Comparative Efficacy of ALK Inhibitors for Treatment-Naïve ALK-Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis: A Network Meta-Analysis.

Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC.

Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury.

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

Inhibition of Virus-Induced Cytokine Production from Airway Epithelial Cells by the Late Addition of Budesonide.

BACKGROUND: Viral infection is the main cause of asthma and COPD (chronic obstructive pulmonary disease) exacerbation and accumulate inflammatory cells to airway tissue. We have reported poly I:C, a mimic product of the virus and ligand of toll-like receptor 3 (TLR3), induced inflammatory chemokines from airway epithelial cells and found prior incubation with corticosteroids diminishes the effect of TLR3 activation. In clinical practice, mild asthma is recommended as-needed budesonide (BUD) when symptoms occur following a viral infection, etc. However, many questions still surround BUD's usefulness if taken after a virus has already infected airway tissue. OBJECTIVE: The aim of this study was to investigate the inhibitory effects of BUD on inflammatory cytokines induced by viral infection. Methods: Normal human bronchial epithelial (NHBE) cells were stimulated with poly I:C or infected with human rhinovirus-16 (HRV16) and BUD was added after the initial stimulation. Expression of both thymic stromal lymphopoietin (TSLP) and CCL26/eotaxin-3 was quantified by real-time RT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Knockdown study was performed. Results: Pre-or post-incubation with BUD inhibited both poly I:C- and HRV16-induced mRNAs and proteins of both thymic stromal lymphopoietin (TSLP) and CCL26 with significance. Knockdown of the glucocorticoid receptor diminished these effects of BUD. Under the same conditions of BUD's experiment, post-incubation with neither fluticasone propionate nor dexamethasone suppressed expression of both TSLP and CCL26, which induced by poly I:C. CONCLUSION: Post-addition of BUD inhibited the virus-induced TSLP and CCL26 from the airway epithelial cells. These results suggest that inhalation of BUD after viral infection has beneficial effects on asthma. CONCLUSION: Late addition of BUD may benefit among patient with viral infection and type 2 allergic airway disease such as asthma.

Blockade of EGFR Activation Promotes TNF-Induced Lung Epithelial Cell Apoptosis and Pulmonary Injury.

Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis factor (TNF) has been reported to transactivate EGFR in pulmonary epithelial cells. Hence, we aimed to test the hypothesis that EGFR tyrosine kinase activity regulates TNF-mediated bronchial epithelial cell survival, and that inhibition of EGFR activity increases TNF-induced lung epithelial cell apoptosis. We used surfactant protein C (SPC)-TNF transgenic (tg) mice which overexpress TNF in the lungs. In this model, gefitinib, an EGFR-TKI, enhanced lung epithelial cell apoptosis and lymphocytic inflammation, indicating that EGFR tyrosine kinase prevents TNF-induced lung injury. Furthermore, IL-17A was significantly upregulated by gefitinib in SPC-TNF tg mice and p38MAPK activation was observed, indicative of a pathway involved in lung epithelial cell apoptosis. Moreover, in lung epithelial cells, BEAS-2B, TNF stimulated EGFR transactivation via the TNF-α-converting enzyme in a manner that requires heparin binding (HB)-EGF and transforming growth factor (TGF)-α. These novel findings have significant implications in understanding the role of EGFR in maintaining human bronchial epithelial cell homeostasis and in NSCLC treatment.

Receptor Tyrosine Kinase-Targeted Cancer Therapy.

In the past two decades, several molecular targeted inhibitors have been developed and evaluated clinically to improve the survival of patients with cancer. Molecular targeted inhibitors inhibit the activities of pathogenic tyrosine kinases. Particularly, aberrant receptor tyrosine kinase (RTK) activation is a potential therapeutic target. An increased understanding of genetics, cellular biology and structural biology has led to the development of numerous important therapeutics. Pathogenic RTK mutations, deletions, translocations and amplification/over-expressions have been identified and are currently being examined for their roles in cancers. Therapies targeting RTKs are categorized as small-molecule inhibitors and monoclonal antibodies. Studies are underway to explore abnormalities in 20 types of RTK subfamilies in patients with cancer or other diseases. In this review, we describe representative RTKs important for developing cancer therapeutics and predicting or evaluated resistance mechanisms.

