Tak Yun

First-SIGNAL: First-Line Single-Agent Iressa Versus Gemcitabine and Cisplatin Trial in Never-Smokers With Adenocarcinoma of the Lung

PURPOSEnGefitinib has shown high response rate and improved progression-free survival (PFS) in never-smokers with lung adenocarcinoma (NSLAs). We compared efficacy of gefitinib with gemcitabine and cisplatin (GP) chemotherapy in this group of patients as first-line therapy.nnnPATIENTS AND METHODSnIn this randomized phase III trial, a total of 313 Korean never-smokers with stage IIIB or IV lung adenocarcinoma, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate organ function were randomly assigned to receive either gefitinib (250 mg daily) or GP chemotherapy (gemcitabine 1,250 mg/m(2) on days 1 and 8; cisplatin 80 mg/m(2) on day 1 every 3 weeks, for up to nine courses). The primary objective was to demonstrate better overall survival (OS) for gefitinib compared with GP in chemotherapy-naive NSLAs.nnnRESULTSnThree hundred nine patients were analyzed per protocol (gefitinib arm, n = 159; GP arm, n = 150). Gefitinib did not show better OS compared with GP (hazard ratio [HR], 0.932; 95% CI, 0.716 to 1.213; P = .604; median OS, 22.3 v 22.9 months, respectively). The 1-year PFS rates were 16.7% with gefitinib and 2.8% with GP (HR, 1.198; 95% CI, 0.944 to 1.520). Response rates were 55% with gefitinib and 46% with GP (P = .101). Myelosuppression, renal insufficiency, and fatigue were more common in the GP arm, but skin toxicities and liver dysfunction were more common in the gefitinib arm. Two patients (1.3%) in the gefitinib arm developed interstitial lung disease and died.nnnCONCLUSIONnGefitinib failed to demonstrate superior OS compared with GP as first-line therapy for NSLAs.

Clinical outcome according to the level of preexisting epidermal growth factor receptor T790M mutation in patients with lung cancer harboring sensitive epidermal growth factor receptor mutations.

Epidermal growth factor receptor (EGFR) T790M mutation drives acquired drug resistance to EGFR tyrosine kinase inhibitors (EGFR‐TKIs) in patients with EGFR‐mutant lung cancer. However, it was reported that this mutation may exist before drug exposure. The objective of the current study was to evaluate whether the clinical outcomes are affected by the percentage of preexisting T790M mutations within a tumor.

Phase II study of weekly paclitaxel and capecitabine in patients with metastatic or recurrent esophageal squamous cell carcinoma

BackgroundThis phase II study assessed the response rate and toxicity profile of weekly paclitaxel and capecitabine in patients with metastatic or recurrent squamous cell carcinoma of the esophagus (SCCE)MethodsPatients with histologically confirmed SCCE were treated with paclitaxel 80 mg/m2 intravenously on days 1 and 8 plus capecitabine 900 mg/m2 orally twice a day on days 1-14. Treatment cycles were repeated every 3 weeks until disease progression or unacceptable toxicity.ResultsBetween 2006 and 2009, 32 patients were enrolled. Twelve patients were chemotherapy-naïve. Twenty patients had received prior chemotherapy including platinum-based regimens. Patients received a median of 5 cycles of treatment (range, 1-12). The response rate was 75% (95%CI; 50.5~99.5%) in the first-line and 45% (95%CI; 26.9~73.1%) in the second-line. With a median follow-up of 20.7 months, median progression-free survival was 5.2 months (95% CI, 4.0 to 6.4) for all patients and median overall survival (OS) was 11.7 months (95% CI, 5.5 to 18.0) for all patients. The median OS was 14.3 months (95% CI, 10.6 to 18.0) for patients receiving therapy as 1st line and 8.4 months (95% CI, 6.6 to 10.1) for those receiving as 2nd-line therapy. Grade 3/4 neutropenia was observed in 53.3% of the patients, which was the most common cause of dose reduction. G3 non-hematologic toxicity included stomatitis (9.4%), asthenia (6.3%), and hand-foot skin reaction (3.1%).ConclusionsWeekly paclitaxel and capecitabine is a highly active and well-tolerated regimen in patients with metastatic or recurrent SCCE in the first-line as well as second-line setting.

