Characteristics and outcomes of patients with EGFR-mutation positive non-small-cell lung cancer receiving gefitinib beyond radiological progression.

BACKGROUND: This study aimed to analyze the characteristics and outcomes of patients suffering from non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor mutations (EGFRm+) receiving gefitinib who remained clinically stable following confirmation of progressive disease (PD) using Response Evaluation Criteria in Solid Tumors (RECIST) (R-PD) and identify those who benefited from tyrosine kinase inhibitor therapy beyond PD. RESEARCH DESIGN AND METHODS: The clinical courses of patients with EGFRm+ advanced NSCLC who received first-line gefitinib were investigated. Clinical PD (C-PD) was defined as one or more of the following: (1) symptomatic PD, (2) worsening performance status resulting from PD, (3) threat to a major organ(s), or (4) unequivocal multiorgan PD. RESULTS: Of 529 patients, 258 experienced R-PD without C-PD. Among 258 patients, 91 received gefitinib beyond R-PD. Females were more likely to receive gefitinib beyond R-PD and exhibit a longer time from R-PD to C-PD than males (median days, 175 vs. 79.5). Survival beyond R-PD tended to be longer for elderly patients who received gefitinib beyond PD than for those who did not (median days, 458 vs. 336), but this was not the case for non-elderly patients (median days, 481 vs. 487). CONCLUSIONS: Some patients may benefit from continuation of gefitinib beyond PD.

Continuing EGFR-TKI beyond radiological progression in patients with advanced or recurrent, EGFR mutation-positive non-small-cell lung cancer: an observational study.

BACKGROUND: Some patients with advanced or recurrent, epidermal growth factor receptor (EGFR) mutation-positive (EGFR M+) non-small-cell lung cancer (NSCLC) continue to receive EGFR tyrosine kinase inhibitors (TKIs) beyond radiological progression. METHODS: We analysed a cohort of 577 patients with EGFR M+ NSCLC, who had received a first-line EGFR-TKI. We classified patients according to clinical course and treatment patterns at Response Evaluation Criteria in Solid Tumors (RECIST) progressive disease (PD). We evaluated the period from RECIST PD to TKI discontinuation or clinical PD and also evaluated survival after RECIST PD and compared it between groups. RESULTS: RECIST PD was documented in 451 cases, of which 283 (62.7%) were clinically stable. 186 (65.7%) discontinued and 97 (34.3%) continued the EGFR-TKI. In those who continued EGFR-TKI, median time between RECIST PD and clinical PD or TKI discontinuation was 5.1 months. Median survival after RECIST PD in patients who discontinued and continued EGFR-TKI after clinically stable RECIST PD was 14.6 and 15.3 months (p=0.5489), respectively. In multivariate analysis, continuing EGFR-TKI therapy, female gender, better performance status and exon 19 deletion subtype were likely positive predictive factors for survival after clinically stable RECIST PD. CONCLUSION: Our study suggests that some patients could benefit from receiving an EGFR-TKI beyond radiological progression.

Impact of Maintenance Therapy for Patients with Non-small Cell Lung Cancer in a Real-world Setting.

BACKGROUND: The purpose of this study was to explore the role of maintenance therapy for patients with advanced non-small cell lung cancer (NSCLC) in a real-world setting. PATIENTS AND METHODS: This was a prospective observational cohort multicenter study. Eligible patients were observed from initiation of first-line platinum-based chemotherapy until final follow-up. RESULTS: Between 2010 and 2011, a total of 864 patients were enrolled in this study. The primary study population was 396 patients who had progressive disease during observation after first-line chemotherapy without maintenance. Of these, 113 patients (29%) did not receive second-line therapy. In contrast, only 18% of patients who had progressive disease during maintenance therapy missed second-line therapy. Overall survival of patients without maintenance who received second-line therapy was similar to that of those who received maintenance, but no second-line therapy. CONCLUSION: Maintenance therapy for patients with advanced NSCLC might be an appropriate strategy to maximize the chance of receiving more active therapy.

