Weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer complicated by idiopathic interstitial pneumonias: a single-arm phase II study.

BACKGROUND: Idiopathic interstitial pneumonias (IIPs) are associated with increased risk of lung cancer. In Japan, acute exaberation of IIPs induced by anticancer treatment is a critical issue. For this reason, there is limited available evidence regarding the optimal treatment approach for lung cancer patients complicated with IIPs. Our previous prospective pilot study demonstrated the safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer (NSCLC) with IIPs. The current study was conducted to confirm the results of the same combination therapy used in a larger patient population. METHODS: Chemotherapy-naïve patients with advanced stage or post-operative recurrent NSCLC patients complicated by IIPs were enrolled. Patients received paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (AUC 5.0) once every 4 weeks. RESULTS: Thirty-three of 35 enrolled patients were evaluable for analysis and received a median of four treatment cycles (range 1-6). Four patients (12.1%; 95% confidence interval 3.4-28.2%) had acute exacerbation (AEx)-related IIPs to the study treatment. However, no fatalities due to AEx were observed. The overall response was 69.7%. The median progression-free survival, median survival time, and 1-year survival were 6.3 months, 19.8 months, and 55.4%, respectively. CONCLUSIONS: The efficacy of carboplatin plus weekly paclitaxel treatment for advanced NSCLC patients with IIPs was comparable to that of conventional chemotherapy in advanced NSCLC patients without IIPs. Moreover, the primary endpoint was set to the frequency of treatment-related acute exacerbation, and the primary endpoint was met. These results suggest that patients with advanced NSCLC complicated by IIPs may benefit from this combination chemotherapy.

Carboplatin and weekly paclitaxel in combination with bevacizumab for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias: A feasibility study.

BACKGROUND: Idiopathic interstitial pneumonias are an independent risk factor of lung cancer, and a chemotherapy-induced acute exacerbation is the most common lethal complication in Japanese patients. The safety and efficacy of carboplatin and weekly paclitaxel for the treatment of non-small cell lung cancer with idiopathic interstitial pneumonias has been previously reported in prospective studies. However, carboplatin + paclitaxel with bevacizumab is currently the standard therapy. We conducted a multicenter, phase II study to confirm the safety and efficacy of carboplatin + weekly paclitaxel + bevacizumab for the treatment of patients with lung cancer complicated by idiopathic interstitial pneumonias. METHODS: Chemotherapy-naïve patients with advanced-stage or patients with post-operative recurrent non-squamous non-small cell lung cancer complicated by idiopathic interstitial pneumonias were enrolled. Patients received carboplatin (area under the curve: 5.0) and bevacizumab (15 mg/kg) on day 1 and paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 4-week cycle. RESULTS: Seventeen patients less than the predetermined number were enrolled and received a median of four treatment cycles (range: 1-6). One patient (5.9%; 95% confidence interval: 0.1-28.7%) had acute exacerbation of interstitial pneumonia related to the study treatment which improved after corticosteroid treatment. The overall response rate was 52.9%. The median progression-free survival, median survival time, and 1-year survival were 5.7 months, 12.9 months, and 52.9%, respectively. CONCLUSION: The addition of bevacizumab to carboplatin and weekly paclitaxel might be safe and effective for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000008189.

Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive disease with a poor prognosis. Although most patients initially respond to topoisomerase inhibitors, resistance rapidly emerges. The aim, therefore, is to overcome resistance to topoisomerase I (irinotecan) or II (etoposide) inhibitors in SCLCs. METHODS: To identify key factors in the chemoresistance of SCLCs, we established four cell lines resistant to etoposide or an active metabolite of irinotecan, SN-38, from SCLC cell lines and evaluated RNA profiles using parental and newly established cell lines. RESULTS: We found that the drug efflux protein, ATP-binding cassette sub-family B member 1 (ABCB1), was associated with resistance to etoposide, and ATP-binding cassette sub-family G member 2 (ABCG2) was associated with resistance to SN-38 by RNA sequencing. The inhibition of ABCB1 or ABCG2 in each resistant cell line induced synergistic apoptotic activity and promoted drug sensitivity in resistant SCLC cells. The ABC transporter inhibitors, elacridar and tariquidar, restored sensitivity to etoposide or SN-38 in in vitro and in vivo studies, and promoted apoptotic activity and G2-M arrest in resistant SCLC cells. CONCLUSIONS: ABC transporter inhibitors may be a promising therapeutic strategy for the purpose of overcoming resistance to topoisomerase inhibitors in patients with SCLC.

Carboplatin plus nanoparticle albumin-bound paclitaxel for the treatment of thymic carcinoma.

Thymic carcinoma is a relatively rare type of malignant tumor. The present retrospective study evaluated the efficacy and safety of carboplatin plus nanoparticle albumin-bound paclitaxel for the treatment of advanced thymic carcinoma. The study included data from 12 patients with advanced thymic carcinoma treated in the Nippon Medical School Hospital (Tokyo, Japan). Response to treatment, patient survival and treatment safety were assessed. The objective response rate was 66.7% (8/12 patients). Disease control was achieved in 11 patients (91.7%). At the median follow-up time of 27.6 months (range, 6.2-75.1 months), the median progression-free survival and median first-line overall survival times were 16.7 months [95% confidence interval (CI), 13.2-37.7] and 14.3 months (95% CI, 4.7-54.6), respectively. There was no occurrence of febrile neutropenia or treatment-related death. The results of the present study showed that carboplatin plus nanoparticle albumin-bound paclitaxel was effective and safe. Therefore, it is a promising chemotherapy regimen for the treatment of advanced thymic carcinoma.

CADM1 and SPC25 Gene Mutations in Lung Cancer Patients With Idiopathic Pulmonary Fibrosis.

