Kuniomi Matsuura

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

BackgroundEpidermal 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.MethodsEGFR-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.ResultsOverall, 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).ConclusionsThese 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.

Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer

BackgroundRash, liver dysfunction, and diarrhea are known major adverse events associated with erlotinib and gefitinib. However, clinical trials with gefitinib have reported different proportions of adverse events compared to trials with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib but not erlotinib. It has been hypothesized that CYP2D6 phenotypes may be implicated in different adverse events associated with gefitinib and erlotinib therapies.MethodsThe frequency of each adverse event was evaluated during the period in which the patients received gefitinib or erlotinib therapy. CYP2D6 phenotypes were determined by analysis of CYP2D6 genotypes using real-time polymerase chain reaction techniques, which can detect single-nucleotide polymorphisms. The CYP2D6 phenotypes were categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of the adverse events associated with each factor, including CYP2D6 activities and treatment types.ResultsA total of 232 patients received gefitinib therapy, and 86 received erlotinib therapy. Reduced function of CYP2D6 was associated with an increased risk of rash of grade 2 or more (OR, 0.44; 95% confidence interval [CI], 0.21–0.94; *p = 0.03), but not diarrhea ≥ grade 2 (OR, 0.49; 95% CI, 0.17–1.51; *p = 0.20) or liver dysfunction ≥ grade 2 (OR, 1.08; 95% CI, 0.52–2.34; *p = 0.84) in the gefitinib cohort. No associations were observed between any adverse events in the erlotinib cohort and CYP2D6 phenotypes (rash: OR, 1.77; 95% CI, 0.54–6.41; *p = 0.35/diarrhea: OR, 1.08; 95% CI, 0.21–7.43; *p = 0.93/liver dysfunction: OR, 0.93; 95% CI, 0.20–5.07; *p = 0.93).ConclusionsThe frequency of rash was significantly higher in patients with reduced CYP2D6 activity who treated with gefitinib compared to patients with functional CYP2D6. CYP2D6 phenotypes are a risk factor for the development of rash in response to gefitinib therapy.

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

BackgroundRenal 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.MethodsIn 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.ResultsThere 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).ConclusionsHigh-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

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/m2/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/m2, 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.

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

ABSTRACT 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.

1283PGEFITINIB AND PEMETREXED AS A FIRST LINE TREATMENT IN PATIENTS WITH EGFR MUTANT ADVANCED NSCLC: A PHASE II STUDY

ABSTRACT Aim: Gefitinib (G) is the key drug for patients (pts) with Non-Small Cell Lung Cancer (NSCLC) harboring mutations of EGFR as a first line treatment. However, they have disease progression in most cases. Pemetrexed (PEM) and G are reported to have a schedule-depended cytotoxic synergism. We evaluated the efficacy and safety of G and PEM as a first line chemotherapy in pts with NSCLC harboring mutations of EGFR. Methods: Eligibilities were histological or cytologically proven non-squamous NSCLC with EGFR active mutation, chemotherapy naive, measurable lesion, ECOG PS 0-1, adequate organ function, life expectancy longer than 12 weeks and written informed consent. G (250mg/body) was administered on day 2-16 and PEM (500mg/m2) was administered on day1. The combination was repeated every 3 weeks until progressive disease (PD). Primary endpoint was overall response rate (ORR) and secondary endpoints were toxicities, disease control rate (DCR), progression free survival (PFS), and overall survival (OS). The planed sample size was 26 pts. Results: From March 2010 to January 2013, 26 pts were enrolled and eligible: males/females 13/13; median age 66 (range 58-84); PS 0/1 3/23; stage III/IV 1/25; Adeno/Others 26/0. All pts were eligible for efficacy and toxicity; a total 398 cycles (median 16 cycles, range 1-35) were given. Major grade 3/4 toxicities were neutropenia, infection, and liver dysfunction. There was no treatment-related death. ORR was 84.6%, and DCR was 96.2%. Median PFS was18.0 months, and median OS was 32.0 months. Conclusions: This combination showed high ORR, long median PFS, and acceptable toxicity. Randomized trial of PEM + G compare with G alone is warranted. Disclosure: All authors have declared no conflicts of interest.