Publications by authors named "Hiromi Aono"

7 Publications

  • Page 1 of 1

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter Phase 2 Trial.

JAMA Oncol 2020 07 9;6(7):e201250. Epub 2020 Jul 9.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Importance: Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients.

Objective: To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer.

Design, Setting, And Participants: Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study.

Interventions: Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks.

Main Outcomes And Measures: The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms.

Results: Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome.

Conclusions And Relevance: Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option.

Trial Registration: UMIN-CTR Identifier: UMIN000015949.
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July 2020

Phase II trial of S-1 plus cisplatin combined with bevacizumab for advanced non-squamous non-small cell lung cancer (TCOG LC-1202).

Jpn J Clin Oncol 2019 Aug;49(8):749-754

Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo.

Background: S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine.

Methods: Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1-14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4-6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL).

Results: From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9-8.7), 21.4 months (95% CI: 14.7-not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen.

Conclusions: S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities.
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August 2019

Rapidly progressive miliary brain metastasis of lung cancer after EGFR tyrosine kinase inhibitor discontinuation: An autopsy report.

Neuropathology 2019 Apr 13;39(2):147-155. Epub 2019 Mar 13.

Department of Pathology, Mitsui Memorial Hospital, Tokyo, Japan.

Miliary brain metastasis is a rare type of brain metastasis, in which carcinoma cells disseminate to numerous foci confined to Virchow-Robin/subpial spaces. Symptoms usually progress within several months, and magnetic resonance imaging (MRI) shows multiple small contrast-enhancing lesions. We report an autopsy case of a patient who rapidly deteriorated within a week due to miliary brain metastasis after epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) discontinuation, without contrast-enhancing lesions on MRI. A 74-year-old woman was diagnosed with stage IV lung adenocarcinoma with EGFR L868R mutation 2 years before presentation. Gefitinib, an EGFR-TKI was started. After 7 months, multiple new punctate contrast-enhancing lesions in the cerebral cortex appeared. After switching to another EGFR-TKI, erlotinib, these lesions disappeared. One year later, erlotinib was discontinued because of disease progression in the lung and docetaxel was initiated. Sixteen days later, cognitive decline appeared which rapidly progressed to bedridden state in 4 days. MRI showed multiple cortical small fluid-attenuated inversion recovery high intensity lesions which lacked contrast enhancement. The patient exhibited a state of akinetic mutism within a few days, and died 52 days after the appearance of neurological symptoms. The rapid progression indicated disease flare after EGFR-TKI discontinuation. Autopsy revealed numerous foci of metastasis in the cerebral cortex, basal ganglia, thalamus, and cerebellum, in which cancer cells were mostly confined to the Virchow-Robin/subpial spaces. These pathological findings were compatible with previous reports of miliary brain metastasis. Recent reports suggest that early disseminated cancer cells can survive for a long time and even remain after chemotherapy in supportive niches, and Virchow-Robin spaces are the niches in the brain. Our case suggests that these cancer cells may rapidly proliferate as a withdrawal burst after discontinuation of molecular targeted drugs, and show pathological findings of miliary brain metastasis.
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April 2019

Feasibility study of docetaxel plus bevacizumab as first line therapy for elderly patients with advanced non-small-cell lung cancer: Thoracic Oncology Research Group (TORG) 1014.

BMC Cancer 2015 Oct 19;15:740. Epub 2015 Oct 19.

Yokohama Municipal Citizen's Hospital, 56 Kazawa-cho, Hodogaya-ku, Yokohama, 240-8555, Japan.

Background: Docetaxel monotherapy is one of the standard treatments for non-small-cell lung cancer in elderly patients. The addition of bevacizumab to docetaxel seems promising; however, the feasibility of this combination has not been investigated in such patients.

Methods: Patients with advanced non-squamous non-small-cell lung cancer aged 70 years or older who had not previously received cytotoxic chemotherapy were enrolled. Patients in the Level 0 cohort received docetaxel 60 mg/m(2) and bevacizumab 15 mg/kg, whereas those in the Level-1 cohort received docetaxel 50 mg/m(2) and bevacizumab 15 mg/kg. Chemotherapy was repeated 3 weekly for six cycles. The primary endpoint was toxicity and the secondary endpoints were response rate, progression-free survival, overall survival, and proportion of patients who underwent three or more cycles of chemotherapy.

Results: Twenty-one patients were enrolled from December 2010 to September 2012 at six institutes. Of the nine patients enrolled in Level 0, two experienced dose-limiting toxicity (febrile neutropenia and prolonged Grade 4 neutropenia in one patient, and Grade 3 infection in another patient) during the first cycle. Enrollment to the Level 0 cohort was terminated because two patients developed Grade 4 sepsis during later cycles. The remaining 12 patients were enrolled in the Level-1 cohort, in which two dose-limiting toxicities (prolonged Grade 4 neutropenia and Grade 3 increased aminotransferase level) were observed. No patient in the Level-1 cohort experienced Grade 4 nonhematologic toxicity. Grade 4 neutropenia occurred in 89 % of Level 0 patients and 50 % of Level-1 patients. The proportion of patients who experienced Grade 3/4 infection, febrile neutropenia or sepsis was 44 % in the Level 0 cohort, and 8 % in the Level-1 cohort. The overall response rate to chemotherapy and progression-free survival were 29 % (95 % CI, 11-52 %) and 5.9 months (95 % CI, 3.6-9.1 months), respectively. Efficacy outcomes did not differ significantly between the cohorts.