Molecular-Targeted Therapies for Epidermal Growth Factor Receptor and Its Resistance Mechanisms.

Cancer therapies targeting epidermal growth factor receptor (EGFR), such as small-molecule kinase inhibitors and monoclonal antibodies, have been developed as standard therapies for several cancers, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, breast cancer, and squamous cell carcinoma of the head and neck. Although these therapies can significantly prolong progression-free survival, curative effects are not often achieved because of intrinsic and/or acquired resistance. The resistance mechanisms to EGFR-targeted therapies can be categorized as resistant gene mutations, activation of alternative pathways, phenotypic transformation, and resistance to apoptotic cell death. Analysis of the processes that modulate EGFR signal transduction by EGFR-targeted inhibitors, such as tyrosine kinase inhibitors and monoclonal antibodies, has revealed new therapeutic opportunities and has elucidated novel mechanisms contributing to the discovery of more effective anticancer treatments. In this review, we discuss the roles of EGFR in cancer development, therapeutic strategies for targeting EGFR, and resistance mechanisms to EGFR-targeted therapies, with a focus on cancer therapies for individual patients.

Relationship of circulating tumor cells to the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer.

The aim of this study was to investigate the relationship of the number of circulating tumor cells (CTCs) with the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We prospectively evaluated CTCs in the peripheral blood of patients with previously untreated metastatic NSCLC. From May 2008 through August 2010, 33 patients (23 men and 10 women; median age, 64 years; range, 46-74 years) were enrolled. All patients received combination chemotherapy with gemcitabine and carboplatin. The CTCs were captured from samples of peripheral blood with a semiautomated system using an antibody against epithelial cell adhesion molecule. Blood samples with one or more CTC per 7.5 ml were defined as positive. Of total 33 patients, 12 (36.4%) had positive CTCs and 5 (15.2%) had five or more CTCs before chemotherapy. There were no differences in response rates to cytotoxic chemotherapy between CTC-positive patients and CTC-negative patients. On the other hand, the rate of progressive disease in cytotoxic chemotherapy was significantly higher in CTC-positive patients (66.7%) than in CTC-negative patients (23.8%, p = 0.02). In conclusion, the number of CTCs could be a useful predictive factor for the effectiveness of cytotoxic chemotherapy in patients with metastatic NSCLC.

[The mechanisms of resistance to EGFR-TKIs and challenges to overcome resistance in EGFR mutant non-small cell lung cancer].

Somatic activating mutations in the epidermal growth factor receptor (EGFR) gene were first identified in 2004 from tumor tissues of non-small cell lung cancer (NSCLC) patients and pulmonary adenocarcinoma cell lines. Although pulmonary adenocarcinoma patients harboring EGFR mutations have increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, the primary and acquired resistant cases remain major clinical problems. Therapeutic strategies for such oncogene-driven carcinomas were intensively investigated at both the clinical and preclinical levels. In this review, we focused on one particular molecularly-defined subset of NSCLC that harbors activating mutations in the EGFR gene. We summarized the rational dissection of the mechanisms of drug sensitivity and resistance to EGFR-TKIs, and the promising molecular-centric strategies for further improving the outcomes of NSCLC patients with EGFR activating mutations.

Diverse Mechanisms of Resistance against Osimertinib, a Third-Generation EGFR-TKI, in Lung Adenocarcinoma Cells with an EGFR-Activating Mutation.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is used as a first-line treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the mechanisms underlying its anticancer activity, particularly the subsequent development of acquired resistance, are unclear. Herein, we investigated the mechanisms underlying the development of osimertinib resistance by treating NSCLC PC-9 cells (harboring an EGFR-activating mutation) with osimertinib, thereby developing five resistant cell lines, i.e., AZDR3, AZDR6, AZDR9, AZDR11, and AZDR14. The amplification of wild-type EGFR in AZDR3 cells and wild-type EGFR and KRAS in AZDR6 cells was also studied. AZDR3 cells showed dependence on EGFR signaling, in addition to afatinib sensitivity. AZDR9 cells harboring KRASG13D showed sensitivity to MEK inhibitors. Furthermore, combination treatment with EGFR and IGF1R inhibitors resulted in attenuated cell proliferation and enhanced apoptosis. In AZDR11 cells, increased Bim expression could not induce apoptosis, but Bid cleavage was found to be essential for the same. A SHP2/T507K mutation was also identified in AZDR14 cells, and, when associated with GAB1, SHP2 could activate ERK1/2, whereas a SHP2 inhibitor, TNO155, disrupted this association, thereby inhibiting GAB1 activation. Thus, diverse osimertinib resistance mechanisms were identified, providing insights for developing novel therapeutic strategies for NSCLC.

Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer.

Homeostasis is achieved by balancing cell survival and death. In cancer cells, especially those carrying driver mutations, the processes and signals that promote apoptosis are inhibited, facilitating the survival and proliferation of these dysregulated cells. Apoptosis induction is an important mechanism underlying the therapeutic efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC). However, the mechanisms by which EGFR-TKIs induce apoptosis have not been fully elucidated. A deeper understanding of the apoptotic pathways induced by EGFR-TKIs is essential for the developing novel strategies to overcome resistance to EGFR-TKIs or to enhance the initial efficacy through therapeutic synergistic combinations. Recently, therapeutic strategies targeting apoptosis have been developed for cancer. Here, we review the state of knowledge on EGFR-TKI-induced apoptotic pathways and discuss the therapeutic strategies for enhancing EGFR-TKI efficiency. We highlight the great progress achieved with third-generation EGFR-TKIs. In particular, combination therapies of EGFR-TKIs with anti-vascular endothelial growth factor/receptor inhibitors or chemotherapy have emerged as promising therapeutic strategies for patients with EGFR-mutated NSCLC. Nevertheless, further breakthroughs are needed to yield an appropriate standard care for patients with EGFR-mutated NSCLC, which requires gaining a deeper understanding of cancer cell dynamics in response to EGFR-TKIs.

Comparative Efficacy and Safety of Immunotherapeutic Regimens with PD-1/PD-L1 Inhibitors for Previously Untreated Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis.

Improving therapeutic strategies for extensive-stage small cell lung cancer (ES-SCLC) remains a challenge. To date, no reports have directly compared the efficacy and safety of immune checkpoint inhibitors plus platinum-etoposide (ICIs+EP) with platinum-irinotecan (IP) or directly compared different ICIs+EP for previously untreated ES-SCLC. This study used a Bayesian approach for network meta-analysis to compare efficacy and safety between ICIs+EP and IP and between each pair of three ICIs+EP. The six treatment arms were: pembrolizumab plus platinum-etoposide (Pem+EP), durvalumab plus platinum-etoposide (Dur+EP), atezolizumab plus platinum-etoposide (Atz+EP), platinum-amrubicin (AP), IP, and platinum-etoposide (EP). No significant differences in overall survival were observed between ICIs+EP and IP and between each pair of three ICIs+EP. The incidence of ≥grade 3 adverse events (G3-AEs) was significantly higher in ICIs+EP than IP, whereas no significant difference was found in G3-AEs between each pair of three ICIs+EP. The incidence of ≥grade 3 neutropenia and thrombocytopenia was significantly higher in ICIs+EP than IP, whereas the incidence of ≥grade 3 diarrhea was significantly lower in ICIs+EP than IP. These findings will help clinicians better select treatment strategies for ES-SCLC.

Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK-Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non-Asian Patients: A Systematic Review and Network Meta-Analysis.

