Publications by authors named "Nobukazu Fujimoto"

87 Publications

Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study.

Lancet Respir Med 2021 Apr 6. Epub 2021 Apr 6.

University of Chicago, Chicago, IL, USA.

Background: Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study.

Methods: The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067.

Findings: Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation.

Interpretation: Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated.

Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
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http://dx.doi.org/10.1016/S2213-2600(20)30515-4DOI Listing
April 2021

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study).

Ther Adv Med Oncol 2021 27;13:1758835921998588. Epub 2021 Feb 27.

Department of Respiratory Medicine, Chugoku Central Hospital, Fukuyama-City, Hiroshima, Japan.

Background: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study.

Methods: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80-120 mg/body, Days 1-14) + cisplatin (60 mg/m, Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate.

Discussion: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab.

Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.
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http://dx.doi.org/10.1177/1758835921998588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917867PMC
February 2021

Catamenial pneumothorax due to heterotopic endometriosis in the pericardium.

BMJ Case Rep 2021 Feb 4;14(2). Epub 2021 Feb 4.

Department of Medical Oncology, Okayama Rosai Hospital, Okayama, Japan

A 46-year-old woman presented with a right pneumothorax at a regular medical examination during menstruation. The pneumothorax resolved without intervention; however, 6 months later, she was referred to our hospital due to chest pain and dyspnoea. A chest X-ray showed grade III pneumothorax and surgery was performed. During surgery, the patient was found to have pleural adhesions around the right upper lung, pores in the diaphragm and a blueberry spot in the pericardium. The margins of the upper lobe and diaphragm were covered with a polyglycolic acid sheet at the operation. Eight days after surgery, she was referred to our hospital again due to massive haemothorax. The reoperation suggested that the aforementioned blueberry spot in the pericardium was the source of bleeding. The spot was resected and shown to be oestrogen and progesterone receptor-positive, providing evidence of heterotopic endometriosis.
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http://dx.doi.org/10.1136/bcr-2020-240335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868189PMC
February 2021

First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.

Lancet 2021 01 21;397(10272):375-386. Epub 2021 Jan 21.

Bichat-Claude Bernard University Hospital, AP-HP, Université de Paris, Paris, France.

Background: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM.

Methods: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m intravenously] plus cisplatin [75 mg/m intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual.

Findings: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression).

Interpretation: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM.

Funding: Bristol Myers Squibb.
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http://dx.doi.org/10.1016/S0140-6736(20)32714-8DOI Listing
January 2021

Novel prospective umbrella-type lung cancer registry study for clarifying clinical practice patterns: CS-Lung-003 study protocol.

Thorac Cancer 2021 03 12;12(5):725-731. Epub 2021 Jan 12.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Introduction: Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice.

Methods: We constructed an umbrella-type lung cancer patient registry (CS-Lung-003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS-Lung-003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017.

Discussion: We successfully launched the umbrella-type CS-Lung-003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment.

Key Points: CS-Lung-003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment.
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http://dx.doi.org/10.1111/1759-7714.13789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919112PMC
March 2021

Retrospective investigation on diagnostic process for benign asbestos pleural effusion (BAPE) using checklist.

J Occup Health 2020 Jan;62(1):e12182

Tohoku Rosai Hospital, Sendai, Japan.

Objectives: In Japan, benign asbestos pleural effusion (BAPE) has been eligible for industrial accident compensation since 2003 as an asbestos-related disease despite the lack of good criteria. We compiled a criteria into a checklist of essential items and for excluding other diseases inducing pleural effusion as a diagnosis process.

Method: Thoracentesis was performed in order to confirm the presence of pleural effusion at the initial diagnosis, and 105 suspected BAPE patients were retrospectively examined. We complied a checklist comprising the following diagnostic items: (a) occupational asbestos exposure; (b) confirmation of exudate of pleural effusion; (c) exclusion of pleural effusion with malignant tumors based on negative results of CEA and hyaluronic acid, and cytology of pleural effusion; (d) exclusion of rheumatic, bacterial, and tuberculous pleuritis; (d) radiological findings for exclusion of malignancies; and (e) histopathological findings based on thoracoscopy that exclude malignancies (when thoracoscopy was not performed, there was confirmation that no malignancies were present during 3-month follow-up observation). Cases that satisfied all items were defined as BAPE.

Results: Among the 105 suspected cases, there were five cases that had no occupational asbestos exposure; six cases in which transudate of on pleural effusion; one case each of rheumatoid pleuritis and tuberculous pleuritis; and five cases of pleural mesothelioma based on chest radiography and histopathological findings within 3 months after initial diagnosis. Therefore, we excluded 18 cases from the 105 candidates and determined 87 cases of BAPE.

