Publications by authors named "Takahisa Kawamura"

37 Publications

EML4-ALK fusion variant.3 and co-occurrent PIK3CA E542K mutation exhibiting primary resistance to three generations of ALK inhibitors.

Cancer Genet 2021 Aug 28;256-257:131-135. Epub 2021 May 28.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

The ALK inhibitors are promising therapeutic agents against lung cancer harboring ALK fusion genes and are currently under development up to the third generation. However, its therapeutic effects are reported to be affected by differences in ALK variants and co-occurrent mutations. Materials and Methods; We experienced an autopsy case of an ALK-positive lung cancer patient who showed primary resistance to three generations of ALK inhibitors. The poor survival time of the case was 14 months. To reveal the mechanism of primary resistance to three generations of ALK inhibitors, we performed next generation sequencing for 12 specimes obtained from an autopsy with covering whole exons of 53 significantly mutated, lung cancer-associated genes and amplicon-based target RNA sequenceing for the ALK fusion gene. The NGS analysis revealed a rare variant.3 of ALK fusion, in which 30 bp of base was inserted at the end of ALK intron.19 and was associated with EML exon.6 [E6_ins30A20] and a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. Structural analysis of the fusion protein ALK [E6_ins30A20] showed no interferance with the binding of ALK inhibitors to the kinase domain. The NGS analysis of primary and metastatic lesions obtained from an autopsy revealed a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. The constitutive activation of PI3K-Akt signal by PIK3CA E542K mutation occurred downstream of ALK signaling pathway, could lead to primary resistance to ALK inhibitors in all generations.
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http://dx.doi.org/10.1016/j.cancergen.2021.05.010DOI Listing
August 2021

Atezolizumab with bevacizumab, paclitaxel and carboplatin was effective for patients with SMARCA4-deficient thoracic sarcoma.

Immunotherapy 2021 Jul 25;13(10):799-806. Epub 2021 May 25.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

SMARCA4-deficient thoracic sarcoma (DTS) is a recently noted progressive thoracic malignancy. We recently experienced three cases of SMARCA4-DTS who were treated with atezolizumab in combination with bevacizumab, paclitaxel and carboplatin (ABCP) as the first-line therapy. Immunohistopathological analysis revealed absent expression of SMARCA4 in all cases. The tumor mutational burden was over 11/Mb and mutations in and were detected in all three cases. Partial response to ABCP treatment was observed in all three cases, with a progression-free survival of approximately 6 months or longer and a continuous response of 1 year or longer in one case. The first-line ABCP treatment demonstrated durable efficacy in SMARCA4-DTS regardless of the degree of PD-L1 expression.
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http://dx.doi.org/10.2217/imt-2020-0311DOI Listing
July 2021

Late recurrence of lung adenocarcinoma harboring EGFR exon 20 insertion (A763_Y764insFQEA) mutation successfully treated with osimertinib.

Cancer Genet 2021 Aug 10;256-257:57-61. Epub 2021 Apr 10.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae Chuoku, Osaka 541-8567, Osaka, Japan.

The EGFR-A763_Y764insFQEA is a unique mutation among EGFR exon 20 insertion mutations in that it is associated with sensitivity to conventional EGFR-tyrosine kinase inhibitors. This mutation, which was not initially covered by conventional reverse transcription polymerase chain reaction (RT-PCR) genotyping method, has only been detected in clinical practice when a next-generation sequencing (NGS)-based cancer panel is implemented. We present the case of a female patient with recurrent lung adenocarcinoma from a lung tumor resected 10 years earlier. Sequential single-gene investigations and the OncomineTM Comprehensive Assay (ver.3) analysis of the recurrent tumor did not reveal any targetable driver mutations. However, the second NGS analysis with the OncoGuideTM NCC oncopanel found the EGFR-A763_Y764insFQEA mutation after tumor progression with carcinomatous lymphangiomatosis and multiple brain metastases. Osimertinib treatment improved her condition immediately. The identical EGFR-A763_Y764insFQEA mutation was detected in the tumor resected 10 years earlier. Based on this common mutation the patient was diagnosed with late recurrence of lung cancer harboring the EGFR-A763_Y764insFQEA mutation. The OncoGuideTM NCC oncopanel covered whole exons of the EGFR gene and was able to detect this mutation. In the present clinical practice, the EGFR-A763_Y764insFQEA mutation is the only treatable mutation among EGFR Ex.20 insertion mutations. We need to understand the gene mutation profile identified by each panel and consider reexamining them for this mutation.
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http://dx.doi.org/10.1016/j.cancergen.2021.04.001DOI Listing
August 2021

Clinical impact of walking capacity on the risk of disability and hospitalizations among elderly patients with advanced lung cancer.

Support Care Cancer 2021 Jul 3;29(7):3961-3970. Epub 2021 Jan 3.

Division of Thoracic Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.

Purpose: Little is known about the impact of decreased walking capacity on clinical outcomes in elderly patients with cancer. This prospective observational study aimed to investigate the impact of walking capacity on the risk of disability and hospitalization in elderly patients with advanced lung cancer.