Serum and urine levels of interleukin-8 in patients with non-Hodgkin's lymphoma

Angiogenesis plays an important role in many types of cancer. Interleukin-8 (IL-8) is known to be a pro-inflammatory and pro-angiogenic cytokine, and IL-8 has been reported to be associated with tumor progression, prognosis and survival in several types of cancers. However, the role of IL-8 in non-Hodgkins lymphoma (NHL) has not been fully determined. Here, we evaluated the usefulness of measuring serum and urine IL-8 levels in patients with NHL. We developed reference intervals for serum and urine IL-8 level in 131 control individuals. We measured serum IL-8 and urine IL-8 levels in patients with NHL, and we compared the concentrations with those of control individuals. The reference intervals for serum IL-8 and urine IL-8 corrected by creatinine (Cr) were 15.9-430.3 pg/mL and 0.0-28.4 pg/mg Cr, respectively. The concentrations of urine IL-8/Cr were significantly higher in patients than in controls (48.9+/-194.4 vs. 5.2+/-13.8 pg/mg Cr, P<0.001). However, there were no significant differences in serum IL-8 concentrations between NHL patients and controls (159.2+/-40.4 vs. 99.6+/-107.1 pg/mL; P=0.099). Receiver operating characteristic (ROC) analysis gave 0.83 and 0.43 ROC area values for urine IL-8/Cr and serum IL-8, respectively. There was no correlation between the serum and urine concentrations of IL-8 and clinical variables, the only exception being the international prognostic index (IPI), which showed a marginal correlation with urine IL-8/Cr levels (P=0.07). This study indicated that urine IL-8/Cr levels might be useful as a diagnostic marker of NHL.

First-line gefitinib treatment for patients with advanced non-small cell lung cancer with poor performance status.

Background: Best supportive care only is recommended for patients with advanced non-small cell lung cancer (NSCLC) with poor performance status (PS) of Eastern Cooperative Oncology Group 3 or 4. Recently, the possibility of using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy has been reported for poor PS patients harboring EGFR mutations. Methods: We retrospectively analyzed 74 patients with advanced NSCLC who were treated with first-line gefitinib during hospitalization for Eastern Cooperative Oncology Group PS 3 or 4. All patients were classified according to three clinical parameters: smoking history, gender, and histology type. Results: The median age was 64 years (range, 35–86 years). The proportions of females, never smokers, and adenocarcinoma were 51.4%, 54.1%, and 78.4%, respectively. An overall response rate, median progression-free survival (PFS), and median overall survival (OS) was 27.0%, 32 days (95% confidence interval [CI], 22–48 days), and 61 days (95% CI, 7–115 days), respectively. Female gender, never smoking, and adenocarcinoma histology were strong predictors of tumor response. Never smoking and adenocarcinoma were independent predictors of better PFS but not of OS. Seven patients experienced treatment-related adverse effects of grade 3 to 4, which included anorexia (n = 2), pneumonitis (n = 4), and elevated liver enzymes (n = 1). Never-smoker females with adenocarcinoma exhibited a response rate of 50.0%, median PFS of 130 days (95% CI, 51–209 days), and median OS of 236 days (95% CI, 150–322 days). Conclusions: Gefitinib may provide clinical benefits for patients with NSCLC with poor PS who were selected according to clinically favorable parameters.

Reference intervals for circulating angiogenic cytokines

Abstract Background: The levels of angiogenic cytokines are important in the definition of baseline characteristics of cancers and to predict patient prognosis; however, the reference intervals for angiogenic cytokines have received only limited attention. Herein, we obtained reference intervals for angiogenic cytokines, including vascular endothelial growth factor (VEGF), hepatocyte growth factor, basic fibroblast growth factor, interleukin-6, vascular endothelial growth factor receptor 1 and vascular endothelial growth factor receptor 2. Methods: We measured these materials in serum, plasma and urine of 131 controls, according to the guidelines of the Clinical and Laboratory Standards Institute. We analyzed the association between angiogenic cytokine levels and other laboratory parameters and explored whether polymorphisms in angiogenic cytokine genes affect the levels of cytokines. Results/Conclusions: These data allowed us to construct reference intervals for angiogenic cytokines, and we also observed that concentrations of angiogenic cytokines generally do not vary with genotype or haplotype. An exception was serum VEGF concentration; this level was marginally affected by the –1154 VEGF polymorphism. Clin Chem Lab Med 2008;46:545–50.

A Phase II Study of Weekly Paclitaxel Plus Gemcitabine as a Second-Line Therapy in Patients with Metastatic or Recurrent Small Cell Lung Cancer