Conclusion: We consider that six items described above are suitable for diagnosing BAPE.
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http://dx.doi.org/10.1002/1348-9585.12182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733549PMC
January 2020

Nivolumab for malignant peritoneal mesothelioma.

BMJ Case Rep 2020 Nov 30;13(11). Epub 2020 Nov 30.

Medical Oncology, Okayama Rosai Hospital, Okayama, Japan

Malignant peritoneal mesothelioma (MPeM) is a highly malignant neoplasm of the peritoneum, which carries a poor prognosis. A 70-year-old man, who was employed in the shipbuilding industry and exposed to asbestos for 50 years, was found to have a low-density lesion in the peritoneum around the liver and spleen, associated with multiple mediastinal and parasternal lymphadenopathy. Laparoscopic exploration was performed, and biopsy specimen analysis led to a diagnosis of MPeM. Initial systemic chemotherapy comprising cisplatin and pemetrexed yielded a modest cytoreductive effect. However, 4 months later, the patient presented with abdominal distension and anorexia. CT images revealed massive ascites, bowel obstruction and an enlarged intra-abdominal tumour, which was considered progression of the MPeM. The patient was treated with nivolumab. Bowel obstruction was improved after the first administration, and his sense of abdomen distension completely disappeared after the third administration. This case supports the utility of immunotherapy in MPeM.
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http://dx.doi.org/10.1136/bcr-2020-237721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705565PMC
November 2020

An appropriate choice for immunotherapy in malignant pleural mesothelioma.

EBioMedicine 2020 Dec 10;62:103057. Epub 2020 Nov 10.

Department of Medical Oncology, Okayama Rosai Hospital, 1-10-25 Chikkomidorimachi, Okayama 7028055, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2020.103057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658483PMC
December 2020

Open-label, multicenter, randomized phase II study on docetaxel plus bevacizumab or pemetrexed plus bevacizumab for treatment of elderly (aged ≥75 years) patients with previously untreated advanced non-squamous non-small cell lung cancer: TORG1323.

Transl Lung Cancer Res 2020 Jun;9(3):459-470

Department of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, Japan.

Background: The effectiveness of bevacizumab monotherapy in elderly patients with non-squamous non-small cell lung cancer (NSCLC) is unclear. The efficacy of the combinations for elderly patients was explored.

Methods: Untreated patients (≥75 years; performance status 0-1) with stage IIIB, IV, or recurrent non-squamous NSCLC were included. Patients with epidermal growth factor receptor () mutation or anaplastic lymphoma kinase () gene rearrangements were eligible even if they received tyrosine kinase inhibitors. Patients were randomized 1:1 to receive docetaxel (50 mg/m) (DB) or pemetrexed (500 mg/m) (PB) with bevacizumab (15 m/kg). The primary endpoint was progression-free survival (PFS). Treatment was administered every 3 weeks until disease progression or unacceptable toxicity.

Results: Overall, 103 patients (DB: n=51; PB: n=52) were enrolled. In the DB and PB arms, median ages [range] were 78 [75-88] and 79 [75-94] years, respectively; median PFS were 6.1 and 4.6 months, respectively [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.66-1.61]; and response rates were 43%, and 40%, respectively (P=0.840). Grade ≥3 leukopenia, neutropenia, and fatigue incidences were significantly higher in the DB arm. Febrile neutropenia incidence did not differ significantly (16% . 12%, P=0.578). One patient in the PB arm died from a ruptured abdominal aortic aneurysm. Quality of life (QoL) analysis revealed less deterioration in the PB arm.

Conclusions: In previously untreated elderly patients with non-squamous NSCLC, PB shows feasibility, better QoL, and promising efficacy in terms of PFS, and an objective response rate for further analysis (UMIN000012786).
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http://dx.doi.org/10.21037/tlcr.2020.03.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354128PMC
June 2020

Rebiopsy with Thoracoscopy under Local Anesthesia for the Detection of EGFR T790M Mutation.

Case Rep Oncol 2019 Sep-Dec;12(3):918-921. Epub 2019 Dec 9.

Department of Medical Oncology, Okayama Rosai Hospital, Okayama, Japan.

A 70-year-old woman underwent right upper lobectomy for adenocarcinoma of the lung (pT1bN2M0 stage IIIA). Five years after the surgery, lymph node recurrence was detected. Gefitinib was administered because epidermal growth factor (EGFR) exon 19 deletion mutation was detected in the previously resected surgical specimen. After a treatment of first-generation EGFR tyrosine kinase inhibitors, an FDG-PET/CT scan demonstrated abnormal FDG uptake in the pleura indicating pleural dissemination. Pleurocentesis revealed tumor cells in the pleural fluid; however, EGFR mutation testing failed due to inadequate tumor cellularity. Thoracoscopy under local anesthesia revealed multiple nodules on the parietal pleura. A biopsy specimen confirmed the diagnosis of lung adenocarcinoma with pleural dissemination and revealed EGFR exon 20-T790M mutation.
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http://dx.doi.org/10.1159/000504932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036578PMC
December 2019

Current evidence and future perspectives of immune-checkpoint inhibitors in unresectable malignant pleural mesothelioma.