Method: This study prospectively enrolled 60 patients aged ≥ 70 years with advanced non-small-cell lung cancer (NSCLC) scheduled to receive first-line chemotherapy or radical radiotherapy between January 2013 and December 2014 (trial registration number: UMIN000009768). Patients were classified into the mobile or less mobile group based on the median incremental shuttle walking distance (ISWD) before initial treatment. Assessments included the Barthel index, disability-free survival time, mean cumulative lengths of hospital stay, and inpatient medical costs.

Results: The median ISWD was 290 m (interquartile range, 245-357.5 m). The mobile group (ISWD ≥ 290 m) had a longer disability-free survival time than the less mobile group (ISWD < 290 m, 24.6 months vs. 8.4 months, p < 0.05). During the first year from study entry, the mobile group had shorter cumulative lengths of hospital stay (41.3 vs. 72.9 days/person, p < 0.05) and lower inpatient medical costs (¥1.9 vs. ¥2.9 million/person, p < 0.05) than the less mobile group.

Conclusion: Elderly NSCLC patients with adequate walking capacity showed lower risks of disability, shorter hospitalizations, and lower inpatient medical costs than patients with reduced walking capacity. Further prospective research is needed to validate these findings. The trial was registered with the University Hospital Medical Information Network as trial number UMIN000009768 on January 13, 2013.

Trial Registration: UMIN000009768.
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http://dx.doi.org/10.1007/s00520-020-05953-5DOI Listing
July 2021

Osimertinib is associated with reversible and dose-independent cancer therapy-related cardiac dysfunction.

Lung Cancer 2021 03 16;153:186-192. Epub 2020 Nov 16.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Introduction: The use of osimertinib is associated with the risk of cancer therapy-related cardiac dysfunction (CTRCD) for EGFR-mutated non-small cell lung cancer (NSCLC) patients. In this study, we aimed to clarify the clinical features of patients with CTRCD associated with osimertinib.

Methods: A total of 183 cases of advanced EGFR-mutated NSCLC who received osimertinib monotherapy from January 2014 to December 2019 were evaluated. Longitudinal changes in LVEF were evaluated in 58 patients by serial echocardiography before and after osimertinib administration.

Results: Of 58 patients, 16 patients (8.7%) had decreased LVEF of 10 units or more and 8 patients (4.4%) met the CTRCD criteria. Overall, LVEF significantly decreased after osimertinib treatment from a mean value of 69% (range, 52-82%) at baseline to 66% (26-75%) (p < 0.001). During osimertinib treatment, LVEF remained low but did not decline any further. Discontinuation, dose reduction, or switching to another EGFR tyrosine kinase inhibitors resulted in recovery in 6 out of 8 CTRCD patients. Multivariate analysis showed that history of heart disease was a significant predictor of CTRCD (ORR, 4.97; 95% confidence interval [CI], 1.26-19.6; P = 0.022).

Conclusions: Osimertinib was associated with the risk of CTRCD, which is dose-independent and reversible with drug withdrawal.
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http://dx.doi.org/10.1016/j.lungcan.2020.10.021DOI Listing
March 2021

Efficacy of pembrolizumab in patients with brain metastasis caused by previously untreated non-small cell lung cancer with high tumor PD-L1 expression.

Lung Cancer 2021 01 15;151:60-68. Epub 2020 Nov 15.

Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka, 411-8777, Japan.

Objectives: Pembrolizumab is recommended for patients with previously untreated non-small cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of ≥1%. The KEYNOTE-024 study described the efficacy of pembrolizumab in patients with previously untreated NSCLC who had a PD-L1 TPS of at least 50 %. However, patients with untreated brain metastasis (BM) were excluded from many clinical trials. Therefore, we assessed the efficacy of pembrolizumab against BM of NSCLC with high tumor PD-L1 expression.

Materials And Methods: We retrospectively reviewed patients who received pembrolizumab as first-line treatment against NSCLC with PD-L1 TPS ≥ 50 % between March 2017 and September 2019. Treatment efficacy was compared between patients with (BM group) and without BM (non-BM group). In addition, the BM group was divided into patients who previously received treatment for BM before pembrolizumab (BM-T group) and those with no prior treatment for BM (BM-not T group).

Results: Eighty-seven patients (23 BM group and 64 non-BM group) were assessable for efficacy. No significant differences in patient characteristics were found between the BM and non-BM groups, but proportion of patients with stage IV at diagnosis was significantly higher in the BM group. Median progression-free survival (PFS) (6.5 months vs. 7.0 months) and overall survival (OS) (21.6 months vs. 24.6 months) did not significantly differ between the two groups. The response rate of BM was 70 %. The BM group was subdivided into 13 patients in the BM-T group and 10 patients in the BM-not T group. No significant differences in patient characteristics were found between the two groups, but maximum diameter of BM and proportion of patients with symptomatic BM were significantly greater in the BM-T group. PFS and OS did not significantly differ between the two groups. The median PFS of BM was 13.6 months in the BM-T group and 18.6 months in the BM-not T group.

Conclusion: Pembrolizumab may be effective for BM caused by previously untreated NSCLC with high PD-L1 tumor expression.
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http://dx.doi.org/10.1016/j.lungcan.2020.11.009DOI Listing
January 2021

Retrospective analysis of osimertinib re-challenge after osimertinib-induced interstitial lung disease in patients with EGFR-mutant non-small cell lung carcinoma.

Invest New Drugs 2021 Apr 21;39(2):571-577. Epub 2020 Sep 21.

Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho Suntou-gun, Shizuoka, 411-8777, Japan.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has exhibited efficacy in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a fatal adverse event of osimertinib treatment, and it requires treatment discontinuation. There are few reports regarding the safety and efficacy of osimertinib re-challenge in patients who experienced osimertinib-induced ILD. This retrospective study assessed this treatment option. We retrospectively collected data for patients treated with osimertinib who developed ILD at Shizuoka Cancer Center from April 2016 to March 2020. ILD was diagnosed by two doctors based on imaging tests and blood tests to exclude other causes. Among 215 patients treated with osimertinib, 28 developed ILD. The median age of patients with ILD was 69.5 years (range, 39.0-80.0). In addition, 29% of patients were men, and 46% had a history of smoking. Eleven patients were re-administered EGFR TKIs, including eight patients treated with osimertinib and three patients treated with alternative EGFR TKIs. Among patients re-challenged with osimertinib, none who previously experienced grade 1 ILD exhibited ILD relapse, even with the same osimertinib dose and without the concurrent administration of systemic steroids. Meanwhile, one of the four patients who previously exhibited grade 2 ILD experienced despite a dose reduction for osimertinib and systemic steroid administration. For patients with EGFR-mutant NSCLC who experience grade 1 ILD during osimertinib therapy, osimertinib re-challenge may be suitable when no other treatments are available.
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http://dx.doi.org/10.1007/s10637-020-01005-1DOI Listing
April 2021

Improvement strategies for successful next-generation sequencing analysis of lung cancer.

Future Oncol 2020 Aug 3;16(22):1597-1606. Epub 2020 Jun 3.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, 541-8567, Japan.

We aimed to improve the success rate of NGS (next-generation sequencing) analysis through improved strategies of lung cancer sampling. The improvement strategies are as follows. Surgically resected specimens were preferentially submitted in cooperation with pathologists and surgeons. In bronchoscopic samples, the size of the sample collection device and the number of samples collected was increased. The strategies increased the success rate of NGS analysis of DNA from 69.3 to 91.1%, and that of RNA from 64.6 to 90.0%. The introduction of strategies aimed at improving the success of NGS analysis resulted in an improvement in the success rate and brought us closer to the delivery of effective precision medicine in cancer therapy.
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http://dx.doi.org/10.2217/fon-2020-0332DOI Listing
August 2020

Osimertinib for patients with poor performance status and EGFR T790M mutation-positive advanced non-small cell lung cancer: a phase II clinical trial.

Invest New Drugs 2020 12 18;38(6):1854-1861. Epub 2020 May 18.

Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Osimertinib is a molecularly targeted agent used to treat non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) T790M mutation. However, its efficacy and safety profile when patients have poor performance status (PS) is unknown. Therefore, we conducted an open-label, multi-center, single-arm phase II study to evaluate its efficacy and safety in EGFR T790M mutation-positive NSCLC patients with Eastern Cooperative Oncology Group PS scores of between 2 and 4. Patients received 80 mg of osimertinib once daily. Our primary endpoint was progression-free survival. Eighteen patients were enrolled between June 2017 and November 2018. The median age was 77 years (range: 55-85 years). Ten, six, and two patients had PS scores of 2, 3, and 4, respectively. All patients had adenocarcinoma with common EGFR mutations and had been treated with first- or second-generation EGFR- tyrosine kinase inhibitors previously. The overall median progression-free survival was 7.0 months (90% confidence interval: 5.5-8.9 months). The overall response rate and median overall survival were 53% and 12.7 months, respectively. Moreover, improved PS scores were observed in 72% of the patients. Although the incidence of grade 3 adverse events was low, with no grade 4 or 5 events observed, three patients required treatment cessation due to the development of interstitial lung disease. Osimertinib therapy could be beneficial for EGFR T790M mutation-positive advanced NSCLC patients with poor PS. This trial was registered with the Japan Registry of Clinical Trials on March 12, 2019 (trial no. jRCT1041180081).
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http://dx.doi.org/10.1007/s10637-020-00943-0DOI Listing
December 2020

PD-L1 expression and response to pembrolizumab in patients with EGFR-mutant non-small cell lung cancer.

Jpn J Clin Oncol 2020 May;50(5):617-622

Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer is less likely to express programmed death-ligand 1 (PD-L1) than tumors with wild-type EGFR and is associated with poor response to pembrolizumab. To understand the relationship between EGFR mutation and PD-L1 expression in pembrolizumab response, we retrospectively evaluated the factors contributing to the high tumor proportion score in 155 EGFR-mutant non-small cell lung cancer cases and their associated response to pembrolizumab. Uncommon EGFR mutations were significantly associated with a PD-L1 tumor proportion score ≥ 50% compared to common EGFR mutations. The objective response rate to pembrolizumab of 14 patients was 36%, including 22% in patients with common EGFR mutations, 60% in patients with uncommon EGFR mutations and 75% in patients with both uncommon mutations and a PD-L1 tumor proportion score ≥ 50%. A PD-L1 tumor proportion score ≥ 50% was more frequent in non-small cell lung cancer patients harboring uncommon EGFR mutations and was associated with pembrolizumab efficacy.
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http://dx.doi.org/10.1093/jjco/hyaa033DOI Listing
May 2020

Association Between Clinical Tumor Burden and Efficacy of Immune Checkpoint Inhibitor Monotherapy for Advanced Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2020 09 26;21(5):e405-e414. Epub 2020 Feb 26.

Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi, Japan.

Background: Programmed cell death 1 (PD-1) inhibitors have become a standard treatment, albeit not completely effective, for patients with advanced non-small-cell lung cancer (NSCLC). Previous studies of advanced melanoma have revealed that the tumor burden predicted the response to PD-1 inhibitors, although this relationship has remained unclear for NSCLC.

Patients And Methods: The present single-center retrospective study evaluated 163 patients with advanced NSCLC who had received PD-1/programmed cell death ligand 1 (PD-L1) inhibitor monotherapy from December 2015 to December 2018. The clinical tumor burden was estimated using the baseline sum of the target lesions' longest diameters (BSLDs), measured according to the Response Evaluation Criteria for Solid Tumors, and the baseline number of metastatic lesions (BNMLs).

Results: The optimal cutoff values for predicting progression-free survival (PFS) were 5 for the BNMLs and 76 mm for the BSLDs, using the minimum P value method. The low-BNML group included 73 patients (44.8%). The median PFS was 12.2 months in the low-BNML group and 2.8 months in the high-BNML group (hazard ratio, 0.51; P = .0005). The low-BSLD group included 92 patients (56.4%). The median PFS was 9.6 months in the low-BSLD group and 3.4 months in the high-BSLD group (hazard ratio, 0.52; P = .0006). Multivariable analysis revealed that low-BSLD, low-BNML, nonsquamous histologic type and a PD-L1 tumor proportion score of ≥ 50% were independently associated with prolonged PFS.

Conclusions: PD-L1 expression and the clinical tumor burden can predict the efficacy of PD-1/PD-L1 inhibitor monotherapy for NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.02.012DOI Listing
September 2020

Clinical and radiation dose-volume factors related to pneumonitis after treatment with radiation and durvalumab in locally advanced non-small cell lung cancer.

Invest New Drugs 2020 10 3;38(5):1612-1617. Epub 2020 Mar 3.

Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka, 411-8777, Japan.

Introduction Durvalumab has been shown to confer a survival benefit after definitive chemoradiotherapy in the patients with locally advanced non-small cell lung cancer, but no studies have attempted to identify risk factors for pneumonitis after durvalumab therapy. The purpose of this study was to investigate associations between clinical and radiation dose-volume factors, and the severity of pneumonitis. Methods We retrospectively assessed the cases of 30 patients who had been started on durvalumab therapy between July 2018 and February 2019. In this study we evaluated the percentage of lung volume receiving radiation dose in excess of 20 Gy (V20) as radiation dose-volume factor. We compared V20 and some baseline factors between a grade 0 or 1 (Gr 0/1) pneumonitis group and a grade 2 or more (≥Gr 2) pneumonitis group, and we performed a logistic regression analysis to establish the associations between variables and ≥ Gr 2 pneumonitis. Results Pneumonitis had developed in 22 patients (73.3%): Gr 1/2/3-5 in 8 (26.7%)/14 (46.7%) /0 (0%), respectively. The difference in V20 between the Gr 0/1 group and Gr 2 group (median: 20.5% vs. 23.5%, p = 0.505) was not statistically significant, and thus V20 was not a risk factor for Gr 2 pneumonitis (odds ratio: 1.047, p = 0.303). None of the clinical factors, including sex, age, smoking history, presence of baseline pneumonitis, type of radiation therapy, location of lesion and facility, were risk factors. Conclusions Our study suggest that the severity of pneumonitis after durvalumab is unrelated to V20 or any of the clinical factors assessed in this study.
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http://dx.doi.org/10.1007/s10637-020-00917-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497668PMC
October 2020

bacteremic pneumonia.

IDCases 2020 5;19:e00712. Epub 2020 Feb 5.

Division of Infectious Diseases, Shizuoka Cancer Center Hospital, Suntou-gun, Shizuoka, Japan.

An 81-year-old man with lung cancer with bone metastases, interstitial pneumonia, and emphysema, was hospitalized for pain control. He developed fever and chills during hospitalization. Physical examination revealed a fever of 39.1 °C, but there were no findings on history or physical examination to suggest the source of the infection. Gram-negative cocci were detected in the blood culture (Fig. 1) and in a Gram stained sputum smear (Figs. 3 and 4). and were ruled out based on history and an absence of suggestive symptoms. The cause of his fever was diagnosed as bacteremic pneumonia based on the blood culture and the sputum smear results, and he was treated with intravenous ceftriaxone. This case illustrates the importance of Gram staining of sputum and blood culture. should be considered in the differential diagnosis when gram-negative cocci are detected in the blood and the sputum.
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http://dx.doi.org/10.1016/j.idcr.2020.e00712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021534PMC
February 2020

Evaluation of gefitinib systemic exposure in EGFR-mutated non-small cell lung cancer patients with gefitinib-induced severe hepatotoxicity.

Cancer Chemother Pharmacol 2020 03 10;85(3):605-614. Epub 2020 Feb 10.

Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Purpose: Severe hepatotoxicity induced by the standard dose of gefitinib (250 mg daily) often becomes manageable by dose reduction to 250 mg every other day. Thus, we hypothesized that systemic exposure of standard-dose gefitinib in patients with experience of severe hepatotoxicity might be higher than that in patients without severe hepatotoxicity.