Conclusions: Toxicities were tolerable in level-1 cohort. The recommended dose of combination chemotherapy with docetaxel and bevacizumab for elderly patients was determined as 50 mg/m(2) of docetaxel and 15 mg/kg of bevacizumab and toxicities were tolerable. Further studies are warranted.

Trial Registration: UMIN Clinical Trial Registry; UMIN000004240 .
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October 2015

A prospective, multicentre phase II trial of low-dose erlotinib in non-small cell lung cancer patients with EGFR mutations pretreated with chemotherapy: Thoracic Oncology Research Group 0911.

Eur J Cancer 2015 Sep 11;51(14):1904-10. Epub 2015 Jul 11.

Thoracic Oncology Research Group, Kanagawa, Japan.

Background: Low-dose erlotinib may be as effective as gefitinib or erlotinib at full dose in non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR) gene.

Methods: Patients with chemotherapy pretreated NSCLC harbouring EGFR mutations received erlotinib at 50 mg/d until disease progression or unacceptable toxicities. The dose was escalated to 150 mg/d in patients showing no response (i.e. without major tumour shrinkage according to Response Evaluation Criteria in Solid Tumours (RECIST)) to the initial dose during the first 4 weeks. The primary end-point was the objective response rate at the dose of 50 mg/d.

Results: Thirty-four patients from seven institutes were enrolled. The study was closed early when no response was confirmed in 15 patients, excluding the possibility that the primary end-point would be met. The objective response and disease control rates at the dose of 50 mg/d as determined by an independent review committee were 54.5% and 84.8%, respectively. Four additional patients achieved partial response with increased 150 mg/d dose. Progression-free survival and median survival times during the entire period of the study were 9.5 and 28.5 months, respectively. Treatment-related toxicities were generally mild, the most common being skin disorders and diarrhoea. Only one case experienced grade 3 toxicity, which was transient increase of hepatic enzymes.

Conclusion: The primary end-point was not met; low-dose erlotinib is not recommended for fit patients with NSCLC harbouring EGFR mutations. However, it may merit further evaluation for elderly or frail patients.
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September 2015

Transbronchial needle aspiration cytology of subcarinal lymph nodes for the staging procedure in the diagnosis of lung cancer.

Respirology 2006 Nov;11(6):782-5

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Yokohama, and First Department of Medicine, Tokyo Women's Medical University, Japan.

Objective And Background: The aim of this study was to improve the staging of lung cancer with or without lymphadenopathy on chest CT by using transbronchial aspiration cytology (TBAC).

Methods: TBAC of the subcarinal lymph nodes was performed on 153 consecutive patients with lung cancer, with or without subcarinal lymphadenopathy on chest CT.

Results: Thirty-four patients had enlargement of the subcarinal lymph nodes (>1 cm). Eighteen of these had TBAC confirmation of metastases. Another seven patients with no mediastinal involvement on CT were positive for metastases on TBAC. TBAC was the only way to confirm lung cancer in two patients. Therefore, routinely performed subcarinal TBAC contributed to an improved non-operative staging of the patients and diagnosis in 16% (25/153) of the patients with lung cancer. Forty-nine patients with NSCLC had surgical resection of the tumour. Surgical procedure revealed metastases to the subcarinal lymph nodes in three patients in whom the preoperative TBAC diagnosis was normal. No significant complications due to TBAC occurred in any of the patients.

Conclusion: TBAC of the subcarinal lymph nodes is a minimally invasive technique for staging of lung cancer and can provide useful information for the diagnosis of metastases to the subcarinal lymph nodes.
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November 2006

Endobronchial ultrasonography for mediastinal and hilar lymph node metastases of lung cancer.

Chest 2002 May;121(5):1498-506

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Study Objectives: Conventional radiologic procedures are frequently unreliable in the diagnosis of mediastinal and hilar lymph node metastases of lung cancer. In order to improve diagnostic accuracy, we performed endobronchial ultrasonography (EBUS) during bronchofiberscopic examinations of patients with lung cancer.

Methods And Patients: To evaluate mediastinal and hilar lymph node metastases, EBUS was performed prospectively using a radial scanning probe of 20 MHz through a bronchofiberscope.

Results: We observed hilar lymph nodes (10R, 11R superior, 11R inferior, 12R, 10L, 11L, 12L) in 20 of 37 patients who underwent EBUS, and we could clearly identify whether direct invasion of the pulmonary artery by a lymph node had occurred. Of the 27 patients who showed no hilar lymph nodes on chest CT scan, lymph node swellings < 10 mm or > or = 10 mm in diameter were identified by EBUS in 9 patients and 2 patients, respectively. Interestingly, EBUS also revealed that the pulmonary artery was directly invaded by an interlobar lymph node < 10 mm in diameter in one patient. In most patients, lymph node 7 was easily identified and was clearly differentiated from the surrounding esophagus, vessels, and mediastinal fat tissue by EBUS. However, fused lymph nodes or lymph nodes with low central density when visualized by chest CT scan were occasionally observed as independent lymph nodes by EBUS. When compared with the pathologic diagnosis of lymph node metastasis in 16 patients who underwent surgery, the most specific and sensitive method for identifying lymph node metastases were EBUS alone (92%) and EBUS in combination with CT scan (100%), respectively. The overall accuracy of EBUS was 94% for the diagnosis of direct invasion of the pulmonary arteries by a hilar lymph node.

Conclusions: EBUS in combination with conventional radiologic tools may contribute to improved staging, especially in surgical cases with hilar lymph node metastases.
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May 2002