Epidermal growth factor receptor tyrosine kinase inhibitors in previously treated advanced non-small-cell lung cancer with wild-type EGFR.

INTRODUCTION: While epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) lead to longer progression-free survival (PFS) when compared with conventional chemotherapy in non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR-TKI remains unclear in EGFR-wild-type (WT) NSCLC. AREAS COVERED: This article reviews selected data from randomized trials regarding the use of TKIs in EGFR-WT NSCLC. Nine randomized phase III trials have compared EGFR-TKI with chemotherapy in NSCLC patients in a second or later line setting. Two of these trials, TAILOR and DELTA, which were designed to investigate treatment benefits according to EGFR genotype, demonstrated that docetaxel chemotherapy displayed significantly better in progression-free survival (PFS) when compared with the EGFR-TKI erlotinib. Biomarkers to predict clinical benefits of the drug against EGFR WT tumor, and the efficacy of combination regimens using erlotinib or single-use afatinib against tumors are also covered in this article. EXPERT OPINION: Considering the modest benefits of erlotinib for EGFR-WT tumors, future studies are warranted, including the exploration of useful biomarkers and new treatment strategies for EGFT-TKI use, as well as the development of more sensitive EGFR mutation tests.

Phase II study of a combination regimen of gefitinib and pemetrexed as first-line treatment in patients with advanced non-small cell lung cancer harboring a sensitive EGFR mutation.

PURPOSE: Patients with advanced non-small cell lung cancer (NSCLC) harboring a sensitive epidermal growth factor receptor (EGFR) mutation have been shown to exhibit a marked response to EGFR-tyrosine kinase inhibitor (TKI) treatment. Pemetrexed and gefitinib were reported to have a schedule-dependent cytotoxic synergism. We evaluated the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in EGFR-mutated NSCLC patients. PATIENTS AND METHODS: Systemic therapy-naïve patients with advanced non-squamous NSCLC harboring a sensitive EGFR mutation were included in this study. Pemetrexed was administered on day 1 at a dose of 500 mg/m(2), and gefitinib was sequentially administered on days 2-16. This treatment regimen was repeated every 3 weeks until disease progression. RESULTS: Twenty-six patients were enrolled in this study. The median number of treatment cycles was 16 (range, 1-35). The overall response rate (ORR) was 84.6% (95% confidence interval [CI], 70.7-98.5%), and the disease control rate (DCR) was 96.2% (95% CI, 88.9-100%). Grade 3/4 hematological toxicities included neutropenia (15.4%), leukopenia (7.7%), and anemia (3.8%). No grade 4 non-hematological toxicities were observed. The main grade 3 non-hematological toxicities were infection (11.5%), increased alanine aminotransferase (11.5%) and aspartate aminotransferase (7.7%) levels, fatigue (3.8%), diarrhea (3.8%), and pneumonitis (3.8%). We observed a median progression-free survival (PFS) of 18.0 months (95% CI, 15.0-21.0 months) and a median survival time (MST) of 32.0 months (95% CI, 28.5-35.5 months). There were no treatment-related deaths. CONCLUSIONS: The combination regimen used in this study showed a high ORR, long median PFS, and acceptable toxicity. A future randomized trial on pemetrexed plus gefitinib compared with gefitinib alone is warranted.

The Macroscopic Appearance of Computed Tomography-guided Needle Biopsy Specimens Correlates with Tumor Metastasis in Non-small Cell Lung Cancer.