To date, there have been no head-to-head randomized controlled trials (RCTs) comparing the safety and efficacy of lorlatinib and alectinib in anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) ALK-inhibitor‒naïve advanced non-small cell lung cancer (NSCLC). We performed a network meta-analysis comparing six treatment arms (lorlatinib, brigatinib, alectinib, ceritinib, crizotinib, and platinum-based chemotherapy) in overall participants and in Asian and non-Asian subgroups. Primary endpoints were progression-free survival (PFS), overall survival (OS), and grade 3 or higher adverse events (G3-AEs). There were no significant differences between lorlatinib and alectinib in overall participants for both PFS (hazard ratio [HR], 0.742; 95% credible interval [CrI], 0.466-1.180) and OS (HR, 1.180; 95% CrI, 0.590-2.354). In the Asian subgroup, there were no significant differences in PFS between lorlatinib and alectinib (HR, 1.423; 95% CrI, 0.748-2.708); however, in the non-Asian subgroup, PFS was significantly better with lorlatinib than with alectinib (HR, 0.388; 95% CrI, 0.195-0.769). The incidence of G3-AEs in overall participants was significantly higher with lorlatinib than with alectinib (risk ratio, 1.918; 95% CrI, 1.486-2.475). These results provide valuable information regarding the safety and efficacy of lorlatinib in ALK-p ALK-inhibitor‒naïve advanced NSCLC. Larger head-to-head RCTs are needed to validate the study results.

The UGT1A1*28 genotype and the toxicity of low-dose irinotecan in patients with advanced lung cancer.

The association between the UGT1A1*28 genotype and the severe toxicity of low-dose irinotecan has been controversial, and few studies have examined this association in patients with lung cancer. The aim of this study was to assess the association between the UGT1A1*28 genotype and the severe toxicity of low-dose irinotecan in Japanese patients with lung cancer. From December 2005 through July 2008, 53 Japanese patients with advanced lung cancer who underwent chemotherapy that included low-dose irinotecan (50 or 60 mg/m2) as a single agent or in combination chemotherapy were retrospectively analyzed. Genomic DNA was extracted from peripheral blood. Genotypes for the UGT1A1*28 were denoted as wild-type for 6/6, heterozygous for 6/7, or homozygous for 7/7 depending on the number of TA repeats found in each allele. Of the 53 patients, 42 (79.2%) were wild-type, 9 (17.0%) were heterozygous, and 2 (3.7%) were homozygous for the UGT1A1*28 genotype. The UGT1A1*28 genotype was not associated with grade 3 or 4 neutropenia, thrombocytopia, diarrhea, or febrile neutropenia. The frequency of dose reduction of irinotecan did not differ between wild-type and heterozygous or homozygous for the UGT1A1*28 genotype. In addition, there were no significant differences in response rates and survival between wild-type and heterozygous or homozygous for the UGT1A1*28 genotype. In conclusion, the UGT1A1*28 genotype did not predict the severe toxicity of low-dose irinotecan in patients with lung cancer. Therefore, low-dose irinotecan could be administered without reducing starting dose in patients with UGT1A1*28 genotype.

[Chemotherapy-induced myelosuppression and treatment efficacy in limited-stage disease small cell lung cancer].

We examined the association between chemotherapy-induced myelosuppression and prognosis in limited-stage disease small cell lung cancer (LD SCLC). We retrospectively analyzed 76 patients with LD SCLC who received combination cisplatin or carboplatin of etoposide or irinotecan. Patients were categorized into two groups (grade 0 to 2 or grade 3 to 4) according to the worst neutropenia, anemia, or thrombocytopenia during first-line chemotherapy and were analyzed for overall survival (OS) and time to progression (TTP). From univariate analysis, OS was significantly better in patients who developed grade 0 to 2 anemia or thrombocytopenia than those who developed grade 3 to 4. In addition, performance status, neuron-specific enolase (NSE), and pro-gastrin-releasing protein were identified as prognostic factors. By multi-variate analysis, NSE was an independent prognostic factor for OS. There were no independent prognostic factors for TTP. Myelosuppression during chemotherapy is not a prognostic factor in LD SCLC. Our results show doses of platinum doublet chemotherapy were adequate in patients with LD SCLC.

Nivolumab plus Ipilimumab versus Existing Immunotherapies in Patients with PD-L1-Positive Advanced Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis.

