A phase II feasibility study of carboplatin and nab-paclitaxel for advanced non-small cell lung cancer patients with interstitial lung disease (YLOG0114).

BACKGROUND: A standard treatment regimen for advanced non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) has not been established since most clinical trials exclude such patients because of the high risk of acute exacerbation of ILD. This study aimed to prospectively investigate the efficacy and safety of carboplatin and nab-paclitaxel as a first-line regimen for NSCLC patients with ILD. METHODS: The enrolled patients had treatment-naïve advanced NSCLC with ILD. The patients received 4-6 cycles of carboplatin (area under the curve = 5) on day 1 and nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 every 4 weeks. The primary endpoint was the completion rate of four or more cycles. Secondary endpoints included toxicity, overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-five patients were enrolled in this study. Nine patients had adenocarcinoma, 11 had squamous cell carcinoma, one had large cell carcinoma, and four had NSCLC, not otherwise specified. The completion rate of ≥4 cycles was 76% (95% confidence interval: 56.2%-88.8%), which met the primary endpoint. The ORR and DCR were 44% and 88%, respectively. The median PFS and OS were 5.8 months and 15.8 months, respectively. Three patients experienced grade ≥2 pneumonitis, and one patient met the acute exacerbation criteria. CONCLUSION: The 4-week modified regimen of carboplatin and nab-paclitaxel showed tolerable toxicity with favorable efficacy in NSCLC patients with ILD. This regimen may be an effective treatment option for patients in real clinical settings.

Non-inferior clinical outcomes of immune checkpoint inhibitors in non-small cell lung cancer patients with interstitial lung disease.

OBJECTIVES: The efficacy of immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) patients with pre-existing interstitial lung disease (ILD) is unclear. MATERIALS AND METHODS: Retrospective medical data from advanced or recurrent NSCLC patients who were treated with nivolumab or pembrolizumab at ten institutions in Japan between January 2016 and September 2018 were analyzed. Eligible patients were divided into two groups according to the presence of pre-existing ILD. RESULTS: A total of 461 NSCLC patients were enrolled, 412 without ILD (Non-ILD group) and 49 with ILD (ILD group). The response rate (RR) and disease control rate (DCR) of the ILD group were not inferior to those of the Non-ILD group [RR: 49.0 % (24/49) vs. 30.1 % (124/412), P < 0.01 and DCR: 69.4 % (34/49) vs. 51.2 % (211/412), P = 0.016, respectively]. Non-inferior outcomes were also observed with respect to progression-free survival (PFS) and overall survival (OS) (median PFS: 5.9 months vs. 3.5 months, P = 0.14 and median OS: 27.8 months vs. 25.2 months, P = 0.74 in the ILD and Non-ILD groups, respectively). Among immune-related adverse effects (irAEs), checkpoint inhibitor pneumonitis (CIP) was more frequently observed among NSCLC patients in the ILD group [30.6 % (15/49) vs. 9.5 % (39/412), P < 0.01]. The frequency of irAEs other than CIP and infusion reactions was not significantly different between the ILD group and the Non-ILD group. CONCLUSION: These results suggest that the clinical outcomes of ICIs are not significantly affected by pre-existing ILD despite the increased frequency of CIP. NSCLC patients with ILD are therefore probable candidates for ICIs.

The utility of ground-glass attenuation score for anticancer treatment-related acute exacerbation of interstitial lung disease among lung cancer patients with interstitial lung disease.

BACKGROUND: Acute exacerbation (AE) of interstitial lung disease (ILD) is a fatal adverse event in the treatment of lung cancer patients with ILD. The value of pre-treatment radiological findings obtained by high-resolution computed tomography for the detection of anticancer treatment-related AE of ILD has not been established. METHODS: Two medical record-based retrospective studies were performed. The chemotherapy cohort included 105 lung cancer patients with ILD who received chemotherapy at Tokyo Medical and Dental University between October 2008 and December 2017. The immune checkpoint inhibitor (ICI) cohort included 48 advanced non-small cell lung cancer patients with ILD treated with ICIs at nine institutions between January 2016 and September 2018. Variables were compared between AE-positive and -negative groups. Candidate variables were analyzed by multivariate logistic regression. A P value < 0.05 was considered statistically significant. RESULTS: Anticancer treatment-related AE of ILD occurred in 12 patients (11.4%) in the chemotherapy cohort and seven patients (14.5%) in the ICI cohort. In the multivariate logistic regression analysis, ground-glass attenuation (GGA) score was the only factor significantly associated with the development of AE of ILD in both cohorts (P = 0.037 and 0.01 in the chemotherapy and ICI cohorts, respectively). CONCLUSION: Evaluation of GGA may help predict anticancer treatment-related AE of ILD.

