1,721,211 research outputs found
Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: Review on emerged mechanisms of resistance
No full textOsimertinib, third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved in the US and EU for the treatment of EGFR mutant T790M-positive non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs, such as gefitinib, erlotinib and afatinib. Although exciting survival data and response rates have been registered in patients treated with this and other third-generation EGFR-TKIs, unfortunately acquired resistance still occurs after approximately 10 months. Mechanisms determining progression of disease are heterogeneous and not fully understood. EGFR-dependent resistance mechanisms (such as new EGFR mutations), bypass pathway activation [as erb-b2 receptor tyrosine kinase 2 (HER2) or MET amplification] and histological transformation [in small cell lung cancer (SCLC)] have been reported, similarly to previous generation TKIs. Here, we review principle mechanisms of innate and acquired resistance described in literature both in clinical and preclinical settings during NSCLC treatment with third-generation EGFR-TKIs
Validation of standard definition of sensitive versus refractory relapsed small cell lung cancer: A pooled analysis of topotecan second-line trials
No full textBackground Relapsed small cell lung cancer (SCLC) is classified into sensitive or resistant according to treatment-free interval (TFI) longer or shorter than 60 (criteria 1) or 90 (criteria 2) days. However, these criteria are based on small old studies and are inconsistent among different studies. The present study aimed at validating these criteria and assessing additional clinical parameters predictive of response rate (RR) and overall survival (OS). Patients and methods A database of six GlaxoSmithKline-sponsored trials of intravenous topotecan-based second-line chemotherapy was analysed. Validation of sensitive/resistant definition was performed on the entire dataset (631 patients), while study of additional parameters and development of prognostic model was conducted dividing the database into derivation and validation sets. Results The association between criterion 1 or 2 and RR was confirmed. Changing TFI cut-off or adding response to first-line did not improve accuracy. In addition to TFI (P = 0.007), only presence of liver metastasis (P = 0.046) was found to affect the probability of objective response. TFI, age, liver metastases, performance status (PS), albumin, haemoglobin and sodium levels were identified as independent prognostic factors for OS. A prognostic model, based on these variables, was able to separate relapsed SCLC into low versus high risk categories (median OS 41.4 versus 20.0 weeks). Conclusions This study confirms the value of standard criteria for relapsed SCLC outcome prediction. Patients with TFI < 60 days are refractory to second-line chemotherapy and have poor OS. Patients with liver metastasis and/or PS2 and/or low albumin, regardless of TFI, have similarly poor outcome.© 2014 Elsevier Ltd. All rights reserved
Gefitinib and afatinib treatment in an advanced non-small cell lung cancer (NSCLC) patient undergoing hemodialysis
No full textRenal failure in cancer patients is not a rare clinical condition and often contraindicates anticancer drug treatment; moreover, chemotherapeutic drugs are frequently identified as possible iatrogenic cause of renal failure. Molecular therapies, when appropriate, could represent a therapeutic option for cancer patients with severe renal disease, but the lack of knowledge in this field, at present, limits their use in patients undergoing dialysis. Herein we describe a case, at our knowledge the first reported, of a patient with advanced lung adenocarcinoma on maintenance hemodialysis treated with gefitinib and then with afatinib; we also reviewed the literature on epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) used in NSCLC patients with concomitant renal impairment
Prognostic role of hyponatremia in 564 small cell lung cancer patients treated with topotecan
No full textObjectives: Hyponatremia is reported in about 15% of small cell lung cancer (SCLC). Variable results of the prognostic significance of low plasmatic sodium (Napl) have been reported. Our study was performed to investigate the prognostic role of hyponatremia in SCLC patients treated in second-line with topotecan chemotherapy. Materials and methods: Data were retrospectively collected from a database including clinical data from 631 patients enrolled in 6 prospective topotecan iv studies. Final data were obtained from 564 patients in which data on baseline Napl were available. Univariate and multivariate analysis were carried out to study the possible correlation between Napl and second-line clinical outcomes. Results: Hyponatremia (Napl<135mequiv./l) was present in 101 cases (17.9%). Napl was <125mequiv./l in 16 patients (2.8%), 126-130mequiv./l in 11 (2%), 130-134mequiv./l in 74 (13.1%), while 463 patients (82.1%) showed normal values. The median survival was 28.7 weeks in patients with normal Napl, and 21.1 weeks in patients with hyponatremia (p<0.0001, HR=1.67, 95%CI=1.32-2.10). By Cox multivariate analysis, hyponatremia was associated with poorer prognosis (p=0.0024, HR=1.44, 95%CI=1.13-1.82). A not statistically significant trend of correlation between hyponatremia and progression-free survival (p=0.085, HR=1.23, 95%CI 0.97-1.55) and response rate (p=0.5037, OR=0.81, 95%CI 0.44-1.49) was observed. Conclusion: Hyponatremia is an independent prognostic factor for patients with SCLC treated with topotecan in second-line setting. Further studies are needed to prospectically confirm these results and to develop an optimal therapy for hyponatremic patients
Efficacy and safety of long-term tolvaptan treatment in a patient with SCLC and SIADH
No full textHyponatremia frequently occurs in patients with cancer and is mostly due to a syndrome of inappropriate antidiuresis caused by ectopic secretion of antidiuretic hormone (SIADH). Small cell lung cancer presents with SIADH in approximately 11%-15% of cases. Recently, a new class of drugs, vasopressin V2-receptor antagonists (vaptans), emerged as a promising treatment for SIADH, but efficacy and safety data in cancer patients are lacking. We present a case of SIADH, heralding small cell lung cancer and persisting after apparent complete remission of primary tumor following chemotherapy/radiotherapy, in a patient who underwent long-term treatment with tolvaptan without any serious adverse effects
Circulating DNA in diagnosis and monitoring EGFR gene mutations in advanced non-small cell lung cancer
No full textEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are current treatments for advanced non-small cell lung cancer (NSCLC) harboring activating EGFR gene mutations. Histological or cytological samples are the standard tumor materials for EGFR mutation analysis. However, the accessibility of tumor samples is not always possible and satisfactory in advanced NSCLC patients. Moreover, totality of EGFR mutated NSCLC patients will develop resistance to EGFR-TKIs. Repeat biopsies to study genetic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumor heterogeneity. Thus, exploring accurate and less invasive techniques to (I) diagnosis EGFR mutation if tissue is not available or not appropriate for molecular analysis and to (II) monitor EGFR-TKI treatment are needed. Circulating DNA fragments carrying tumor specific sequence alterations [circulating cell-free tumor DNA (cftDNA)] are found in the cell-free fraction of blood, representing a variable and generally small fraction of the total circulating DNA. cftDNA has a high degree of specificity to detect EGFR gene mutations in NSCLC. Studies have shown the feasibility of using cftDNA to diagnosis of EGFR activating gene mutations and also to monitor tumor dynamics in NSCLC patients treated with EGFR-TKIs. These evidences suggested that non-invasive techniques based on blood samples had a great potential in EGFR mutated NSCLC patients. In this review, we summarized these non-invasive approaches and relative scientific data now available, considering their possible applications in clinical practice of NSCLC treatment
Combination of EGFR-TKIs and chemotherapy in advanced EGFR mutated NSCLC: review of the literature and future perspectives
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