Comparison of the efficacy of radiotherapy between postoperative mediastinal lymph node recurrence and stage III disease in non-small cell lung cancer patients.

PURPOSE: It is unknown if local treatment is equally effective in non-small cell lung cancer (NSCLC) patients with postoperative mediastinal lymph node recurrence or primary stage III disease. The purpose of this study was to investigate the effectiveness of radiotherapy, with or without chemotherapy, in patients with postoperative mediastinal lymph node recurrence. METHODS: Patient characteristics, treatment response and survival were compared between NSCLC patients with mediastinal lymph node metastases treated between 2002-2009 by radiotherapy alone or by chemoradiotherapy (group A, N=33) and those with primary stage III disease (group B, N = 157). RESULTS: Men accounted for 60.6% of group A and 78.9% of group B (p=0.04 patients). ECOG performance status 0 was detected in 78.7% of group A and 57.3% of group B (p=0.02). The response rates in groups A and B were 66.6 and 72.3%, respectively (p=0.64). Progression-free survival (PFS) was similar between groups A and B (median 15.0 vs 11.0 months; hazard ratio [HR] 0.78; 95% CI 0.51-1.20; p=0.26). However, overall survival (OS) was better in group A than in group B (median 67.0 vs 39.0 months; HR 0.56; 95% CI 0.29-0.97; p=0.03). Postoperative PFS (median 12.5 vs 19.0 months; HR 1.50; 95% CI 0.64-3.49; p=0.34) and OS (median, 67.0 vs 60.0 months; HR 1.22; 95% CI 0.36-4.14; p=0.74) were similar between the group A treatments (radiotherapy and chemoradiotherapy, respectively). CONCLUSION: Postoperative mediastinal lymph node recurrent NSCLC demonstrated distinctive features including better OS compared to patients with primary stage III disease, despite similar response rates and PFS.

Clinical impact of postprogression survival for overall survival in elderly patients (aged 75 years or older) with advanced nonsmall cell lung cancer.

INTRODUCTION: The effects of first-line single-agent chemotherapy on overall survival (OS) might be confounded by subsequent treatments in elderly patients with nonsmall cell lung cancer (NSCLC). We, therefore, aimed to evaluate whether progression-free survival (PFS), postprogression survival (PPS), or tumor response might be a valid surrogate endpoint for OS in this patient population. PATIENTS AND METHODS: We retrospectively reviewed the clinical data of 58 elderly patients with advanced NSCLC, who received first-line single-agent cytotoxic chemotherapy at our institution between October 2003 and November 2013. The relationships of PFS, PPS, and tumor response with OS were individually analyzed. RESULTS: The study cohort included 46 men and 12 women with a median age of 79 years (range: 75-87 years). There were 30 adenocarcinomas, 22 squamous cell carcinomas, and 6 other histologic types with 1 stage IIIA, 9 IIIB, and 48 IV cases. The performance status (PS) scores were 0, 1, and 2 in 18, 35, and 5 patients, respectively. The median PFS and OS were 2.8 and 5.4 months, respectively. Our analyses revealed a strong correlation of PPS and PFS with OS, whereas that between tumor shrinkage and OS was weak. Tumor stage and PS after initial treatment were significantly associated with PPS. Individual analysis indicated that PPS might serve as a surrogate for OS in elderly patients with advanced NSCLC receiving first-line single-agent chemotherapy. CONCLUSION: Our findings suggested that the disease course after progression following first-line single-agent chemotherapy might influence the OS of elderly patients with advanced NSCLC.

First-line gefitinib treatment in elderly patients (aged ≥75 years) with non-small cell lung cancer harboring EGFR mutations.

PURPOSE: The efficacy of gefitinib [an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor] in elderly patients with non-small cell lung cancer (NSCLC) and EGFR mutation has not been elucidated. Therefore, the objective of this study was to investigate the efficacy and feasibility of gefitinib in elderly chemotherapy-naive patients with NSCLC harboring sensitive EGFR mutations. METHODS: We retrospectively evaluated the clinical effects of gefitinib as a first-line treatment for elderly (≥75 years) NSCLC patients with EGFR mutations (exon 19 deletion or exon 21 L858R mutation). All patients were initially treated with gefitinib (250 mg/day) at seven institutions. RESULTS: Between January 2006 and December 2012, 62 patients (17 men, 45 women) with a median age of 80 years (range, 75-89 years) were included in our analysis. The overall response and disease control rates were 61.2 and 83.8 %, respectively, and the median progression-free survival and overall survival were 13.2 and 19.0 months, respectively. Common adverse events included rash, diarrhea, and liver dysfunction. Major grade 3 or 4 toxicities included skin rash (3.2 %) and increased levels of aspartate aminotransferase or alanine aminotransferase (21.0 %). Gefitinib treatment was discontinued owing to adverse events of liver dysfunction in 3 patients, drug-induced pneumonitis in 2, and diarrhea in 1. CONCLUSION: First-line gefitinib could be a preferable standard treatment in elderly patients with advanced NSCLC harboring sensitive EGFR mutations.