Methods: Patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer who were receiving gefitinib either at a reduced dose (250 mg every other day) because of intolerable severe toxicity or at a standard dose (250 mg daily) were enrolled. A series of blood samples were collected to estimate pharmacokinetic parameters and calculate systemic exposure of standard-dose gefitinib (area under the concentration-time curve from 0 to 24 h at steady state, AUC). Systemic exposure of unbound gefitinib (fu·AUC) was also assessed, because gefitinib is extensively bound to serum proteins.

Results: Of the 38 enrolled patients, 34 (23 patients without experience of severe hepatotoxicity, 11 patients with experience of severe hepatotoxicity) were evaluable. There was no significant differences in total AUC or unbound fu·AUC between patients with and without experience of severe hepatotoxicity. Analysis of the time to severe hepatotoxicity indicated no difference between patients with a high AUC and those with a low AUC of either total or unbound gefitinib.

Conclusion: This study suggests that reversible severe hepatotoxicity is not caused by high systemic exposure of gefitinib.
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http://dx.doi.org/10.1007/s00280-020-04034-yDOI Listing
March 2020

Efficacy of Second-line Chemotherapy in Patients With Sensitive Relapsed Small-cell Lung Cancer.

In Vivo 2019 Nov-Dec;33(6):2229-2234

Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi, Japan.

Background/aim: To evaluate treatment efficacy of cisplatin, etoposide, and irinotecan combined therapy (PEI), platinum-rechallenge chemotherapy (Pt-Re) and amrubicin monotherapy (AMR) for patients with sensitive relapsed small cell lung cancer (SCLC).

Patients And Methods: We defined sensitive relapse as treatment-free interval (TFI) ≥90 days. We retrospectively collected patients' data from medical records between September 2002 and December 2016. Patients with sensitive relapsed SCLC who received second-line chemotherapy were separated into those treated with PEI, with Pt-Re, or with AMR.

Results: Seventy-one patients (16 PEI group, 27 Pt-Re group, and 28 AMR group) were assessable for efficacy. No significant differences in patient characteristics were found among the three groups. The median overall survival (MST) was 29.3 months in the PEI group, 24.6 months in the Pt-Re group, and 20.6 months in the AMR group (p=0.042).

Conclusion: A significant difference was observed in the overall survival of patients treated with PEI, Pt-Re and AMR and the MST of PEI was the longest.
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http://dx.doi.org/10.21873/invivo.11727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899092PMC
March 2020

Acquired immunodeficiency associated with thymoma: a case report.

BMC Cancer 2019 Aug 2;19(1):762. Epub 2019 Aug 2.

Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.

Background: Acquired immunodeficiency associated with thymoma is a rare disorder. Here we reported a case of acquired immunodeficiency with thymoma, with an unusual pattern of low CD4 count with normal gammaglobulin levels.

Case Presentation: A 70-year-old man presented to the emergency room of our hospital with a high-grade fever, headache, and nausea. He had a five-year history of unresectable thymoma treatment, including several cytotoxic regimens. He had received thoracic palliative radiotherapy 2 months prior to the emergent visit. During the previous month, he had experienced multiple febrile episodes, dry cough, fatigue, weight loss, and watery diarrhea. Upon admission, he had a high-grade fever, nausea, and immobility. Physical examination revealed indistinct consciousness, neck stiffness, and oropharyngeal candidiasis. Both cerebrospinal fluid and blood cultures yielded multiple short chains of Gram-positive rods later identified as Listeria monocytogenes, so he was diagnosed with Listeria meningitis. Intravenous administration of antibiotics was initiated, and the patient fully recovered and was discharged. Additional examination found normal immunoglobulin levels. Peripheral-blood cell counts revealed low CD4 cell count (108 CD4 cells/μl). His CD4 cell count remained low after discharge.

Conclusions: Our findings suggest that physicians need to be aware of severe infections due to immunodeficiency with thymoma.
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http://dx.doi.org/10.1186/s12885-019-5980-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679538PMC
August 2019

Negative impact of malignant effusion on osimertinib treatment for non-small cell lung cancer harboring EGFR mutation.

Invest New Drugs 2020 02 10;38(1):194-201. Epub 2019 Jun 10.

Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka, 411-8777, Japan.

3rd-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, have reasonable efficacy in non-small-cell lung cancers (NSCLC) with EGFR mutations. However, the efficacy of osimertinib in NSCLC patients with fluids, such as pleural, pericardial and abdominal effusions, is unclear. We evaluated the efficacy of osimertinib in this specific setting. NSCLC patients harboring EGFR T790 M mutations who experienced progressive disease after first EGFR-TKI treatment and started osimertinib treatment between April 2016 and August 2018 were retrospectively screened. In particular, we assessed the efficacy of osimertinib for NSCLC with EGFR T790 M mutations in patients who were diagnosed with EGFR T790 M mutation by malignant effusion. Among 90 patients with EGFR T790 M mutation who started osimertinib treatment after EGFR-TKI failure, 21 were diagnosed from malignant effusions excluding cerebrospinal fluid (F group) and 69 using other methods including tissue biopsies (NF group). Patient characteristics were well-balanced between the two groups. Overall response was 50%, and significantly worse in the F group (29%) than the NF group (57%; P = 0.025). Median progression-free survival with osimertinib treatment in the F group (7.1 months, 95% confidence interval [CI]: 2.3-14.0) was significantly shorter than that in the NF group (11.9 months, 95% CI: 9.5-16.0; P = 0.046)). Median drainage-free time was 10.9 months (95% CI: 1.4 months- not reached). The present study showed that the efficacy of osimertinib for NSCLC in which EGFR T790 M mutation is detected by malignant effusion may be less than in EGFR T790 M-mutated NSCLC detected by other methods.
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http://dx.doi.org/10.1007/s10637-019-00808-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985082PMC
February 2020

Optimal Sequence of Local and EGFR-TKI Therapy for EGFR-Mutant Non-Small Cell Lung Cancer With Brain Metastases Stratified by Number of Brain Metastases.