J Immunother Cancer 2020 02;8(1)

Department of Medical Oncology and Medicine, Okayama Rosai Hospitalosai Hospital, Okayama, Japan.

Platinum-based chemotherapy is commonly used as the standard first-line treatment for unresectable malignant pleural mesothelioma (MPM). However, in recent times, immune-checkpoint inhibitors (ICIs) have led to a paradigm shift. Herein, we review relevant literature and ongoing trials of ICIs used as both first-line and salvage therapies. Specifically, in the Japanese single-arm, phase II trial, the MERIT trial, nivolumab, an antiprogrammed cell death 1 (PD-1) antibody showed favorable efficacy when used as a salvage therapy. Currently, multiple ICI monotherapy or combination therapy trials have been conducted, which could provide further evidence. Among available ICIs, the anti-PD-1 antibody is promising for unresectable MPM, despite the limited efficacy of anti-CTLA4 monotherapy. Ongoing studies will further confirm the potential efficacy of ICIs for MPM, as observed across other malignancies. It is also crucial to identify any clinically useful predictive biomarkers that could reveal ICIs with maximal effects in MPM.
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http://dx.doi.org/10.1136/jitc-2019-000461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057421PMC
February 2020

Nivolumab for the treatment of unresectable pleural mesothelioma.

Expert Opin Biol Ther 2020 02 16;20(2):109-114. Epub 2019 Dec 16.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

: Platinum-based chemotherapy is the current first-line standard therapy for unresectable malignant pleural mesothelioma (MPM). Recently, immune-checkpoint inhibitors (ICI) have been intensively investigated as treatment options for this disease. Nivolumab, an anti-programmed cell death (PD)-1 agent, was one of the first drugs used and is representative of available ICIs.: This review discusses previous relevant reports and current ongoing trials of nivolumab. The efficacy and safety of nivolumab have been investigated mostly in second-line or later treatment settings as both monotherapy and in combination with other ICIs. Particularly, nivolumab monotherapy yielded promising efficacy with an objective response rate of 29% and median overall survival of 17.3 months in salvage settings in the single-arm, Japanese phase 2 trial (MERIT). Notably, the study led to Japanese approval of nivolumab for unresectable recurrent MPM. Several trials with monotherapy or cotherapy with nivolumab have commenced, including randomized trials of nivolumab monotherapy vs. placebo in the salvage setting, and cotherapy with nivolumab and ipilimumab vs. the platinum doublet in the frontline setting.: Nivolumab seems like a reasonable option for unresectable, relapsed MPM despite the lack of randomized trial data. Ongoing pivotal trials will confirm its efficacy.
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http://dx.doi.org/10.1080/14712598.2020.1703945DOI Listing
February 2020

Serum levels of the chemokine CCL2 are elevated in malignant pleural mesothelioma patients.

BMC Cancer 2019 Dec 10;19(1):1204. Epub 2019 Dec 10.

Nanotoxicology Project Lab, Nagoya City University, 3-1 Tanabedohri, Mizuho-ku, Nagoya, 467-8603, Japan.

Background: Malignant pleural mesothelioma (MPM) is a debilitating disease of the pleural cavity. It is primarily associated with previous inhalation of asbestos fibers. These fibers initiate an oxidant coupled inflammatory response. Repeated exposure to asbestos fibers results in a prolonged inflammatory response and cycles of tissue damage and repair. The inflammation-associated cycles of tissue damage and repair are intimately involved in the development of asbestos-associated cancers. Macrophages are a key component of asbestos-associated inflammation and play essential roles in the etiology of a variety of cancers. Macrophages are also a source of C-C motif chemokine ligand 2 (CCL2), and a variety of tumor-types express CCL2. High levels of CCL2 are present in the pleural effusions of mesothelioma patients, however, CCL2 has not been examined in the serum of mesothelioma patients.

Methods: The present study was carried out with 50 MPM patients and 356 subjects who were possibly exposed to asbestos but did not have disease symptoms and 41 healthy volunteers without a history of exposure to asbestos. The levels of CCL2 in the serum of the study participants was determined using ELISA.

Results: Levels of CCL2 were significantly elevated in the serum of patients with advanced MPM.