No head-to-head trials have compared the efficacy and safety of nivolumab (Niv) plus ipilimumab (Ipi) combination therapy (Niv+Ipi) and existing regimens with immunotherapies approved as first-line treatment in patients with programmed cell death ligand 1 (PD-L1)-positive previously untreated advanced non-small cell lung cancer (NSCLC). We conducted a network meta-analysis of four relevant Phase Ⅲ trials to compare the efficacy and safety of Niv+Ipi, pembrolizumab (Pem) plus platinum-based chemotherapy (PBC) (Pem+PBC), Pem, Niv, or PBC using Bayesian analysis. The primary efficacy endpoint was progression-free survival (PFS) in patients with advanced NSCLC with PD-L1 expression ≥1%. The primary safety endpoint was the incidence of Grade 3-5 drug-related adverse events (G3-5AEs). Efficacy and safety were ranked using surface under the cumulative ranking curve (SUCRA). With regard to PFS, Niv+Ipi was inferior to Pem+PBC, and superior to Pem, Niv, or PBC alone. SUCRA ranking showed Pem+PBC had the highest efficacy for PFS, followed by Niv+Ipi, Niv, PBC, and Pem. The safety outcome analysis revealed Niv+Ipi was generally well tolerated compared to existing immunotherapy regimens. These results provide clinical information regarding the efficacy and safety of Niv+Ipi and indicate the possibility of the Niv+Ipi combination as a new therapeutic option in PD-L1-positive advanced NSCLC.

Comparative Efficacy and Safety of Anti-PD-1/PD-L1 Immune Checkpoint Inhibitors for Refractory or Relapsed Advanced Non-Small-Cell Lung Cancer-A Systematic Review and Network Meta-Analysis.

The efficacy and safety of immune checkpoint inhibitors (ICIs) in refractory or relapsed advanced non-small-cell lung cancer (NSCLC) have not yet been compared with those of ramucirumab (Ram) plus docetaxel (Doc). Furthermore, comprehensive comparisons between ICIs have not been conducted to date. In the current study, a Bayesian network meta-analysis of related phase III clinical trials was performed to compare the efficacy and safety of Ram+Doc, Niv, Atz, and Doc treatments in patient groups lacking the PD-L1 constraint. Surface under the cumulative ranking area (SUCRA) revealed that the overall survival (OS) of patients treated with Niv was the highest, followed by Atz, Ram+Doc, and Doc. Regarding grades 3-5 treatment-related adverse events (G3-5AEs), the use of Niv was ranked the safest, followed by Atz, Doc, and Ram+Doc. Significant differences in OS were observed between Niv and Ram+Doc, while significant differences in G3-5AEs were observed between Ram+Doc and Niv or Atz. In the PD-L1 positive (≥1%) patient subgroup, Pem (10 mg/kg) ranked the highest in efficacy for OS, followed by Niv, Pem (2 mg/kg), Atz, and Doc. These findings may expectedly provide oncologists with useful insights into therapeutic selection for refractory or relapsed advanced NSCLC.

Brigatinib and Alectinib for ALK Rearrangement-Positive Advanced Non-Small Cell Lung Cancer With or Without Central Nervous System Metastasis: A Systematic Review and Network Meta-Analysis.

To date, no head-to-head trials have compared the efficacy of brigatinib and alectinib against anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p), ALK-inhibitor-naïve, advanced non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis. We conducted an indirect treatment comparison (ITC) between brigatinib and alectinib, with crizotinib as a common comparator, using a Bayesian model with non-informative prior distribution and assessed the between-study heterogeneity of the studies. The primary efficacy endpoint was progression-free survival (PFS), and efficacy was ranked using the surface under the cumulative ranking (SUCRA) curve values. ITC analysis showed that there were no significant differences in PFS between the brigatinib and alectinib arms. However, the SUCRA values revealed that alectinib ranked the highest by efficacy in the overall patient population, whereas brigatinib ranked the highest by efficacy in the CNS metastasis sub-group. Although there were no significant differences in the incidence of G3-5 adverse events between the brigatinib and alectinib arms in the overall patient population, the data were deemed insufficient for the CNS metastasis sub-group analysis. This study provides critical information to clinicians regarding the efficacy of brigatinib for ALK-p, ALK-inhibitor-naïve, advanced NSCLC patients, with and without CNS metastasis. Larger randomized, controlled trials are warranted to confirm our results.

Correlation of Arterial CO2 and Respiratory Impedance Values among Subjects with COPD.