Purpose Paclitaxel (P) and gemcitabine (G) are clinically synergistic in small cell lung cancer (SCLC). We evaluated the efficacy of PG as a salvage treatment for SCLC patients whose disease progressed after a platinum-containing regimen. Materials and Methods Eligibility included histologically confirmed SCLC, one dimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and progressive disease after platinum-based chemotherapy. Treatment consisted of P (80 mg/m2) and G (1,000 mg/m2) on days 1 and 8 of each cycle of 21 days until disease progression. Results Thirty-three patients seen between December 2005 and February 2009 were selected into this study. Thirty patients (91%) had received irinotecan-platinum, and three had received etoposide-platinum. Sixteen patients (49%) had a treatment-free interval of less than 3 months. The overall response rate was 30.3% (29.4% in sensitive relapse and 31.3% in refractory relapse). The median time to progression was 12.0 weeks and median overall survival (OS) 31.0 weeks, with a 1-year OS rate of 30.3%. Toxicities were moderate and manageable with 18.2% grade (G) 4 neutropenia, 24.2% G3 thrombocytopenia, 6.1% G3 sensory neuropathy, and 3% G3 asthenia. One patient developed febrile neutropenia. Conclusion Second-line paclitaxel and gemcitabine were well-tolerated and moderately active in SCLC patients previously treated with platinum-based chemotherapy.

Incorporating Erlotinib or Irinotecan Plus Cisplatin into Chemoradiotherapy for Stage III Non-small Cell Lung Cancer According to EGFR Mutation Status.

Purpose Concurrent chemoradiotherapy (CCRT) is the standard care for stage III non-small cell lung cancer (NSCLC) patients; however, a more effective regimen is needed to improve the outcome by better controlling occult metastases. We conducted two parallel randomized phase II studies to incorporate erlotinib or irinotecan-cisplatin (IP) into CCRT for stage III NSCLC depending on epidermal growth factor receptor (EGFR) mutation status. Materials and Methods Patients with EGFR-mutant tumors were randomized to receive three cycles of erlotinib first and then either CCRT with erlotinib followed by erlotinib (arm A) or CCRT with IP only (arm B). Patients with EGFR unknown or wild-type tumors were randomized to receive either three cycles of IP before (arm C) or after CCRT with IP (arm D). Results Seventy-three patients were screened and the study was closed early because of slow accrual after 59 patients were randomized. Overall, there were seven patients in arm A, five in arm B, 22 in arm C, and 25 in arm D. The response rate was 71.4% and 80.0% for arm A and B, and 70.0% and 73.9% for arm C and D. The median overall survival (OS) was 39.3 months versus 31.2 months for arm A and B (p=0.442), and 16.3 months versus 25.3 months for arm C and D (p=0.050). Patients with sensitive EGFR mutations had significantly longer OS than EGFR-wild patients (74.8 months vs. 25.3 months, p=0.034). There were no unexpected toxicities. Conclusion Combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC. EGFR-mutant patients appear to be a distinct subset with longer survival.

DNA repair gene polymorphisms and benefit from gefitinib in never-smokers with lung adenocarcinoma (NSLA).

7621 Background: DNA repair gene polymorphisms are thought to modulate DNA repair capacity and may affect response and prognosis. We investigated the impact of DNA repair gene polymorphisms on clin...

A Phase II Study of Erlotinib as a First-Line Therapy for Patients with Non—Small-Cell Lung Cancer with Favorable Clinical Predictors

Abstract Background Many studies of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors suggest positive and negative predictors for response and survival. We conducted the study to evaluate the efficacy of erlotinib as a first-line therapy for patients with non—small-cell lung cancer who have favorable clinical predictors, such as never having smoked, adenocarcinoma, or female sex. Patients and Methods The eligible patients should have ≥ 2 of 3 favorable clinical predictors, including female sex, adenocarcinoma, and never-smoker status. Additional inclusion criteria were as follows: stage IIIB or IV disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, adequate organ function, and measurable lesions. Neither previous chemotherapy nor targeted therapy nor radiation therapy for measurable disease was allowed. Treatment consisted of erlotinib 100–150 mg orally given once daily till disease progression, unacceptable toxicity, or patients refusal. Objective tumor responses were assessed 1 month after the commencement of erlotinib and then every 2 months. Results Between October 2006 and June 2007, all 38 patients enrolled (median age, 54 years; male/female, 1/37; ECOG PS 0/1/2, 2/29/7; stage IIIB/IV disease, 3/35; never/current smoker 36/2) were evaluable for response. Among them, 26 reached a partial response (PR), 6 had stable disease (SD), and 6 had progressive disease (PD), giving an overall response rate of 68.4% (95% CI, 52.5%–81%) and a disease control rate of 84.2% (95%CI, 69.2%–92.9%). Out of 6 patients identified to have an EGFR gene mutation before initiating treatment, 5 reached a PR, and 1 had PD, while out of 6 patients with wild-type of EGFR, there were 2 PRs, 1 SD, and 3 PDs. After a median follow-up of 7.9 months, the expected median progression-free survival is 10.7 months, with an expected 1-year survival rate of 91.2%. The most common toxicity was skin rash, which was manageable. Conclusion Erlotinib showed promising response rates as a first-line therapy for patients who have favorable predictors and could be a treatment of choice in this clinical setting.