Conclusions: Our findings are consistent with the premise that the CCL2/CCR2 axis and myeloid-derived cells play an important role in MPM and disease progression. Therapies are being developed that target CCL2/CCR2 and tumor resident myeloid cells, and clinical trials are being pursued that use these therapies as part of the treatment regimen. The results of trials with patients with a similar serum CCL2 pattern as MPM patients will have important implications for the treatment of MPM.
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http://dx.doi.org/10.1186/s12885-019-6419-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905076PMC
December 2019

Clinical Efficacy and Safety of Nivolumab: Results of a ulticenter, Opn-label, Single-am, Japanese Phase II study in Malgnant Pleural Mesohelioma (MERIT).

Clin Cancer Res 2019 Sep 4;25(18):5485-5492. Epub 2019 Jun 4.

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Purpose: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM.

Patients And Methods: Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s) were enrolled. Patients received nivolumab 240 mg intravenously every 2 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate by central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated.

Results: Thirty-four patients were enrolled between July 2016 and October 2016. Median follow-up was 16.8 (range: 1.8-20.2) months. Ten (29%, 95% confidence interval, 16.8-46.2) patients showed a centrally assessed objective response. The objective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and biphasic histologic subtypes, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The objective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with <1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs.

Conclusions: Nivolumab met the primary endpoint as second- or third-line treatment for patients with MPM and showed promising efficacy with manageable toxicity..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0103DOI Listing
September 2019

A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cancers Harboring HER2 Aberration in Japan (HER2-CS STUDY).

Chest 2019 08 6;156(2):357-366. Epub 2019 May 6.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Background: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined.

Methods: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations.

Results: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively.

Conclusions: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations.

Trial Registry: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691.
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http://dx.doi.org/10.1016/j.chest.2019.01.011DOI Listing
August 2019

Physician requests by patients with malignant pleural mesothelioma in Japan.

BMC Cancer 2019 Apr 25;19(1):383. Epub 2019 Apr 25.

Department of Medical Oncology, Okayama Rosai Hospital, 1-10-25 Chikkomidorimachi, Okayama, 7028055, Japan.

Background: Malignant pleural mesothelioma (MPM) is a fatal and rare disease that is caused by the inhalation of asbestos. Treatment and care requests made by MPM patients to their physicians were collected and analyzed.

Methods: This cross-sectional survey was part of a larger study (N = 133) regarding the quality of life of MPM patients. Specific responses to two open-ended questions related to patients' requests regarding treatment and care were quantified, analyzed and divided into categories based on content.

Results: Responses (N = 217) from MPM patients (N = 73) were categorized into 24 subcategories and then abstracted into 6 categories. The majority of requests were related to patient-physician communication. Patients wanted clear and understandable explanations about MPM and wanted their physician to deliver treatment based on the patient's perspective by accepting and empathizing with their anxiety and pain. Patients expected physicians to be dedicated to their care and establish an improved medical support system for MPM patients.

Conclusion: Patients with MPM had a variety of unmet needs from their physicians. Physicians who provide care to MPM patients should receive training in both communication skills and stress management. A multidisciplinary care system that includes respiratory and palliative care for MPM patients should be established.
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http://dx.doi.org/10.1186/s12885-019-5591-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485076PMC
April 2019

Droplet digital PCR as a novel system for the detection of microRNA‑34b/c methylation in circulating DNA in malignant pleural mesothelioma.

Int J Oncol 2019 Jun 1;54(6):2139-2148. Epub 2019 Apr 1.

Department of General Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8558, Japan.

Malignant pleural mesothelioma (MPM) is a rare malignancy arising from the pleura that is difficult to diagnose, contributing to its dismal prognosis. Previously, we reported that the degree of microRNA (miR)‑34b/c methylation in circulating DNA is associated with the development of MPM. Herein, we present a newly developed droplet digital PCR (ddPCR)‑based assay for the detection of miR‑34b/c methylation in circulating DNA in patients with MPM. We originally prepared two probes within a short amplicon of 60 bp, designing one from the positive strand and the other from the complementary strand. The two probes functioned cooperatively, and our established assay detected DNA methylation accurately in the preliminary validation. We subsequently verified this assay using clinical samples. Serum samples from 35 cases of MPM, 29 cases of pleural plaque and 10 healthy volunteers were collected from 3 different institutions and used in this study. We divided the samples into 2 groups (group A, n=33; group B, n=41). A receiver‑operating characteristic curve analysis using the samples in group A determined the optimal cut‑off value for the diagnosis of MPM, with a sensitivity of 76.9% and a specificity of 90%. On the other hand, the use of the same criterion yielded a sensitivity of 59.1% and a specificity of 100% in group B, and corresponding values of 65.7 and 94.9% for the entire cohort, indicating a moderate sensitivity and a high specificity. In addition, when the analysis was focused on stage II or more advanced MPM, the sensitivity improved to 81.8%, suggesting the possibility that the methylated allele frequency in MPM may be associated with the stage of disease progression. On the whole, the findings of this study indicate that miR‑34b/c methylation in circulating DNA is a promising biomarker for the prediction of disease progression in patients with MPM.
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http://dx.doi.org/10.3892/ijo.2019.4768DOI Listing
June 2019

A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin, Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol.

