Purpose
Docetaxel or pemetrexed monotherapy is recommended either as a second-line treatment for non-small cell lung cancer (NSCLC) patients without
EGFR
mutation or
ALK
fusion genes or as a ...third-line treatment for patients with
EGFR
mutation or
ALK
fusion. However, efficacy and survival for these two settings have not been compared, leaving it unclear whether these two populations can be included in the same clinical trials. Moreover, prognostic factors for patients who are recommended to receive docetaxel/pemetrexed monotherapy are largely unknown.
Methods
Docetaxel or pemetrexed was administered to 67
EGFR
wild-type patients as a second-line treatment following one platinum-based combination chemotherapy and to 17
EGFR
mutant patients as a third-line treatment following EGFR tyrosine kinase inhibitors and one platinum-based combination chemotherapy. Docetaxel and pemetrexed were administered at 60 and 500 mg/m
2
, respectively, every 3 weeks until disease progression, intolerable toxicity, or patient refusal. Overall survivals (OSs) between the two groups were compared using the log-rank test, and prognostic factors were evaluated via Cox’s proportional hazards models.
Results
The median OS was 345.5 days in the
EGFR
wild-type second-line group and 616 days in the
EGFR
mutant third-line group. Multivariate analyses revealed that the stage before first-line treatment, performance status, and
EGFR
status were significant prognostic factors.
Conclusions
When planning clinical studies of NSCLC patients recommended to receive docetaxel or pemetrexed as single-agent chemotherapy, the
EGFR
status and stage before first-line treatment should be considered as stratification factors of randomized clinical studies.
Several clinical studies have demonstrated the efficacy and safety of adjuvant chemotherapy in patients with completely resected small cell lung cancer for a selected limited stage. However, it is ...unclear whether adjuvant chemotherapy is feasible in clinical practice. The objective of this study was to analyze the efficacy and safety of adjuvant chemotherapy for small cell lung cancer patients retrospectively in clinical practice.
From January 2002 to March 2012, 56 small cell lung cancer patients underwent surgery as initial therapy in our institute. Of these, 26 patients received adjuvant chemotherapy. The clinical data of patients who received adjuvant chemotherapy were retrospectively analyzed.
The chemotherapy regimens were cisplatin and irinotecan in 16 patients, cisplatin and etoposide in 1 and carboplatin and etoposide in 9. Median follow-up time was 44.8 months. Nineteen (73%) patients received the full course of chemotherapy. Median recurrence-free survival was 21.4 months. Median survival time was not reached. There was no treatment-related death.
Adjuvant chemotherapy may be generally safe and efficacious in selected small cell lung cancer patients.
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid progression. The mechanisms that lead to a shift from initial therapeutic sensitivity to ultimate ...therapeutic resistance are poorly understood. Although the SCLC genomic landscape led to the discovery of promising agents targeting genetic alterations that were already under investigation, results have been disappointing. Achievements in targeted therapeutics have not been observed for over 30 years. Therefore, the underlying disease biology and novel targets urgently require a better understanding. Epigenetic regulation is deeply involved in the cellular plasticity that could shift tumor cells to the malignant phenotype. We have focused on a histone modifier, LSD1, that is overexpressed in SCLC and is a potent therapeutic target. Interestingly, the LSD1 splice variant LSD1+8a, the expression of which has been reported to be restricted to neural tissue, was detected and was involved in the expression of neuroendocrine marker genes in SCLC cell lines. Cells with high expression of LSD1+8a were resistant to CDDP and LSD1 inhibitor. Moreover, suppression of LSD1+8a inhibited cell proliferation, indicating that LSD1+8a could play a critical role in SCLC. These findings suggest that LSD1+8a should be considered a novel therapeutic target in SCLC.
A 53-year-old female patient was admitted with pain and a progressively enlarging mass in the right upper chest. Chest computed tomography revealed a mass lesion in the region of the right upper ...ribs. Ten years prior to this admission, the patient had undergone right lobectomy for lung adenocarcinoma. One year after the surgery, follow-up computed tomography had revealed tumor recurrence in the mediastinal and supraclavicular lymph nodes, and the patient had been treated by chemoradiotherapy. Thereafter, regular follow-up had revealed no evidence of recurrence of the non-small-cell lung cancer. Histopathological findings revealed proliferation of spindle-shaped malignant tumor cells in a background of osteoid, consistent with the diagnosis of osteosarcoma. The location of the tumor was consistent with the radiation field. Based on the clinicopathological findings, the patient was diagnosed as having secondary osteosarcoma occurring as a result of the chemoradiotherapy administered previously for the recurrent non-small-cell lung cancer. Unfortunately, the patient died of rapid progression of the osteosarcoma within a week of admission to the hospital. The autopsy revealed contiguous invasion by the tumor of the heart, with massive thrombus formation. The peripheral pulmonary arteries were diffusely occluded by metastatic tumors. Our case serves to highlight the risk of development of secondary sarcoma as a life-threatening late complication after chemoradiotherapy for locally advanced non-small-cell lung cancer, even after complete cure of the primary tumor.
•E7130 is a novel microtubule inhibitor and a promising ameliorator of the tumor microenvironment.•An analytical method was developed to quantify E7130 in mouse plasma.•A sensitive method was ...established at a LLOQ of 0.2 ng/mL for plasma microsamples (10 µL).•HRMS provided a high selectivity for quantification of E7130 in the biological matrix prepared via protein precipitation.
E7130 is a novel microtubule inhibitor and a promising tumor microenvironment ameliorator. Since the amount of the administration in preclinical study is very small due to the high potency of E7130, this study aimed to establish a sensitive analytical method to measure E7130 concentration in mouse plasma samples obtained via microsampling. A sensitive and validated method was developed based on ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC–HRMS). Chromatographic separation was achieved using a Waters ACQUITY UPLC BEH C18 1.7 µm (2.1 × 50 mm) column. Mobile phase A comprised 0.1% formic acid and 10 mM ammonium formate in water, and mobile phase B was methanol. A gradient elution was applied at a flow rate of 0.5 mL/min. The calibration curve drawn was linear in the 0.2–100 ng/mL E7130 concentration range for mouse plasma microsamples (10 µL). Analytical results demonstrated good precision (<6.7%) and accuracy (88.5%–100.0%) in E7130 quantitation, indicating that UHPLC–HRMS is a useful method for pharmacokinetic analysis and a valuable approach for the quantitation of hardly fragmented compounds.
The concentration and distribution of a drug and its metabolites in tissues are key factors for elucidating both drug efficacy and toxicity in drug development. In this study we developed a ...pharamaco-imaging procedure for 12 agents and investigated the relationship between the properties of target compounds and the sensitivities of detection in matrix-assisted laser desorption/ionization-mass spectrometer imaging (MALDI-MSI). We prepared mock samples with mouse liver homogenates diluted with gelatin solution, limit of detection concentrations of each compound was confirmed. The correlation was evaluated between the intensities of mass signals obtained in MALDI-MSI with each test compound (the intensities of the test compounds) at a consistent concentration and the properties of each test compound. The liver homogenate diluted with gelatin solution showed easier handling and lower coefficients of variation than did liver homogenate only, and can be used as a good surrogate matrix. Based on the analysis of 12 agents, the protein binding ratios showed significant correlation to the detection sensitivities. We presented a procedure for standardization of pharmaco-imaging method development with an in-tissue method using MALDI-MS. Our results indicated the correlation between test compound’s sensitivity and their protein binding ratios in plasma or serum.
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