Clinical characteristics of patients with Aspergillus species isolation from respiratory samples: Comparison of chronic pulmonary aspergillosis and colonization.

BACKGROUND: With advancements in anti-fungal drugs, it has become more important to correctly diagnose chronic pulmonary aspergillosis (CPA); however, it is not easy to distinguish CPA from colonization when Aspergillus species are isolated from respiratory samples. The aim of the study was to clarify the particular clinical characteristics of patients with CPA vs. those with colonization. METHODS: We retrospectively reviewed the medical records of 110 patients with Aspergillus species isolation from respiratory samples, to analyze and compare the differences between CPA and colonization of the Aspergillus species. RESULTS: The median age of all analyzed was 71 years (range: 31-92 years); 64 were female (58%). The most frequently cultured Aspergillus species was Aspergillus fumigatus (48.3%), followed by A. niger (29.2%). Thirty patients (27.4%) were diagnosed with CPA, vs. 75 (68.2%) with colonization and 5 (4.5%) with allergic bronchopulmonary aspergillosis. Compared with the colonization group, the CPA group included more males (CPA vs. colonization: 49.3% vs. 13.3%) and subjects with a low body mass index (18.45 kg/m2 vs. 21.09 kg/m2). As for the underlying pulmonary diseases, the patients with CPA showed a significantly higher prevalence of sequelae of pulmonary tuberculosis (40% vs. 8%) and a history of thoracic surgery (43% vs. 13%) than those with colonization. Asthma was less frequent in the CPA group than in the colonization group (0% vs. 20%). We found no significantly important underlying extrapulmonary diseases. CONCLUSIONS: Patients with CPA display clinical characteristics distinct from those seen in subjects with colonization.

Brain metastasis effectively treated with erlotinib following the acquisition of resistance to gefitinib: a case report.

INTRODUCTION: Non-small-cell lung cancer harboring an activated epidermal growth factor receptor mutation exhibits a good response to epidermal growth factor receptor-tyrosine kinase inhibitors; however, clinicians often experience treatment failure following the development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor. CASE PRESENTATION: We here report a case of a 56-year-old Japanese woman with non-small-cell lung carcinoma with a secondary T790M mutation associated with resistance to epidermal growth factor receptor-tyrosine kinase inhibitor that maintained sensitivity of brain metastases to epidermal growth factor receptor-tyrosine kinase inhibitor. An autopsy showed that the primary focus had a T790M mutation; however, no mutations of T790M were found in the brain metastases. CONCLUSION: This case demonstrates the detection of T790M was associated with the clinical responsiveness to epidermal growth factor receptor-tyrosine kinase inhibitor.

Figitumumab combined with carboplatin and paclitaxel in treatment-naïve Japanese patients with advanced non-small cell lung cancer.

OBJECTIVES: The insulin-like growth factor (IGF) signaling pathway has been implicated in the pathogenesis of numerous tumor types, including non-small cell lung cancer (NSCLC). Figitumumab is a fully human IgG2 monoclonal antibody against IGF-1 receptor (IGF-1R). METHODS: This phase I, open-label, dose-escalation study (ClinicalTrials.gov: NCT00603538) assessed the safety and tolerability of figitumumab (6, 10 and 20 mg/kg) in combination with carboplatin (area under the curve: 6 mg·min/mL) and paclitaxel (200 mg/m(2)) in Japanese patients (N = 19) with chemotherapy-naïve, advanced NSCLC. Treatments were administered intravenously on day 1 of a 21-day cycle for four to six cycles. Pharmacokinetics, biomarkers, and antitumor activity were also evaluated. RESULTS: Figitumumab in combination with carboplatin and paclitaxel was well tolerated at doses up to 20 mg/kg; no dose-limiting toxicities were observed at this dose level. When given in combination, figitumumab plasma exposure increased in an approximately dose-proportional manner. The approximate 2-fold accumulation following repeated administration supported the 21-day regimen as appropriate for figitumumab administration. Serum total IGF-1 and IGF binding protein-3 concentrations increased following figitumumab dosing, but a clear dose-dependent relationship was not demonstrated. Seven of 18 evaluable patients experienced a partial response. CONCLUSIONS: Figitumumab 20 mg/kg in combination with carboplatin and paclitaxel was well tolerated in chemotherapy-naïve Japanese patients with NSCLC. Further analysis of biomarker data is necessary for the development of figitumumab therapy.