Comparison of platinum combination re-challenge therapy and docetaxel monotherapy in non-small cell lung cancer patients previously treated with platinum-based chemoradiotherapy.

Platinum-based chemoradiotherapy (CRT) is a standard front-line treatment for locally advanced non-small cell lung cancer (NSCLC). However, no clinical trials have compared the efficacy and toxicity of platinum combination and docetaxel as subsequent re-challenge chemotherapies after cancer recurrence following CRT. This study aimed to evaluate the efficacy and toxicity of platinum combination chemotherapy versus docetaxel monotherapy in NSCLC patients previously treated with platinum-based CRT. From September 2002 to December 2009, at three participating institutions, 24 patients with locally advanced NSCLC, who had previously received platinum-based CRT, were treated with platinum combination re-challenge therapy, whereas 61 received docetaxel monotherapy. We reviewed their medical charts to evaluate patient characteristics and data regarding treatment response, survival, and toxicity. The response rates were 16.7% and 6.6% in the platinum combination chemotherapy and docetaxel monotherapy groups, respectively (p = 0.09), whereas disease control rates were 58.3% and 57.4%, respectively (p = 0.82). Progression-free survival was similar between the two groups (median, 4.2 vs. 2.3 months; hazard ratio [HR] = 0.81; 95% confidence interval [CI] = 0.51-1.29; p = 0.38), as was overall survival (median, 16.5 vs. 13.0 months; HR = 0.82; 95% CI = 0.47-1.41; p = 0.47). The incidence and severity of toxicity was also similar between the two groups. Hematological toxicity, particularly leukopenia and neutropenia, was more frequent in the docetaxel group. Our results indicated that platinum combination re-challenge was equivalent to docetaxel for relapsed patients previously treated with platinum-based CRT.

Single-nucleotide polymorphism (c.309T>G) in the MDM2 gene and lung cancer risk.

Murine double minute 2 (MDM2) is a negative regulator of p53. A single-nucleotide polymorphism (SNP) (rs2279744: c.309T>G) in the promoter region of the MDM2 gene has been shown to result in higher levels of MDM2 RNA and protein. Regarding the contribution of c.309T>G in the MDM2 gene to the lung cancer risk, previous studies are conflicting. In order to evaluate the association between c.309T>G and the lung cancer risk, a case-control study was performed. The MDM2 genotypes were determined in 762 lung cancer patients and in 700 cancer-free control subjects using the Smart Amplification Process. Statistical adjustment was performed for gender, age and pack-years of smoking. The distributions of c.309T>G (T/T, T/G, G/G) were 20.1, 49.7, 30.2% in the case group and 21.7, 47.9, 30.4% in the healthy-control group. There were no overall associations between the MDM2 genotypes and the risk of lung cancer [T/G genotype: Adjusted odds ratio (AOR), 1.30; 95% confidence interval (CI), 0.88-1.93; and G/G genotype: AOR, 1.18; 95% CI, 0.78-1.80]. The subgroup analysis of gender, histology, smoking status and epidermal growth factor receptor mutation status also indicated that there was no association with lung cancer. Additionally, the genotypes did not have an effect on the age at the time of diagnosis of lung cancer (P=0.25). In conclusion, the G allele frequency in the lung cancer cases was 0.551, which was similar to other studies. The results of the present study suggest that the c.309T>G is not significantly associated with lung cancer.

Surrogate endpoints for overall survival in advanced non-small-cell lung cancer patients with mutations of the epidermal growth factor receptor gene.

Subsequent therapies confound the ability to discern the effect of first-line chemotherapy on overall survival (OS). We investigated whether progression-free survival (PFS), post-progression survival (PPS) and tumor response were valid surrogate endpoints for OS following first-line chemotherapy in individual patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epidermal growth factor receptor gene mutations. We retrospectively analyzed 35 patients with advanced NSCLC treated with first-line gefitinib. The associations of PFS, PPS and tumor response with OS were analyzed. PPS was found to be strongly correlated with OS, unlike PFS and tumor shrinkage. The factors significantly associated with PPS were performance status (PS) after first-line treatment, best response to second-line treatment and number of regimens used after disease progression. PPS may be a surrogate for OS in this patient population and further therapy after disease progression following first-line chemotherapy may significantly affect OS. However, a larger study is required to validate these results.

Safety and efficacy of high-dose leukocytapheresis in patients with refractory asthma.