Int J Radiat Oncol Biol Phys 2019 07 6;104(3):604-613. Epub 2019 Mar 6.

Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Purpose: It is unclear whether local therapy (LT) or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) should take precedence for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases (BMs). The number of BMs is important in the choice of LT, including whole-brain radiation therapy, stereotactic radiosurgery, and surgery.

Methods: We retrospectively evaluated cases of EGFR-mutant non-small cell lung cancer with BMs from a single site. Patients were divided into 2 groups based on upfront therapy-EGFR-TKI (TKI) or LTs-and subsequently stratified by the number of BMs.

Results: Among 176 patients, 61% received upfront EGFR-TKI, and 39% received upfront LT. The number of patients with 1 to 4 BMs was similar (56% vs 52%; P = .61). All patients with 1 to 4 BMs in the LT group, except for surgical cases, received stereotactic radiosurgery (n = 31). Among those with ≥5 BMs, most (n = 27; 82%) received whole-brain radiation therapy. There was no significant difference in OS between LT and TKI groups (median overall survival, 28 vs 23 months; hazard ratio, 0.75; 95% confidence interval, 0.52-1.07). In patients with 1 to 4 BMs, the LT group showed significantly better OS compared with the TKI group (median overall survival, 35 vs 23 months; hazard ratio, 0.54; 95% confidence interval, 0.32-0.90). There was no difference in OS between the LT and TKI groups for patients with ≥5 BMs. Multivariable analysis showed that upfront LT yielded significantly better OS for patients with 1 to 4 BMs.

Conclusion: Upfront LT followed by EGFR-TKI is more effective than upfront EGFR-TKI for the survival of untreated patients harboring EGFR mutations with 1 to 4 BMs.
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http://dx.doi.org/10.1016/j.ijrobp.2019.02.051DOI Listing
July 2019

Leptomeningeal recurrence after long-term alectinib therapy for non-small cell lung cancer harboring an EML4-ALK fusion protein.

Invest New Drugs 2019 02 3;37(1):184-187. Epub 2018 Jul 3.

Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.

The recent approval of anaplastic lymphoma kinase (ALK) inhibitors for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC) has dramatically transformed cancer therapy. However, leptomeningeal metastases (LM) are frequent and often devastating complications of ALK-rearranged NSCLC, and treatment against LM remains challenging. Herein we report a case of a 19-year-old male diagnosed with ALK-rearranged NSCLC with LM. He experienced heavy treatment before introduction of alectinib therapy, which continued for approximately 5.5 years with marked efficacy. However, he experienced recurrence of a bulbar metastasis after discontinuation of alectinib. Reintroduction of standard-dose alectinib therapy resolved the lesion again. Our findings suggest that ALK-tyrosine kinase inhibitor therapy should be continued in patients showing a long-term complete response, unless intolerable toxicities are present, and that rechallenge treatment with alectinib may represent a therapeutic option for central nervous system metastases.
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http://dx.doi.org/10.1007/s10637-018-0633-6DOI Listing
February 2019

Pharmacodynamic analysis of eribulin safety in breast cancer patients using real-world postmarketing surveillance data.

Cancer Sci 2018 Sep 23;109(9):2822-2829. Epub 2018 Jul 23.

Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, Tokyo, Japan.

Postmarketing surveillance is useful to collect safety data in real-world clinical settings. In this study, we applied postmarketing real-world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer. Demographic and safety data were collected using an active surveillance method from eribulin-treated recurrent or metastatic breast cancer patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that might affect the severity of neutropenia were investigated, and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony-stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were as follows: mean transit time = 104.5 h, neutrophil proliferation rate constant = 0.0377 h , neutrophil elimination rate constant = 0.0295 h , and linear coefficient of drug effect = 0.0413 mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of postmarketing surveillance data to a model-based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin.
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http://dx.doi.org/10.1111/cas.13708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125471PMC
September 2018

Crizotinib-induced simultaneous multiple cardiac toxicities.

Invest New Drugs 2018 10 2;36(5):949-951. Epub 2018 May 2.

Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.

Crizotinib is a receptor tyrosine kinase inhibitor that has several targets, including c-ros oncogene 1 and the MET proto-oncogene. Considering its known cardiac toxicity, bradycardia is often investigated following treatment with crizotinib. Our patients had bradycardia, QT prolongation, ventricular rhythm, ventricular fibrillation, and pericarditis simultaneously. The cardiotoxicity of crizotinib can sometimes be simultaneous; thus, intensive observation is needed.
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http://dx.doi.org/10.1007/s10637-018-0605-xDOI Listing
October 2018

Efficacy of prophylactic cranial irradiation in patients with limited-disease small-cell lung cancer who were confirmed to have no brain metastasis via magnetic resonance imaging after initial chemoradiotherapy.