Pharmacokinetic and pharmacodynamic study on amrubicin and amrubicinol in Japanese patients with lung cancer.

PURPOSE: The pharmacokinetic (PK)-pharmacodynamic (PD) relationship of amrubicin and its active metabolite, amrubicinol, has only been evaluated using trough levels of these agents since the full PK profiles not yet been clarified so far. This study was performed to analyze the full PK profiles of amrubicin and amrubicinol and to evaluate their toxicity-PK relationships in Japanese patients. METHODS: Amrubicin (35-40 mg/m(2)) was administered to 21 lung cancer patients on days 1-3 every 3-4 weeks. Fourteen blood samples were obtained per patient over the course of 3 administration days. The plasma concentrations of amrubicin and amrubicinol were quantitated by HPLC, and the relationships between PK parameters of these compounds and hematological toxicities were evaluated. RESULTS: The overall PK profiles of amrubicin and amrubicinol were well characterized using a 3-compartment model and a 1-compartment model with a first-order metabolic process, respectively. The major toxicities were hematological. The clearance of amrubicinol was significantly correlated with grade 4 neutropenia (P = 0.01). The percentage decreases in the neutrophil count, hemoglobin level and platelet count were well correlated with the amrubicinol AUC. CONCLUSION: The pharmacokinetic profiles of amrubicin and amrubicinol were clarified, and the subsequent PK-PD analyses indicate that the clearance of amrubicinol is the major determinant of neutropenia.

The Frequency of Epidermal Growth Factor Receptor Mutation of Nonsmall Cell Lung Cancer according to the Underlying Pulmonary Diseases.

Background. Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective in patients with nonsmall cell lung cancer with epidermal growth factor receptor (EGFR) mutation, EGFR-TKIs have a risk of inducing fatal interstitial lung disease (ILD). The selection of chemotherapy based on the EGFR mutation status is recommended, however, the frequency of EGFR mutation in patients with ILD and the efficacy and safety of EGFR-TKI in patients with ILD and EGFR mutation are unknown. Methods. We retrospectively reviewed the association of the EGFR mutation status of nonsmall cell lung cancer and pulmonary diseases. Based on high-resolution computed tomography (HRCT) performed at diagnosis of lung cancer, patients were categorized into three groups: normal, emphysema, and fibrosis. Results. Of 198 patients with nonsmall cell lung cancer, we identified 52 (26.3%) patients with an EGFR mutation. EGFR mutations were identified in 43 (35.2%) of 122 patients with normal lungs, 8 (13.6%) of 59 with emphysema, and 1 (5.9%) of 17 with pulmonary fibrosis. Of the 52 patients with EGFR mutation, 43 patients received gefitinib. One patient with an EGFR mutation and fibrosis developed fatal ILD. There was not a significant difference in median overall survival from gefitinib treatment between never-smokers and smokers (797 days versus not reached; P = 0.96). Conclusions. Patients with sensitive EGFR mutation and normal lungs may benefit from an EGFR-TKI treatment even if they have smoking history.

Characteristics and outcomes of patients with advanced gastric cancer who declined to participate in a randomized clinical chemotherapy trial.