OBJECTIVE AND DESIGN: An open-label, non-randomized, single-arm study was performed to investigate the safety and efficacy of high-dose leukocytapheresis (pulse LCAP) for refractory asthma. SUBJECTS: Six patients who fulfilled the ATS workshop criteria for refractory asthma were enrolled and completed this clinical study. TREATMENT: After 4 weeks of observation, pulse LCAP using a large LCAP filter, Cellsorba(®) CS-180S, was performed twice with a 1-week interval at a target dose of 5 L per treatment session. METHODS: The clinical response was assessed by monitoring the peak expiratory flow rate (PEFR) twice a day. The asthma control test (ACT) was used to evaluate the condition of asthma symptoms. The fraction of exhaled nitric oxide (FeNO) as a biomarker for eosinophilic airway inflammation was measured using a chemiluminescence analyzer. RESULTS: PEFR in the morning or the evening and the sum total of the score on the ACT were increased after two consecutive sessions of pulse LCAP. FeNO decreased after pulse LCAP. CONCLUSIONS: The results suggest the efficacy of pulse LCAP for refractory asthma.

Phase II study of oral S-1 and cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer.

PURPOSE: To determine the efficacy and safety of oral S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: S-1 (50mg/m(2)) was administered orally twice daily for 14 days, with cisplatin (40 mg/m(2)) on days 1 and 8 of each cycle every 3 weeks, for 2-4 cycles. Thoracic radiation therapy was administered in 2 Gy fractions five times weekly for a total dose of 60 Gy. The primary endpoint was the response rate, and secondary endpoints included progression-free survival, overall survival and safety. RESULTS: Forty-one patients were enrolled in this study. The objective response rate was 87.8% (98% CI: 77.8-97.8%). The median progression-free survival was 467 days (15.4 months), and the median survival time was 904 days (29.7 months). The overall survival rates at 1- and 2-years were 85.7% and 52.9%, respectively. Hematological toxicities included grade 3/4 neutropenia (17%) and grade 3/4 leukopenia (27%). No grade 3 febrile neutropenia was detected, and grade 3/4 non-hematological toxicities were also mild. A grade 3 gastrointestinal hemorrhage was observed in one patient. CONCLUSIONS: The combination of oral S-1 plus cisplatin with concurrent radiotherapy is a promising treatment with a high efficacy and lower toxicity in patients with locally advanced NSCLC.

Phase II study of oral S-1 plus cisplatin with bevacizumab for advanced non-squamous non-small cell lung cancer.

BACKGROUND: We conducted a phase II study to evaluate the efficacy and safety of S-1 plus cisplatin with bevacizumab followed by maintenance bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naïve patients received S-1 plus cisplatin with bevacizumab. S-1 (80 mg/m(2)) was administered orally twice daily for 14 days, cisplatin (60 mg/m(2)) on day 1, and bevacizumab (15 mg/kg) on day 1 and every 3 weeks for 4-6 cycles. Patients with an objective response or stable disease received maintenance bevacizumab every 3 weeks until disease progression. RESULTS: Thirty patients were enrolled in this study. The median number of chemotherapy was four (range, 1-6 cycles), and the median number of bevacizumab alone was three (range, 1-31 cycles). The grade 3/4 toxicities were neutropaenia (23%), thrombocytopaenia (10%), febrile neutropaenia (3%), hypertension (17%), pneumonia (7%), and bowel perforation (3%). The objective response rate was 71% (95% CI, 55-88%) for a disease control rate of 100%. The median progression-free and overall survival times were 7.0 months and 20.0 months, respectively. CONCLUSIONS: S-1 plus cisplatin with bevacizumab is an active and well-tolerated regimen in patients with chemotherapy-naïve non-squamous NSCLC.

Efficacy and safety of platinum combination chemotherapy re-challenge for relapsed patients with non-small-cell lung cancer after postoperative adjuvant chemotherapy of cisplatin plus vinorelbine.

BACKGROUND: There is no standard therapy for relapsed patients who have received postoperative platinum-based adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of platinum combination chemotherapy re-challenge for such patients. METHODS: Medical records from 3 institutes from April 2005 to July 2012 were retrospectively reviewed. Patients who underwent complete surgical resection were eligible if they received postoperative adjuvant chemotherapy consisting of cisplatin plus vinorelbine once and then re-challenge with platinum combination chemotherapy. RESULTS: Sixteen patients were enrolled in this study. After re-challenge with platinum combination chemotherapy, we observed an overall response rate of 31.2% (5/16) and a disease control rate of 81.2% (13/16). Median progression-free survival and overall survival from the start of the re-administration of platinum combination chemotherapy were 6.5 and 28.0 months, respectively. Frequently observed severe adverse events (≥grade 3) included neutropenia (31.2%), thrombocytopenia (31.2%), leukopenia (12.5%) and hyponatremia (12.5%). Frequently observed non-hematological toxicities (≥grade 2) were anorexia (37.5%) and nausea (37.5%). CONCLUSION: Re-challenge with platinum combination chemotherapy was effective and safe; therefore, this therapy should be considered as a treatment option for relapsed patients after postoperative cisplatin-based adjuvant chemotherapy for resected NSCLC.