INTRODUCTION: To investigate the genomic profiles of patients with lung cancer with idiopathic pulmonary fibrosis (IPF-LC), mechanism of carcinogenesis, and potential therapeutic targets. METHODS: We analyzed 29 matched, surgically resected, cancerous and noncancerous lung tissues (19 IPF-LC and 10 non-IPF-LC) by whole-exome sequencing and bioinformatics analysis and established a medical-engineering collaboration with the Department of Engineering of the Tokyo University of Science. RESULTS: In IPF-LC, CADM1 and SPC25 were mutated at a frequency of 47% (9 of 19) and 53% (10 of 19), respectively. Approximately one-third of the IPF-LC cases (7 of 19; 36%) had both mutations. Pathway analysis revealed that these two genes are involved in transforming growth factor-ß1 signaling. CADM1 and SPC25 gene mutations decreased the expression of CADM1 and increased that of SPC25 revealing transforming growth factor-ß1-induced epithelial-to-mesenchymal transition and cell proliferation in lung cancer cells. Furthermore, treatment with paclitaxel and DNMT1 inhibitor suppressed SPC25 expression. CONCLUSIONS: CADM1 and SPC25 gene mutations may be novel diagnostic markers and therapeutic targets for IPF-LC.

Impact of prior antibiotic use on the efficacy of nivolumab for non-small cell lung cancer.

Gut microbiota serves an important role in shaping systemic immune responses. Antibiotics cause changes in the gut microbiota that may influence the efficacy of cancer immunotherapy. In the present study, a retrospective analysis of the data from 90 patients treated with nivolumab for non-small cell lung cancer (NSCLC) was conducted. A total of 13 patients were treated with antibiotics prior to nivolumab therapy. The median progression-free survival time in patients treated with antibiotics was 1.2 months [95% confidence interval (CI), 0.5-5.8], while the time for patients who were not treated with antibiotics was 4.4 months (95% CI, 2.5-7.4). The median overall survival time in patients treated with antibiotics was 8.8 months, while it was not reached in those not treated with antibiotics, respectively. The differences between the survival curves with regard to PFS and OS were statistically significant (P=0.04 and P=0.037, respectively). However, in multivariate analysis, no statistically significant association was indicated between survival and prior antibiotic use, although a certain trend concerning the negative influence of antibiotic use was conveyed.

Statins improve survival in patients previously treated with nivolumab for advanced non-small cell lung cancer: An observational study.

There are a number of suggested predictive factors of nivolumab for non-small cell lung cancer (NSCLC), however, there is not enough evidence to determine a single factor that can predict the efficacy of nivolumab. As the progress of biomarkers for cancer treatment is improving, it has been speculated that certain clinical factors serve an important role when predicting the outcome of chemotherapy. A total of 67 patients treated with nivolumab for NSCLC from 2016-2017 were prospectively investigated. Age, sex, the Eastern Cooperative Oncology Group Performance Status, histology, epidermal growth factor receptor (EGFR) mutation, history of chemotherapy, smoking status, use of statins, use of fibrates, use of dipeptidyl peptidase-4 (DPP-4) inhibitors, and use of metformin were examined as clinical factors. Statistical analyses were performed using the Kaplan-Meier method and Cox regression adjusted for risk factors and the tumor response of 67 patients was assessed. The patients had a median age of 67 years (range, 36-87 years), and 46 males and 21 females were enrolled; performance status 0/1 was 59. Cases were categorized as adenocarcinoma (n=41), squamous cell carcinoma (n=17) and other (n=9). A total of 13 patients (19.4%) had EGFR mutations. These clinical factors were not statistically significant in overall survival (OS). Clinical laboratory findings, complications and use of medical agents including antidiabetes mellitus or lipidemia were also analyzed. Statins exhibited statistical significance for response (P=0.02). Time-to-treatment failure (TTF) in statin-use group was not reached [95% confidence interval (CI): 1.9-not reached] and was 4.0 months (95% CI: 2.0-5.4) in the non-statin group (P=0.039). The median OS in statin-use group was not reached (95% CI: 8.7-not reached) and was 16.5 months (95% CI: 7.5-not reached) in the non-statin group (P=0.058). NSCLC patients previously treated with nivolumab who were administered statins exhibited an increased response rate and longer TTF. This response was not statistically significant in OS.

Severe Pneumonitis with Alveolar Hemorrhage Associated with Herbal Medicines: A Case Report.

We report a case of pneumonitis with alveolar hemorrhage induced by herbal medicines in a 73-year-old woman who was admitted to our hospital because of dyspnea and an abnormal shadow on a chest radiograph. She had received treatment with numerous drugs, including the herbal medicines Seisin-renshi-in, Chotosan, Rikkunshi-to, and Shakuyakukannzo-to. Chest radiography revealed diffuse ground-glass shadows in both lungs, and bronchoalveolar lavage fluid was progressively hemorrhagic. A culture of the fluid showed no evidence of microorganisms. Moreover, there were no findings suggestive of rheumatic disease or vasculitides. On the basis of this evidence, we suspected drug-induced diffuse alveolar hemorrhage. She discontinued all medicines and started treatment with corticosteroids. Her respiratory condition and chest radiographic findings improved. The timing of administration and rechallenge with other drugs suggested that the herbal medicines were the causative drugs. The primary concern was Seisin-renshi-in, because it contains Ougon (skullcap; a known cause of pneumonitis) and because a drug lymphocyte stimulation test was positive for Seisin-renshi-in. This is the first report indicating that Seisin-renshi-in may cause diffuse alveolar hemorrhage. Diffuse alveolar hemorrhage due to herbal medicines is a rare but emergent disorder. Therefore, treating physicians should be aware that it may be caused by herbal medicines, including Seisin-renshi-in.