Chronic obstructive pulmonary disease (COPD) is a respiratory illness characterized by airflow limitation and chronic respiratory symptoms with a global prevalence estimated to be more than 10% in 2010 and still on the rise. Furthermore, hypercapnic subject COPD leads to an increased risk of mortality, morbidity, and poor QoL (quality of life) than normocapnic subjects. Series of studies showed the usefulness of the forced oscillation technique (FOT) to measure small airway closure. Traditional findings suggested that hypercapnia may not be the main treating targets, but recent findings suggested that blood stream CO2 may lead to a worse outcome. This study aimed to seek the relationship between CO2 and small airway closure by using FOT. Subjects with COPD (n = 124; hypercapnia 22 and normocapnia 102) were analyzed for all pulmonary function values, FOT values, and arterial blood gas analysis. Student's t-test, Spearman rank correlation, and multi linear regression analysis were used to analyze the data. COPD subjects with hypercapnia showed a significant increase in R5, R20, Fres, and ALX values, and a greater decrease in X5 value than normocapnic patients. Also, multiple linear regression analysis showed R5 was associated with hypercapnia. Hypercapnia may account for airway closure among subjects with COPD and this result suggests treating hypercapnia may lead to better outcomes for such a subject group.

Patient willingness to undergo chemotherapy and thoracic radiotherapy for locally advanced non-small cell lung cancer.

OBJECTIVES: To determine how Japanese patients with lung cancer weigh the chance of cure and potential survival against the potential toxicity of different treatment strategies for locally advanced non-small cell lung cancer (NSCLC). METHODS: We used a questionnaire describing a hypothetical situation involving locally advanced NSCLC. Seventy-three patients with lung cancer who had received chemotherapy and a control group of 120 patients without cancer were asked to state the minimal benefit that would make two hypothetical treatments acceptable. RESULTS: Patients with lung cancer were significantly more likely than were patients without cancer to accept either intensive or less-intensive chemoradiotherapy for a potentially small benefit for 'chance of cure' and 'response but not cure'. The percentages of patients who would accept intensive or less-intensive chemoradiotherapy to prolong survival did not differ significantly between the two groups. When the chance of cure was 20%, 56 and 64% of patients with lung cancer were willing to receive intensive and less-intensive chemoradiotherapy, respectively. If their lives were prolonged by 6 months, 20 and 30% of patients with lung cancer would choose to receive intensive and less-intensive chemoradiotherapy, respectively. The chance of cure and the survival advantage that patients require for accepting chemoradiotherapy varied widely. No factors were associated with the choice of chemoradiotherapy in patients with lung cancer. CONCLUSIONS: Physicians must consider the substantial range of attitudes to chemoradiotherapy among patients when selecting treatment and give patients opportunities to be included in the treatment-selection process.

Induction chemoradiotherapy followed by surgery for locally advanced non-small cell lung cancer.

We examined the efficacy and toxicity of a divided schedule of cisplatin and vinorelbine with concurrent radiotherapy followed by surgery in patients with locally advanced non-small cell lung cancer (NSCLC). Patients with clinical stage IIIA or IIIB NSCLC were eligible if they had a performance status of 0 or 1, were 75 years or younger, and had adequate organ function. Patients were treated with cisplatin (40 mg/m2) and vinorelbine (20 mg/m2) on days 1 and 8 every 3 weeks. Thoracic radiotherapy (2 Gy per fraction; total dose, 40 Gy) was given concurrently. Surgical resection was performed after induction therapy had been completed. If disease was considered clinically inoperable after induction therapy, patients received 2 additional cycles of the chemotherapy and 20 Gy of additional radiotherapy. Twenty-three patients (20 men and 3 women; median age, 63 years; age range, 45-72 years) were enrolled. The overall response rate was 78.3%. Although grade 3-4 toxicities included neutropenia in 95.7% of patients and anemia in 39.1%, no grade 3-4 radiation pneumonitis or esophagitis occurred. Thirteen patients (56.5%) underwent thoracotomy and complete resection. There were no treatment-related deaths. The median survival time was 36 months (range, 4-78 months), the 2-year survival rate was 74%, and the median time to disease progression was 15 months (range, 2-59 months). This trimodality therapy is effective and well tolerated and is an acceptable therapeutic option for patients with locally advanced NSCLC.