PURPOSE: There is insufficient data to verify whether participation in clinical trials in itself can lead to better clinical outcomes. We have analyzed the characteristics and outcomes of patients who declined to participate in a randomized trial in comparison with those who participated in the trial. PATIENTS AND METHODS: A randomized trial for naive advanced gastric cancer was offered to 286 patients. The trial investigated the superiority of irinotecan plus cisplatin and the noninferiority of S-1 compared with continuous fluorouracil infusion. We retrospectively reviewed the characteristics and outcomes for both participants and nonparticipants in this trial. RESULTS: Of the 286 patients, 98 (34%) declined to participate in the trial. The rate of declining was significantly higher among younger patients (P = .003), and it varied significantly between attending physicians (range, 23% to 58%; P = .004). There were no other significant correlations between rate of declining and patient characteristics. No significant differences were observed in the clinical outcomes between the participants and nonparticipants, for whom the median survival times were 367 versus 347 days, respectively. The hazard ratio for overall survival, adjusted for other confounding variables, was 1.21 (95% CI, 0.91 to 1.60). No interaction was observed between participation and the various regimens. CONCLUSION: There was no difference in clinical outcomes between participants and nonparticipants. However, the patient's age and the doctor-patient relationship may have an effect on patient accrual to randomized trials.

Interstitial lung disease during chemotherapy combined with oxaliplatin and/or bevacizumab in advanced colorectal cancer patients.

OBJECTIVE: Interstitial lung disease in patients with colorectal cancer during chemotherapy combined with bevacizumab is rare. METHODS: We reviewed 104 colorectal cancer patients treated with standard chemotherapy with bevacizumab and examined the incidence of interstitial lung disease and its clinical features. RESULTS: We identified interstitial lung disease in four patients (3.85%). All patients were male. The median age was 64.5 years. Three of four patients had a history of smoking; median smoking index was 40 pack-years. Except one patient who had asymptomatic pulmonary fibrosis, chest computed tomography before chemotherapy showed no fibrotic changes. Pulmonary function test before chemotherapy showed normal values. All patients had received median 10 cycles (range 10-15 cycles) of FOLFOX before the onset of interstitial lung disease. Interstitial lung disease developed during FOLFOX + bevacizumab in two patients and during FOLFIRI + bevacizumab in two patients. The initial symptom of interstitial lung disease was fever in all patients. The median duration from the last chemotherapy to the onset of interstitial lung disease was 3.5 days (range 2-8 days). Three of four patients showed Grade 3 or more severity of interstitial lung disease according to Common Terminology Criteria for Adverse Events v3.0. High-dose steroid therapy was effective in all patients. CONCLUSIONS: Interstitial lung disease induced by standard chemotherapy with bevacizumab is rare, but rapidly progressed and were severe in our experience.

The prevalence of pulmonary fibrosis combined with emphysema in patients with lung cancer.

BACKGROUND AND OBJECTIVE: Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder of the upper lobe, whereas emphysema is usually associated with lower lobe fibrosis. Although CPFE might increase the risk of lung cancer, the prevalence of CPFE in patients with lung cancer and the incidence of lung cancer in patients with CPFE are unknown. The objective of this study was to determine the prevalence of CPFE in lung cancer patients and to assess the clinical features of these patients. METHODS: A total of 1143 patients with lung cancer were reviewed. Based on HRCT performed at diagnosis of lung cancer, patients were categorized into four groups: normal, emphysema, fibrosis and CPFE. The clinical characteristics of patients with CPFE were compared with those of the other groups. RESULTS: CPFE, emphysema and fibrosis were identified in 101 (8.9%), 404 (35.3%) and 15 (1.3%) patients with lung cancer, respectively. The median overall survival of CPFE patients (n = 101, 10.8 months) was significantly less than that of normal patients (n = 623, 53.0 months) or that of patients with emphysema alone (n = 404, 21.9 months). Acute lung injury occurred in 20 (19.8%) patients with CPFE. CONCLUSIONS: CPFE is more prevalent than fibrosis in patients with lung cancer, and patients with CPFE had a poorer prognosis in the present study. Further investigation is therefore necessary to elucidate whether CPFE is an independent risk factor for lung cancer.