BACKGROUND: Computed tomography (CT)-guided needle biopsy is a well-established and dependable procedure for the diagnosis of pulmonary lesions. Some tissue biopsy samples have loose cohesion and disintegrate into tiny pieces before formalin fixation. The purpose of this study was to assess the association between the fresh macroscopic appearance of samples obtained using CT-guided needle biopsy and the clinicopathological features of non-small cell lung cancer (NSCLC). METHODS: A total of 111 patients who underwent CT-guided lung needle biopsy at Osaka City University Hospital between May 2009 and May 2013 were enrolled. Macroscopic appearance was categorized as either loose or tight cohesion. Samples were evaluated using Azan staining to detect collagen fibers. The staining intensity was multiplied by the percentage of positive cells, and the specimen was categorized as having either low (<100) or high expression ( ≥100). Univariate and multivariate logistic regression models were used to evaluate significant covariates for tumor metastasis. RESULTS: In the cohort of 111 patients, the diagnostic rates in loose and tight cohesions were 82.6% and 87.5%, respectively (p=0.509). In 60 patients diagnosed with NSCLC, Azan staining of collagen fibers was positive in 93.5% of the samples with tight cohesion and 28.6% of the samples with loose cohesion (p<0.001). In the multivariate logistic regression models, distant metastasis was significantly associated with loose cohesion (p=0.026). CONCLUSIONS: These results suggest that the macroscopic appearance of CT-guided biopsy samples correlates with tumor metastasis in NSCLC.

Magnesium supplementation and high volume hydration reduce the renal toxicity caused by cisplatin-based chemotherapy in patients with lung cancer: a toxicity study.

BACKGROUND: Renal toxicity is a clinical problem that affects 28-42% of patients undergoing treatment with cisplatin. Renal toxicity can be minimized by high volume hydration with mannitol diuresis. Recent reports have shown that cisplatin induces depletion of Mg and that Mg supplementation can reduce renal toxicity. We hypothesized that Mg infusion combined with low volume hydration may not be sufficient to overcome cisplatin-induced renal toxicity. METHODS: In total, 85 patients with lung cancer receiving their first cycle of cisplatin-based chemotherapy at the Osaka City University Hospital were classified into three groups: those administered high volume hydration without Mg infusion (high-volume Mg-), high volume hydration with Mg infusion (high-volume Mg+), and with low volume hydration with Mg infusion (low-volume Mg+). Serum creatinine (sCr) and creatinine clearance (CrCl) were examined before and after treatment with cisplatin. Multivariable analysis was carried out to identify the most important contributing factors. RESULTS: There were no significant differences in pre-treatment sCr levels or CrCl between groups. In the high-volume Mg- group, post-treatment sCr significantly increased compared with pre-treatment levels, while post-CrCl significantly decreased compared with pre-treatment CrCl (p < 0.001 and p < 0.001, respectively). In the high-volume Mg+ group, there was no significant difference between pre- and post-treatment levels of sCr, or between pre- and post-treatment CrCl (p = 0.118 and p = 0.254, respectively). In the low-volume Mg+ group, there was a trend towards increased sCr levels and decreased CrCl after treatment (p = 0.068 and p = 0.055, respectively). Multivariate analysis revealed that the absence of Mg infusion and low-volume hydration were both independent factors for decreased CrCl (p < 0.001 and p = 0.001, respectively). CONCLUSIONS: High-volume hydration and Mg infusion reduces the renal toxicity induced by cisplatin. A low-volume Mg+ regimen may be considered for patients with adequate renal function. TRIAL REGISTRATION: Observational Study UMIN000013950; Registered 13 May 2014.

Reaction of plasma adiponectin level in non-small cell lung cancer patients treated with EGFR-TKIs.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are routinely used to treat advanced non-small cell lung cancer (NSCLC) patients with activated EGFR mutations, and are associated with excellent response and improvement of performance status. Adipose tissue produces and releases substances called adipokines, which include adiponectin, leptin, resistin, and hepatocyte growth factor (HGF), etc. Previously, we reported that high levels of plasma HGF at diagnosis indicated intrinsic resistance to EGFR-TKIs. EGFR-TKIs have been hypothesized to affect these adipokines. METHODS: This prospective study, to evaluate the correlation between plasma adiponectin and insulin levels and non-hematological adverse effects in advanced NSCLC following EGFR-TKIs administration, was conducted at the Osaka City University Hospital. Plasma adiponectin and insulin levels were determined at diagnosis and on treatment day 30. RESULTS: Overall 33 patients were enrolled. We obtained plasma samples for analyses from all patients at diagnosis and from 26 patients on day 30. Increased adiponectin (13.69 to 14.42 microg/mL, p = 0.0092), and decreased insulin (404.0 to 351.2 pg/mL, p = 0.022) were observed after EGFR-TKI treatments. High levels of adiponectin at diagnosis were associated with severities of skin rash (p = 0.035). CONCLUSIONS: The adiponectin was affected by EGFR-TKI treatments for NSCLC. Besides, the adverse events by EGFR-TKIs were influenced by the plasma adipokines at diagnosis. Our study may provide useful information regarding patient outcomes to EGFR-TKI treatments. A prospective large clinical trial is warranted to clarify these results.

