methods. The performance (Az) of each method in predicting the 5-year relapse-free survival was evaluated using receiver operating characteristic analysis. RESULTS: The mean Az value obtained by the length, area, modified length, and VR methods in the receiver operating characteristic analyses was 0.683, 0.702, 0.728, and 0.784, respectively. The differences between the mean Az value obtained by the VR method and by the other 3 methods were significant. CONCLUSIONS: Vanishing ratio method was the most accurate predictor of the 5-year relapse-free survival of patients with peripheral NSLC.

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.

Randomized trial of drip infusion versus bolus injection of vinorelbine for the control of local venous toxicity.

Vinorelbine is a moderate vesicant that is well known to cause local venous toxicity such as drug induced-phlebitis. We conducted a prospective randomized trial to determine whether a 1-min bolus injection (1 min bolus) of vinorelbine reduced the incidence of local venous toxicity compared with a 6-min drip infusion (6 min infusion). Non-small cell lung cancer patients who were to receive chemotherapy containing vinorelbine were randomly assigned to receive either 6 min infusion or 1 min bolus of the drug. All infusions were administered through a peripheral vein. Local venous toxicity was evaluated at each infusion up to two cycles. Eighty-three patients were randomized into the study and 81 of them assessable for analysis. One hundred thirty-eight infusions to 40 patients in 6 min infusion and 135 infusions to 41 patients in 1 min bolus were delivered. Vinorelbine induced-local venous toxicity was observed in 33% of patients in 6 min infusion and 24% in 1 min bolus. There was no statistically significant difference between the two arms (P=0.41). The incidence of local venous toxicity per infusions was 16% (22 of 138 infusions) in 6 min infusion and 11% (15 of 135 infusions) in 1 min bolus (P=0.47). No severe local venous toxicity was seen in either arm. In this study, the administration of in 1 min bolus of vinorelbine did not significantly reduce the incidence of local venous toxicity compared with 6 min infusion. Further studies for the control of local venous toxicity of vinorelbine are warranted.

Phase II trial of carboplatin and paclitaxel in non-small cell lung cancer patients previously treated with chemotherapy.

The purpose of this phase II trial was to evaluate the efficacy and toxicity of carboplatin plus paclitaxel in the treatment of advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy. Patients with a performance status (PS) of 0 or 1 who had received one or two previous chemotherapy regimens for advanced NSCLC were eligible. Paclitaxel 200mg/m(2) was infused over 3h and followed by carboplatin (area under the curve 6) infusion over 1h, once every 3 weeks. Thirty patients were enrolled. A complete response was observed in 1 patient and a partial response in 10 patients, for an overall response rate of 36.7%. The median time to progression was 5.3 months. The median survival time was 9.9 months, and the 1-year survival rate was 47%. Hematological toxicity in the form of grade 3/4 neutropenia occurred in 54%, but grade 3 febrile neutropenia developed in only 3%. Non-hematological grade 3 toxicities were less frequent. There were no treatment-related deaths. The combination of carboplatin plus paclitaxel is an active and well-tolerated regimen for the treatment of NSCLC patients who have previously been treated with chemotherapy and have a good PS.

Detection of unsuspected distant metastases and/or regional nodes by FDG-PET [corrected] scan in apparent limited-disease small-cell lung cancer.

We retrospectively investigated the clinical usefulness of fluorodeoxyglucose positron emission tomography (FDG-PET) for evaluation of patients with limited-disease small-cell lung cancer (LD-SCLC) diagnosed by conventional staging procedures. Sixty-three patients received whole body FDG-PET scans after routine initial staging procedures. The findings of FDG-PET scans suggesting extensive-stage disease were confirmed by other imaging tests or by the patient's clinical course. FDG-PET scan findings indicated distant metastases in 6 of 63 patients. Metastatic disease was confirmed in five of these six patients (8%, 95% confidence interval: 3-18%). FDG-PET scan also detected regional lymph node metastases even in nine patients (14%) in whom computed tomography images had been negative, including contralateral lymph node metastasis in three patients. FDG-PET scan detected additional lesions in patients diagnosed as having LD-SCLC by conventional staging procedures. The therapeutic strategies were changed in 8% of patients based on the results of FDG-PET. FDG-PET scan is recommended as an initial staging tool for patients with this disease.

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.