Oncotarget 2018 Apr 3;9(25):17664-17674. Epub 2018 Apr 3.

Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Background: Prophylactic cranial irradiation (PCI) is recommended for patients with limited-disease small-cell lung cancer (LD-SCLC) who achieved good response to definitive chemoradiotherapy. However, most clinical studies lacked brain imaging scans before PCI. Our study aimed to investigate whether PCI has a survival benefit in patients who have no brain metastases (BM) confirmed via magnetic resonance imaging (MRI) before PCI.

Results: Eighty patients were included in this study. Sixty patients received PCI (PCI group) and 20 patients did not (non-PCI group). OS was not significantly different between the two groups. The median OS time was 4.3 years (95% CI: 2.6 years-8.6 years) in the PCI group and was not reached (NR) (95% CI: 1.9 years-NR) in the non-PCI group ( = 0.542). Moreover, no differences were observed in the 3-year rates of PFS (46.2% and 44.4%, = 0.720) and cumulative incidence of BM (24.0% vs. 27%, = 0.404).

Conclusions: Our result suggests that PCI may not have a survival benefit in patients with LD-SCLC confirmed to have no BM after initial therapy, even if patients achieve a good response to definitive chemoradiotherapy.

Patients And Methods: We retrospectively evaluated patients with LD-SCLC who were confirmed to have no BM via MRI after initial chemoradiotherapy at the Shizuoka Cancer Center between September 2002 and August 2015. The overall survival (OS), progression-free survival (PFS), and cumulative incidence of BM were estimated using the Kaplan-Meier method between patients who received PCI and those who did not. Propensity score matching was used to balance baseline characteristics.
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http://dx.doi.org/10.18632/oncotarget.24830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915147PMC
April 2018

Clinical Factors Predicting Detection of T790M Mutation in Rebiopsy for EGFR-Mutant Non-small-cell Lung Cancer.

Clin Lung Cancer 2018 03 10;19(2):e247-e252. Epub 2017 Aug 10.

Division of Thoracic Oncology, Shizuoka Cancer Center, Suntou-gun, Shizuoka, Japan.

Background: T790M, a secondary epidermal growth factor receptor (EGFR) mutation, accounts for approximately 50% of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs). To facilitate the use of third-generation EGFR-TKIs to potentially overcome T790M-mediated resistance, we evaluated the clinical factors influencing the incidence of T790M mutation.

Patients And Methods: We retrospectively screened patients with non-small-cell lung cancer harboring EGFR mutations with progressive disease who were rebiopsied between January 2013 and December 2016. Factors influencing T790M status were evaluated by univariate and multivariate analysis.

Results: Among 131 rebiopsied patients for whom EGFR mutation status was available, 58 (44%) had T790M mutations. Patient characteristics at rebiopsy were not significantly different between T790M-positive and -negative groups, except for surgical history (postsurgery recurrence). Total duration of EGFR-TKI treatment before rebiopsy, TKI-free interval, EGFR-TKI treatment history immediately before rebiopsy, continuation of initial EGFR-TKI beyond progressive disease, progression-free survival after initial TKI treatment, and rebiopsy site (other than fluid samples) significantly influenced T790M status. The incidence of T790M mutation was shown by multivariate analysis to be significantly higher in patients with postsurgery recurrence and total duration of EGFR-TKI treatment ≥ 1 year before rebiopsy (odds ratio, 4.2; 95% confidence interval, 1.3-15.7 and odds ratio, 4.4; 95% confidence interval, 1.1-19.8, respectively).

Conclusion: Postsurgery recurrence and longer total duration of EGFR-TKI treatment before rebiopsy may represent useful predictive markers for T790M detection. In patients with these clinical factors, rebiopsies are more recommended to detect T790M mutation.
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http://dx.doi.org/10.1016/j.cllc.2017.07.002DOI Listing
March 2018

The incidence and risk factors of febrile neutropenia in chemotherapy-naïve lung cancer patients receiving etoposide plus platinum.

Cancer Chemother Pharmacol 2017 Jun 28;79(6):1229-1237. Epub 2017 Apr 28.

Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka, 411-8777, Japan.

Purpose: This study was to determine the incidence and risk factors of febrile neutropenia in chemotherapy-naïve Japanese patients treated systemically with etoposide plus platinum for lung cancer.

Methods: The study was a retrospective analysis of 244 patients who were monitored for febrile neutropenia through multiple cycles of the combination of etoposide with platinum, and the associations between incidence of febrile neutropenia and patient characteristics were evaluated.

Results: Eighty-eight patients were treated with etoposide plus cisplatin and 156 were treated with etoposide plus carboplatin. Of the 244 patients treated, 198 (81.1%) completed 4 cycles for chemotherapy. Febrile neutropenia was observed in 48 of 244 patients (19.7%), including 18 of 88 (20.5%) patients who received etoposide plus cisplatin and 30 of 156 (19.2%) patients who received etoposide plus carboplatin. Grade 3 or 4 of neutropenia was experienced by a total of 208 patients (85.2%); 79 of 88 (89.8%) receiving etoposide plus cisplatin and 129 of 156 (82.7%) receiving etoposide plus carboplatin. Male gender and previous radiotherapy were identified by multivariate analysis as independent risk factors for febrile neutropenia.