Association of DNA repair gene polymorphisms with response to platinum-based doublet chemotherapy in patients with non-small-cell lung cancer.

PURPOSE: To identify polymorphisms in DNA repair genes that affect responses to platinum-based doublet chemotherapy in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In total, 640 patients with NSCLC who received platinum-based doublet chemotherapy in the National Cancer Center Hospital in Japan from 2000 to 2008 and whose responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) participated in a study of the association between response and genotypes for 30 single nucleotide polymorphisms (SNPs) in 27 DNA repair genes. Candidate SNPs were selected in a discovery set of 201 patients, and their associations were validated in an independent set of 439 patients by prespecified P value criteria. RESULTS: Homozygotes for the minor allele TP53-72Pro of the Arg72Pro SNP in the TP53 gene showed a better response rate (54.3%) than those for the major allele TP53-72Arg (29.1%; P = 4.4 × 10(-5)) irrespective of therapeutic regimens, and minor allele homozygotes had significantly longer progression-free and overall survivals than major allele homozygotes (hazard ratio [HR], 0.85; 95% CI, 0.74 to 0.98; P = .020; and HR, 0.86; 95% CI, 0.74 to 0.99; P = .039). Minor allele carriers for SNP Lys940Arg in the poly (ADP-ribose) polymerase 1 (PARP1) gene showed a better response rate to the paclitaxel regimen (45.8%) than to the gemcitabine regimen (10.5%; P for interaction = .019). CONCLUSION: Polymorphisms in the TP53 and PARP1 genes are involved in inter-individual differences in the response to platinum-based doublet chemotherapy in patients with NSCLC.

[Clinical analysis of 12 cases of pneumothorax during intensive chemotherapy for malignant neoplasms].

Twelve cases of pneumothorax during intensive chemotherapy for malignant neoplasms were found in a retrospective study of patients being treated at our hospital in the period 2001-2009. All of the patients were men, and their diseases were lung cancer (9 cases), gastric cancer (2 cases) and esophageal cancer (one case). Operation for pneumothorax was performed 9 times in 7 patients(twice in two patients). Thoracoscopic surgery was done in 6 patients, and one patient with severe pulmonary emphysema was performed by open thoracotomy. Pleurodesis was performed 5 times using OK-432 only or OK-432 and minocyclin. Five patients died during the treatment for pneumothorax. The causes of death were interstitial pneumonia after pleurodesis (one case), and progression of cancer during interruption of chemotherapy (4 cases). Development of pneumothorax during intensive chemotherapy should be recognized and treated as soon as possible because it may hinder the treatment for malignant tumors and lead to severe pulmonary dysfunction.

A phase I study of enzastaurin combined with pemetrexed in advanced non-small cell lung cancer.

INTRODUCTION: Enzastaurin is an oral serine/threonine kinase inhibitor, which suppress signaling through protein kinase C-beta and the phosphatidylinositol 3-kinase/AKT pathway. Preclinical studies suggested synergic antitumor activity of enzastaurin and pemetrexed. We conducted this phase I study to evaluate the safety, pharmacokinetics, and clinical activity of this combination in patients with previously treated advanced non-small cell lung cancer. METHODS: An oral daily dose of 500 mg enzastaurin was administered once daily (QD) or twice daily (BID) in combination with 500 mg/m pemetrexed on day 1 in repeated 21-day cycles. Cycle 1 started with a 7-day enzastaurin lead-in treatment that preceded pemetrexed administration: a loading dose of 1125 mg enzastaurin on day 1 followed by a 500 mg total daily dose on days 2-7. RESULTS: Twelve patients were treated QD (n = 6) or BID (n = 6). One dose-limiting toxicity (grade 3 QTc prolongation) was reported in the QD cohort. Grade 3/4 hematological toxicities were slightly increased in the BID cohort compared with the QD cohort. After beginning the combination therapy, enzastaurin exposures decreased slightly but remained above the target plasma concentration of 1400 nmol/L. Compared with QD, there was a higher exposure with BID. The enzastaurin dosing regimen (QD or BID) had no effect on pemetrexed pharmacokinetics. Two patients had partial responses as defined by RECIST. Five patients received more than 10 cycles of treatment without disease progression. CONCLUSIONS: Both schedules of enzastaurin in combination with pemetrexed were well tolerated and clinically active in patients with advanced non-small cell lung cancer.