Clin Lung Cancer 2018 09 9;19(5):e705-e707. Epub 2018 May 9.

Center of Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan.

Background: The purpose of this study is to assess the efficacy and safety of combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma (MPM).

Patients And Methods: Patients with untreated, advanced, or metastatic MPM who meet the inclusion and exclusion criteria will be included. A total of 18 patients will be enrolled from 4 Japanese institutions within 1 year. Combination chemotherapy with cisplatin (75 mg/m), pemetrexed (500 mg/m), and nivolumab (360 mg/person) is administered every 3 weeks for a total of 4 to 6 cycles. Then, maintenance therapy with nivolumab will be administered until disease progression, unacceptable toxicities, or the patient's condition meets the withdrawal criteria. The primary end point is the centrally reviewed overall response rate. The secondary end points include the disease control rate, overall survival, progression-free survival, and adverse events.

Conclusion: This phase II trial evaluating first-line combination chemotherapy for unresectable MPM commenced in January 2018. This is the first prospective trial to evaluate the effect of an anti-programmed death-1 antibody combined with cisplatin and pemetrexed for unresectable MPM.
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http://dx.doi.org/10.1016/j.cllc.2018.05.001DOI Listing
September 2018

Prospective registry database of patients with malignant mesothelioma: directions for a future Japanese registry-based lung cancer study.

J Thorac Dis 2018 Mar;10(3):1968-1971

Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: The International Association for the Study of Lung Cancer, in collaboration with members of the International Mesothelioma Interest Group (IMIG), developed a large international database and TNM-based system to study malignant pleural mesothelioma (MPM). However, this database has some limitations since it was a retrospective study and it was based predominantly on surgical cases. The Japanese Joint Committee of Lung Cancer Registry (JJCLCR) employs a project of prospective registry database of patients in Japan with MPM in order to clarify MPM's epidemiology, current management practices, and prognosis and also to investigate the potential capabilities to target the best patients for therapy.

Methods: Tumor stage is described using the 7th and 8th versions of IMIG staging system. This prospective cohort study has been conducted from April 1, 2017 to March 31, 2019.

Discussion: We will analyze the data in this registry to determine the most recent outcomes and trends related to MPM treatment in Japan. The present prospective study is expected to validate the 8th version of IMIG staging system, and to investigate whether tumor thickness is a reliable T-descriptor.

Trial Registration: ClinicalTrials.gov Identifier: UMIN 000024664.
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http://dx.doi.org/10.21037/jtd.2018.03.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906251PMC
March 2018

Quality of life of survivors of malignant pleural mesothelioma in Japan: a cross sectional study.

BMC Cancer 2018 03 27;18(1):350. Epub 2018 Mar 27.

Department of Medical Oncology, Okayama Rosai Hospital, 1-10-25 Chikkomidorimachi, Okayama, 7028055, Japan.

Background: Previous studies have indicated that people with malignant pleural mesothelioma (MPM) have a poor quality of life (QOL); however, information about the QOL of people with MPM in Japan is anecdotal. The aims of this study were to investigate the QOL of survivors of MPM in Japan and to determine the factors that correlate with their QOL.

Methods: This was a cross sectional study. The included patients were those diagnosed with MPM in Japan. We created a self-administered questionnaire consisting of 64 questions. The questionnaires were sent to hospitals and patient advocacy groups, distributed to the patients, completed, and sent back to the researchers by postal mail. QOL was assessed with the European Organization for Research and Treatment of Cancer 16 questionnaire (QLQ) and the short version of the core domains of the Comprehensive Quality of Life Outcome questionnaire (CoQoLo).

Results: In total, 133 questionnaires were collected. The QLQ assessments demonstrated that the survivors of MPM most frequently complained of fatigue, pain, sleep disturbances, and dyspnea. The symptom scales were acceptable, but the functional scales were significantly poorer for the patients with poor performance statuses (PSs). The short CoQoLo assessment was very unfavorable for 'Being free from physical pain.' Being a long-term survivor and a survivor with a poor PS were significantly correlated with poor global health status.

Conclusions: Survivors of MPM have impaired function, a variety of symptoms, and lower QOL. Survivors of MPM, even those in good physical condition, need broad support.
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http://dx.doi.org/10.1186/s12885-018-4293-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872515PMC
March 2018

Low-dose chest computed tomography screening of subjects exposed to asbestos.