Treatment of asthma in smokers: A questionnaire survey in Japanese clinical practice.

BACKGROUND: Cigarette smoking in patients with asthma leads to poor symptom control. As patients who are current smokers have been excluded from enrollment in many clinical trials on asthma, there are few reports on the treatment in current smokers with asthma. In this study, we aimed to assess how respiratory physicians manage asthma in current smokers in Japan. METHODS: Respiratory physicians in 16 Japanese hospitals answered a questionnaire on treatment for patients with asthma between December 2014 and February 2015. Medical records were reviewed for 1756 patients with asthma. RESULTS: The mean patient age was 61.1 years, and 62.9% of the patients were female. A total of 102 patients (5.8%) were current smokers, and 546 patients (31.1%) were former smokers. Long-acting muscarinic antagonists (LAMA) were prescribed more frequently for current smokers with asthma than for former smokers and never smokers with asthma (10.8% vs 4.6%, p = 0.01, 10.8% vs 3.8%, p < 0.01). In contrast, macrolides were prescribed more frequently for former smokers and never smokers with asthma than for current smokers with asthma (7.7% vs 1.0%, p = 0.01, 6.4% vs 1.0%, p = 0.03). Triple therapy, i.e., inhaled corticosteroids, long-acting beta agonists, and LAMA concomitantly, was prescribed for current smokers with asthma more frequently than for former smokers and never smokers with asthma (9.8% vs 4.0%, p = 0.01, 9.8% vs 3.3%, p < 0.01). CONCLUSIONS: According to this survey, current smokers with asthma received more intensive therapy, including LAMA, than did former smokers with asthma.

Feasibility study of adjuvant chemotherapy of S-1 and carboplatin for completely resected non-small cell lung cancer.

BACKGROUND: The purpose of this study was to evaluate the feasibility and compliance of adjuvant chemotherapy of S-1 plus carboplatin for patients with completely resected non-small cell lung cancer (NSCLC) of pathological stage IB-IIIB. METHODS: S-1 was given orally at a dose of 80 mg/m²/day for 2 weeks, followed by a 2-week period of no treatment. Carboplatin was given intravenously on day 8 at an area under the curve of 6. This regimen was repeated for four to six 28-day courses. RESULTS: Seventeen patients were enrolled in this study. Fourteen of them completed at least 4 cycles of chemotherapy. Nine patients had grade 2 and three patients had grade 3 thrombocytopenia, respectively. Severe nonhematologic toxicities were uncommon. Treatment was delayed in a few patients because of prolonged thrombocytopenia. CONCLUSION: We concluded that the regimen was feasible and tolerable for patients with completely resected NSCLC as adjuvant chemotherapy.

[Clinical features of reversed halo sign in cryptogenic organizing pneumonia].

Reversed halo sign (RHS) is often seen in computed tomography (CT) scans of cryptogenic organizing pneumonia (COP). To investigate its clinical features, we retrospectively reviewed 30 cases of COP in 13 men and 17 women, whose age range 28 to 73, with a mean of 58.4 years. All diagnoses were made with transbronchial lung biopsy (TBLB), but it took an average of 24.8 days from the first visit until the diagnosis of COP. RHS was seen in 7 cases (23%) and multiple RHSs were seen in 3 cases. We treated 5 cases (71%) with steroids. Their CT images showed parenchymal abnormalities which started as nodular lesions, then enlarged, and then the central lesion changed into ground-glass opacities, until finally, RHS was formed. The presence of RHS does not necessarily indicate a marked difference in the clinical course of COP. In conclusion, in the present series RHS was a phase of the clinical course of COP, and was useful to diagnose COP.

[A case of extranodal NK/T-cell lymphoma, nasal type, with skin ulceration and multiple nodules in the lung].