Plasma RANTES, IL-10, and IL-8 levels in non-small-cell lung cancer patients treated with EGFR-TKIs.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), routinely used to treat advanced non-small-cell lung cancer (NSCLC) patients with activated EGFR mutations, are associated with excellent response and improved performance status. Recently, pro-inflammatory cytokines, such as regulated upon activation normal T cell expressed and secreted (RANTES), interleukin (IL)-10 and IL-8 have been proposed as mediators of cancer development. EGFR-TKIs have been found to affect this network of pro-inflammatory cytokines. METHODS: EGFR-TKIs (erlotinib, 150 mg/day; and gefitinib, 250 mg/day) were administered once per day. Treatment was continued until disease progressed or the patient developed intolerable symptoms of toxicity, or withdrew his/her consent for study participation. The treatment was a part of standard care. We investigated the correlation between plasma pro-inflammatory cytokines (including plasma RANTES, IL-10, and IL-8) levels and clinical outcomes following EGFR-TKI treatment in lung cancer patients. Pro-inflammatory cytokine levels were evaluated at diagnosis and on treatment day 30 after the first administration of EGFR-TKIs. RESULTS: Overall, 33 patients were enrolled. Plasma pro-inflammatory cytokine levels were determined for all patients at diagnosis. Plasma samples from 26 patients were obtained on treatment day 30. High level of RANTES at diagnosis was associated with severe general fatigue (P = .026). Low level of RANTES at diagnosis was significantly associated with long-term survival (P = .0032). Percent decrease change of IL-10 was associated with severity of rash (P = .037). The plasma IL-8 level on treatment day 30 (median, 5.48 pg/mL; range, 0.49-26.13 pg/mL) was significantly lower than the level at diagnosis (median 10.45 pg/mL; 3.04-54.86 pg/mL; P = .021). CONCLUSIONS: These results suggest that EGFR-TKIs may suppress systemic inflammation and promote tumor shrinkage. The network of pro-inflammatory cytokines was affected by EGFR-TKI treatment for NSCLC. In addition, the clinical outcomes of EGFR-TKI treatment were influenced by the status of the plasma pro-inflammatory cytokines at diagnosis.

C609T Polymorphism of NADPH Quinone Oxidoreductase 1 Correlates Clinical Hematological Toxicities in Lung Cancer Patients Treated with Amrubicin.

BACKGROUND: Amrubicin hydrochloride (AMR) is a key agent for lung cancer. NADPH quinone oxidoreductase 1 (NQO1) metabolizes the quinone structures contained in both amrubicin (AMR) and amrubicinol (AMR-OH). We hypothesized that NQO1 C609T polymorphism may affect AMR-related pharmacokinetics and clinical outcomes. METHODS: Patients received AMR doses of 30 or 40 mg/m(2)/day on days 1-3. Plasma sampling was performed 24 hours after the first and third AMR injections. Concentrations of AMR and AMR-OH were determined by HPLC and the NQO1 C609T polymorphism was assayed by RT-PCR. RESULTS: A total of 35 patients were enrolled. At a dose of 40 mg/m(2), the T/T genotype exhibited a tendency toward a relationship with decrease concentrations of AMR-OH on days 2 and 4. The genotype also showed a significant decrease of hematological toxicities (P < 0.05). CONCLUSIONS: NQO1 C609T polymorphism had a tendency of correlation with the plasma concentrations of AMR-OH, and thereby had significant correlations with hematologic toxicities.