Eur J Radiol 2018 Apr 16;101:124-128. Epub 2018 Feb 16.

Department of Internal Medicine, Okayama Rosai Hospital, 1-10-25 Chikkomidorimachi, Okayama, 7028055, Japan.

Objectives: The primary aim was to reveal the prevalence of lung cancer (LC) and malignant pleural mesothelioma (MPM) in subjects with past asbestos exposure (AE). We also examined pulmonary or pleural changes correlated with the development of LC.

Materials And Methods: This was a prospective, multicenter, cross-sectional study. There were 2132 subjects enrolled between 2010 and 2012. They included 96.2% men and 3.8% women, with a mean age of 76.1 years; 78.8% former or current smokers; and 21.2% never smokers. We screened subjects using low-dose computed tomography (CT). The CT images were taken with a CT dose Index of 2.7 mGy. The evaluated CT findings included subpleural curvilinear shadow/subpleural dots, ground glass opacity or interlobular reticular opacity, traction bronchiectasia, honeycombing change, parenchymal band, emphysema changes, pleural effusion, diffuse pleural thickening, rounded atelectasis, pleural plaques (PQs), and tumor formation.

Results: The PQs were detected in most of subjects (89.4%) and emphysema changes were seen in 46.0%. Fibrotic changes were detected in 565 cases (26.5%). A pathological diagnosis of LC was confirmed in 45 cases (2.1%) and MPM was confirmed in 7 cases (0.3%). The prevalence of LC was 2.5% in patients with a smoking history, which was significantly higher than that in never smokers (0.7%, p = 0.027). The prevalence of LC was 2.8% in subjects with emphysema changes, which was higher than that of subjects without those findings (1.6%); although, the difference was not statistically significant (p = 0.056). The prevalence of LC in subjects with both fibrotic plus emphysema changes was 4.0%, which was significantly higher than that of subjects with neither of those findings (1.8%, p = 0.011). Logistic regression analysis revealed smoking history, fibrotic plus emphysema changes, and pleural effusion as significant explanatory variables.

Conclusions: Smoking history, fibrotic plus emphysema changes, and pleural effusion were correlated with the prevalence of LC.
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http://dx.doi.org/10.1016/j.ejrad.2018.02.017DOI Listing
April 2018

Clinical features of secondary spontaneous pneumothorax complicated with silicosis.

Respir Investig 2018 Mar 1;56(2):144-149. Epub 2018 Mar 1.

Asbestos Research Center, Okayama Rosai Hospital, 1-10-25 Chikkomidorimachi, Minamiku, Okayama 702-8055, Japan.

Background: Few studies have focused on the management of secondary spontaneous pneumothorax (SSP) as a complication of pneumoconiosis. The aim of this study was to investigate the clinical features and therapeutic course of SSP associated with silicosis.

Methods: Between April 2005 and March 2015, 17 patients with silicosis underwent chest tube drainage for SSP in our institution. We retrospectively analyzed patient characteristics, type of treatment, clinical course, rate of recurrence, and survival time, and compared them with those of 30 patients diagnosed with chronic obstructive pulmonary disease (COPD) during the same period.

Results: Fourteen patients with silicosis had performance status score ≥ 2 and modified Medical Research Council Grade ≥ 2; these were significantly different from those in patients with COPD (P = 0.047, P = 0.026). Patients with silicosis had a significantly longer duration of chest tube placement and hospital stay. Recurrent pneumothorax occurred in 47.1% of patients with silicosis, which was not significantly different from the proportion of patients with COPD (40.9%, P = 0.843). However, in the silicosis group, patients treated with chest tube drainage alone tended to have a higher rate of ipsilateral recurrence than those who had pleurodesis, although this was not statistically significant. The median overall survival time of patients with silicosis was 82.6 months, while that of patients with COPD was 104.1 months.

Conclusions: Patients with silicosis had worse physical status and respiratory functions at the time of occurrence of pneumothorax than those with COPD. Pleurodesis could be an effective treatment for SSP complicating silicosis.
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http://dx.doi.org/10.1016/j.resinv.2017.11.007DOI Listing
March 2018

A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404.

Lung Cancer 2018 01 28;115:103-108. Epub 2017 Nov 28.

Department of Respiratory Medicine and Allergy, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan.

Objective: In advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis.

Materials And Methods: Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40mg/day (level 0) and 30mg/day (level -1), were evaluated in combination with 15mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose.

Results: Nineteen patients were enrolled (level 0:5, level -1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level -1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level -1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease.

Conclusion: Afatinib plus bevacizumab (level -1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2017.11.025DOI Listing
January 2018

A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor: The Okayama Lung Cancer Study Group Trial 1202.