We report a rare case of extranodal NK/T-cell lymphoma, nasal type, with skin ulceration and multiple nodules in the lung, and will compare this case with others in the literature. A 54-year-old man was troubled with flare and swelling of his right arm for one month. He was referred to our hospital because of subcutaneous nodules with ulceration on the right arm, fever, and general fatigue. Chest radiograph revealed multiple nodular shadows in both lungs. The patient was admitted for further evaluation. Chest computed tomography revealed multiple nodules in both lungs with ground-glass opacities around some of them. Some nodules seemed to be clustered in the right lower lobe. Biopsy specimens of subcutaneous nodules and transbronchial biopsy specimens of pulmonary tissue demonstrated only extensive necrosis. A VATS lung biopsy from the right S9 was then taken. Pathological and immunohistological findings suggested a diagnosis of extranodal NK/T-cell lymphoma, nasal type (WHO classification), stage IVB. The patient was transferred to the department of hematology in another hospital for systemic chemotherapy, but died 2 months later.

[A case of hypersensitivity pneumonitis resulting from inhalation of Aspergillus niger in a greenhouse worker who raised roses].

A 57-year-old woman was referred because of exertional dyspnea, fever, and cough in June 2006. She had been employed to culture roses in greenhouses since 1991 and had developed a cough during the summer from 2003. Chest CT scan revealed diffuse centrilobular micronodules. Transbronchial lung biopsy specimens demonstrated alveolitis with lymphocytes and non-necrotizing epithelioid cell granulomas. After admission, both the patient's symptoms and laboratory data improved without medication. However, upon her return to work in the greenhouse, cough and exertional dyspnea reappeared. Aspergillus niger was detected in the greenhouse. Her serum was assayed for precipitating antibodies against various antigens, and precipitating antibodies against Aspergillus fumigatus, Aspergillus flavus, Aspergillus glaucus, and Aspergillus niger were demonstrated. In a double immunodiffusion test, cross-reactivity between Aspergillus niger and other Aspergillus species was indicated. Consequently, she was diagnosed as having hypersensitivity pneumonitis resulting from the inhalation of Aspergillus niger.

[A case of sarcoidosis with pleural involvement but with no mediastinal or hilar lymph node enlargement].

A 66-year-old woman was referred to our hospital because of right chest pain on inspiration. Chest X-ray film revealed diffuse opacities, predominantly in the lower lung field, and right pleural thickening. Serum ACE and lysozyme levels were elevated. Chest CT revealed diffuse ground-glass opacity, centrilobular granular nodules, bronchovascular bundle irregular thickening and right pleural irregular thickening over the right inferior lobe, but bilateral hilar lymph node enlargement was not present. Bronchoalveolar lavage (BAL) fluid demonstrated increased numbers of total cells and CD4 T-helper lymphocytes. The transbronchial lung biopsy specimen revealed non-caseating epithelioid cell granulomas. From these findings, we established a diagnosis of type III sarcoidosis with pleural involvement. The patient has been observed without treatment, and 10 months later the lung involvement and pleural thickening have disappeared.

[Randomized phase II study of carboplatin/paclitaxel followed by gemcitabine versus carboplatin/gemcitabine followed by docetaxel in patients with advanced nonsmall cell lung cancer].

PURPOSE: To evaluate the chemotherapeutic regimens suitable for the outpatient settings, we conducted a randomized phase II study of carboplatin/paclitaxel followed by gemcitabine versus carboplatin/gemcitabine followed by docetaxel. METHODS: Group CP(n=25): carboplatin AUC 6.0 day 1 and paclitaxel 70 mg/m2 day 1, 8, 15 every 4 weeks followed by gemcitabine 1.0 g/m2 day 1, 8, 15 every 4 weeks; group CG(n=26): carboplatin AUC 2.0 and gemcitabine 0.8 g/m2 day 1, 8 every 3 weeks followed by docetaxel 60 mg/m2 day 1, 8 every 3 weeks. RESULTS: The response rate of the first line therapy was 18.0% in group CP and 21.7% in group CG and that of the second line therapy was 10.0% and 14.3%, respectively. Time to progression of the first line therapy was 4.0 months in group CP and 4.3 months in group CG, that of the second line therapy was 2.1 months and 2.8 months, respectively. The median survival time was 10.9 months in group CP and 10.3 months in group CG. No statistically significant differences were documented in the response rate, time to progression, and overall survival between these two groups. Severe hematologic toxicity was rare in both groups and no symptomatic peripheral neuropathy was documented in carboplatin/paclitaxel therapy. CONCLUSION: Carboplatin /paclitaxel followed by gemcitabine and carboplatin/gemcitabine followed by docetaxel were well tolerated and equal in efficacy. Both regimens in this study seemed to be suitable for the outpatient settings because of their mild hematologic toxicity and peripheral neuropathy.