A case of long-term survival after surgical resection of solitary pulmonary metastasis from gastric cancer.

We describe a 60-year-old male patient who survived for a long period after pulmonary metastasectomy for gastric cancer. The patient initially underwent distal gastrectomy for gastric cancer. Seventeen months after the gastrectomy, surgical resection of solitary pulmonary metastasis was performed and following resection, the patient has survived without relapse for more than 5 years. Carefully selected patients have a good chance of benefiting from pulmonary metastasectomy for gastric cancer.

Gender difference in treatment outcomes in patients with stage III non-small cell lung cancer receiving concurrent chemoradiotherapy.

OBJECTIVE: To identify any gender differences in the outcomes of concurrent platinum-based chemotherapy and thoracic radiotherapy for unresectable stage III non-small cell lung cancer (NSCLC). METHODS: A comparative retrospective review of the clinical characteristics and treatment outcomes between female and male NSCLC patients receiving chemoradiotherapy. RESULTS: Of a total of 204 patients, 44 (22%) were females and 160 (78%) were males. There was no difference in age, body weight loss, performance status or disease stage between the sexes, whereas never-smokers and adenocarcinoma were more common in female patients (55% vs. 3%, P < 0.001, and 73% vs. 55%, P = 0.034, respectively). Full cycles of chemotherapy and radiotherapy at a total dose of 60 Gy were administered to approximately 70% and >80% of the patients, respectively, of both sexes. Grade 3-4 neutropenia was observed in 64% of the female patients and 63% of the male patients. Severe esophagitis was encountered in <10% of the patients, irrespective of the sex. The response rate was higher in the female than in the male patients (93% vs. 79%, P = 0.028), but the median progression-free survival did not differ between the sexes. The median survival time in the female and male patients was 22.3 and 24.3 months, respectively (P = 0.64). CONCLUSIONS: This study failed to show any gender differences in the survival or toxicity among patients treated by concurrent chemoradiotherapy. These results contrast with the better survival in female patients undergoing surgery for localized disease or chemotherapy for metastatic disease.

[Effective treatment with rituximab in a patient with refractory idiopathic thrombocytopenic purpura].

A 75-year-old woman had an episode of sudden nasal and oral bleeding. After that, petechiae appeared on her entire body. She received a platelet transfusion, and was referred to our hospital. On admission, the platelet count was as low as 1.2 X 10(4)/microl, and the PAIgG level was slightly elevated. Bone marrow cellularity was low, with a normal count of megakaryocytes. Anti-glycoprotein IIb/IIIa antibody-secreting B cells in the peripheral blood and platelet-associated anti-glycoprotein IIb/ IIIa antibodies were significantly high, and the patient was diagnosed as having idiopathic thrombocytopenic purpura (ITP). She failed to respond to corticosteroids, splenectomy and other therapies, so we administered rituximab, anti-CD20 monoclonal antibody, 375 mg/m2 weekly for four weeks. After the second infusion of rituximab, the platelet count began to increase. The platelet count continued to rise until a peak count (15.0 x 10(4)/microl) observed after 2 weeks from the fourth infusion, and the response was maintained for 8 more weeks. The levels of anti-glycoprotein IIb/IIIa antibody-secreting B cells and platelet-associated anti-glycoprotein IIb/IIIa antibodies decreased after the administration of rituximab. Rituximab was effective in this case of refractory ITP.