Lung Cancer 2017 10 12;112:188-194. Epub 2017 Aug 12.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Introduction: S-1 is an oral fluoropyrimidine-based combination of tegafur, gimeracil, and oteracil potassium. Although the combination of S-1 with carboplatin is a first-line chemotherapy regimen for advanced non-small cell lung cancer (NSCLC), the efficacy and safety of the regimen in the elderly remain unknown.

Methods: The patient inclusion criteria were previously untreated advanced NSCLC, wild-type epidermal growth factor receptor, aged 70 years or more, and a performance status (PS) of 0-2. The patients received oral S-1 (40mg/m, twice daily) for 2 weeks and carboplatin (area under the curve: 5) on day 1 every 4 weeks as induction treatment. After four induction cycles, S-1 alone (40mg/m, twice daily) was administered for 2 weeks every 4 weeks as a maintenance therapy until disease progression. The primary endpoint was the overall response rate (ORR), which was expected to exceed 20%, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the toxicity profile. The associations between clinical outcomes and expression of genes such as thymidylate synthase and thymidine phosphorylase in the tumors were evaluated.

Results: Thirty-three patients were enrolled between March 2013 and June 2015. The median age was 78 (range 70-89) years, and 51.5% had a PS of 0. The ORR was 30.3% (95% confidence interval (CI): 14.6-46.0) and the DCR 57.6% (95% CI: 40.7-74.4). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%), and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. The median PFS and OS were 134days (95% CI: 79-173) and 479days (95% CI: 250-571), respectively. Low thymidine phosphorylase expression was associated with the DCR (P<0.01).

Conclusion: This study met the predesigned primary endpoint, and the regimen seems to be a favorable treatment option.
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http://dx.doi.org/10.1016/j.lungcan.2017.08.010DOI Listing
October 2017

Adenocarcinoma of the Lung Acquiring Resistance to Afatinib by Transformation to Small Cell Carcinoma: A Case Report.

Case Rep Oncol 2017 May-Aug;10(2):666-670. Epub 2017 Jul 21.

Department of Medicine, Okayama Rosai Hospital, Okayama, Japan.

A 65-year-old woman visited our hospital due to right chest pain and dyspnea on exertion. Chest radiography revealed decreased permeability of the right lung. Computed tomography demonstrated a huge mass in the right upper lobe and right pleural effusion. Right pleural effusion cytology yielded a diagnosis of adenocarcinoma and was positive for mutation of epidermal growth factor receptor (EGFR; exon 21 L858R). Afatinib was selected for the initial treatment. Multiple tumors regressed remarkably, but then rapidly progressed 3 months later. We performed re-biopsy to detect the mechanism of resistance to afatinib. Histopathology revealed a mixture of small cell carcinoma (SCC) and adenocarcinoma harboring same EGFR mutation. To the best of our knowledge, this is the first report of transformation to SCC after treatment with afatinib.
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http://dx.doi.org/10.1159/000479147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582498PMC
July 2017

Esophagobronchial Fistula in a Patient with Squamous Cell Carcinoma of the Lung: A Case Report.

Case Rep Oncol 2017 May-Aug;10(2):553-557. Epub 2017 Jun 22.

Department of Medicine, Okayama Rosai Hospital, Okayama, Japan.

A 73-year-old man was referred to our hospital after a 2-week history of bloody sputum and cough. Computed tomography (CT) images of the chest showed a mass grouped with mediastinal lymph nodes, and bronchoscopy showed a projecting mass in the right main bronchus. After a transbronchial biopsy, the patient was diagnosed with squamous cell carcinoma (T4N2M0 stage IIIB). The patient was treated with systemic chemotherapy, consisting of cisplatin (40 mg/m, days 1 and 8) and docetaxel (30 mg/m, days 1 and 8), and concurrent thoracic irradiation at a daily dose of 2 Gy. On day 35 of treatment, the patient complained of a sore throat and cough. A CT of the chest showed punctate low-attenuation foci between the esophagus and bronchus. Gastrointestinal endoscopy and bronchoscopy demonstrated a fistula in the middle intrathoracic esophagus and the left main bronchus. The patient's symptoms gradually improved, and the fistula was closed after the suspension of chemoradiotherapy. Radiotherapy was resumed and completed on day 82. However, on day 108, he developed a fever and cough, and a tumor with fistula was revealed in the right main bronchus. He had an esophageal stent inserted, but he later died of sudden hemoptysis.
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http://dx.doi.org/10.1159/000477659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567114PMC
June 2017

A phase II study of topotecan and cisplatin with sequential thoracic radiotherapy in elderly patients with small-cell lung cancer: Okayama Lung Cancer Study Group 0102.

Cancer Chemother Pharmacol 2016 Oct 20;78(4):769-74. Epub 2016 Aug 20.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Purpose: The treatment outcome in elderly patients with limited-disease small-cell lung cancer (LD-SCLC) remains poor. We carried out a phase II trial of split topotecan and cisplatin (TP) therapy and sequential thoracic radiotherapy for elderly LD-SCLC patients as a follow-up to our previous phase I trial.

Methods: In total, 30 patients aged 76 years or older, with untreated LD-SCLC were enrolled. Four courses of topotecan (1.0 mg/m(2), days 1-3) and cisplatin (20 mg/m(2), days 1-3) were administered, followed by thoracic radiotherapy (1.8 Gy/day, total of 45 Gy). The primary end point was the overall response rate (ORR).

Results: The trial was terminated early with 22 patients because of slow accrual. Their median age was 79 years. The median number of courses of chemotherapy administered was three, and the actual completion rate of the entire treatment course was 41 %. The ORR was 68 % with a 95 % confidence interval of 47-89 % (15/22 cases). The median progression-free survival and overall survival were 9.1 and 22.2 months, respectively. The main toxicity was myelosuppression, with grades 3-4 neutropenia (96 %), thrombocytopenia (50 %), and febrile neutropenia (32 %).

Conclusions: This regimen produced a favorable survival outcome, despite moderate-to-severe toxicity profiles. Further efforts are necessary to define an optimal regimen for elderly patients with limited SCLC.
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http://dx.doi.org/10.1007/s00280-016-3135-2DOI Listing
October 2016

Pleural irregularities and mediastinal pleural involvement in early stages of malignant pleural mesothelioma and benign asbestos pleural effusion.

Eur J Radiol 2016 Sep 21;85(9):1594-600. Epub 2016 Jun 21.

Department of Internal Medicine, Okayama Rosai Hospital, 1-10-25 Chikkomidorimachi, Okayama 7028055, Japan.

Objective: To elucidate differences in the level and localization of pleural irregularities in early malignant pleural mesothelioma (eMPM) and benign asbestos pleural effusion (BAPE) using CT.

Study Design: Retrospective assessment of CT findings of consecutive patients with BAPE at a single centre and patients with eMPM reported in Japanese vital statistics.

Methodology: Thirty-six patients with confirmed diagnoses of BAPE and sixty-six patients with confirmed diagnoses of eMPM (mesothelioma stages T1 or T2) were included. Informed consent, CT scans, and clinical and pathologic details were obtained for all patients and were reviewed by one radiologist, two pathologists, and two pulmonologists. Asbestosis, pleural plaque, rounded atelectasis, and diffuse pleural thickening were assessed in all patients.

Results: Prevalence of asbestosis, pleural plaque, rounded atelectasis, and diffuse pleural thickening was significantly higher in the BAPE group. Low-level irregularity was more common in the BAPE group (p<0.001), whereas high-level irregularity, mediastinal localization, and interlobar fissure were more prevalent in the eMPM group (p<0.001). Interlobar pleural irregularity was not observed in any patients in the BAPE group, although 55% of patients in the eMPM group showed interlobar pleural irregularity. Mediastinal pleural involvement was observed in 74% of patients in the eMPM group and had a positive predictive value of 89%.

Conclusion: This study demonstrates that the level and localization of plural irregularities significantly differed between patients with BAPE and eMPM. Large-scale prospective studies are needed to fully establish the diagnostic utility of such differences.
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http://dx.doi.org/10.1016/j.ejrad.2016.06.013DOI Listing
September 2016

[Clinical Pathological Diagnosis, and Treatment for Pleural Mesothelioma].

Gan To Kagaku Ryoho 2016 May;43(5):513-7

Research Center for Asbestos-Related Diseases, Okayama Rosai Hospital.

For the differential diagnosis between fibrous pleuritis and other malignancies such as lung cancer, multiple immunostaining is essential to diagnose pleural mesothelioma. For cytological diagnosis of pleural effusions, differentiation between mesothelioma cells and reactive mesothelial cells is very difficult. Therefore, histological diagnoses of tumor tissues obtained via biopsy are essential. To diagnose epthelioid mesothelioma, more than 2 positive and negative markers must be consistent with those known for mesothelioma. To diagnose sarcomatoid mesothelioma, keratin is usually positive, differentiating the diagnosis from that for real sarcoma. For surgical treatment for pleural mesothelioma, extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) are usually performed. The proportion of P/D increases because of the low death rates with surgery and similar survivals. However, a trimodal approach, such as EPP with chemotherapy and radiotherapy, is best for longer survival and expected to be curative. For chemotherapy, only cisplatin (CDDP) combined with pemetrexed (PEM) is effective, and no other agents have been identified for this disease. Nowadays, clinical immunotherapy trials start with phase II study.
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May 2016