Conclusions: These results contrast with findings in Western patients and suggest that ethnic differences exist in the incidence of febrile neutropenia in patients receiving etoposide plus platinum chemotherapy. In addition, our results suggest that primary prophylaxis with granulocyte colony-stimulating factor should be considered for patients with these risk factors for febrile neutropenia prior to treatment with etoposide plus platinum.
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http://dx.doi.org/10.1007/s00280-017-3324-7DOI Listing
June 2017

Rebiopsy for patients with non-small-cell lung cancer after epidermal growth factor receptor-tyrosine kinase inhibitor failure.

Cancer Sci 2016 Jul 21;107(7):1001-5. Epub 2016 Jun 21.

Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Although third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) can overcome T790M-mediated resistance in non-small-cell lung cancer (NSCLC), rebiopsy to confirm T790M status is occasionally difficult. We aimed to investigate the current tendency and the limitations of rebiopsy in clinical practice. This study included 139 consecutive NSCLC patients with EGFR mutations, who had experienced progressive disease (PD) after EGFR-TKI treatment. We retrospectively reviewed patient characteristics, tumor progression sites and rebiopsy procedures. Of 120 patients (out of the original 139) who were eligible for clinical trials, 75 (63%) underwent rebiopsy for 30 pleural effusions, 32 thoracic lesions, four bone, two liver, and seven at other sites. Rebiopsy procedures included 30 thoracocentesis, 24 transbronchial biopsies, 13 computed tomography (CT)-guided needle biopsies and 8 other procedures. Of the 75 rebiopsied patients, 71 (95%) were pathologically diagnosed with malignancy; and 34 (45%) had available tissue samples for EGFR analyses. Of the 75 biopsied patients, 61 (81%) were analyzed for EGFR mutation, using tissue or cytology samples; T790M mutations were identified in 20 (33%) of the 61 patients. Of the 120 patients, 45 (38%) did not undergo rebiopsy, because of inaccessible tumor sites (n = 19), patient refusal (n = 6) or decision of physician (n = 10). In conclusion, among patients with EGFR mutations who had PD after EGFR-TKI treatment, 63% underwent rebiopsy. Most rebiopsy samples were diagnosed with malignancy. However, tissue samples were less available and T790M mutations were identified less frequently than in previous studies. Skill and experience with rebiopsy and noninvasive alternative methods will be increasingly important.
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http://dx.doi.org/10.1111/cas.12963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946719PMC
July 2016

Evaluation of discomfort and tolerability to bronchoscopy according to different sedation procedures with midazolam.

Exp Ther Med 2015 Aug 4;10(2):659-664. Epub 2015 Jun 4.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo 650-0047, Japan.

Patients frequently experience great discomfort during a bronchoscopy for the diagnosis of lung neoplasms. Sedation is generally recommended during bronchoscopy; however, few studies have evaluated the discomfort and tolerability of patients to a bronchoscopy with regard to the administration procedures. The aim of the present study was to evaluate the discomfort and tolerability of patients undergoing a bronchoscopy using different sedation procedures with midazolam. The retrospective survey of sedation during bronchoscopy involved the comparison of two periods: January-March 2012 (first period) and July-September 2012 (second period). A numerical rating score, which ranged between 1 (best) and 5 (worst) according to the subjective view of the patients, was used to rate patient discomfort, pain, sensation, time and tolerability to the bronchoscopy. In the first period, 2.5 mg midazolam was administered prior to the initiation of surgery, and additional doses of midazolam was added in 2.5-mg increments whenever the patient deviated from the target sedation level. In the second period, 2.0 or 3.0 mg midazolam was administered prior to the initiation of surgery, and additional midazolam doses were administered in 1.0-mg increments until the patients were sedated to the target sedation level. In total, 60 and 68 valid responses were obtained in the first and second periods, respectively. The patients in the second period exhibited significantly improved discomfort and pain scores during the bronchoscopy and higher rates of consent to re-examination, as compared with the patients in the first period (1.89±1.40 vs. 2.78±1.52, P<0.001; 1.48±1.13 vs. 2.00±1.37, P=0.005; 2.45±1.62 vs. 3.13±1.47, P=0.013, respectively). The amount of midazolam administered was significantly higher in the second period. There were no fatal complications during the bronchoscopy in either period. In conclusion, the present study observed that the administration of additional midazolam in small doses, until the target sedation level is achieved, is a safe procedure that is associated with significantly less discomfort and pain during bronchoscopy and a greater consent to re-examination when compared with the administration of a fixed dose of midazolam.
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http://dx.doi.org/10.3892/etm.2015.2547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508987PMC
August 2015

Recurrence of a mediastinal liposarcoma 20 years after surgery: A case of carbon ion radiotherapy resulting in fatal tracheoesophageal fistula.

Respir Investig 2015 Jul 16;53(4):170-2. Epub 2015 Mar 16.

Department of Clinical Pathology, Kobe City Medical Center General Hospital, Kobe, Japan.

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http://dx.doi.org/10.1016/j.resinv.2015.02.002DOI Listing
July 2015

High-dose erlotinib for refractory leptomeningeal metastases after failure of standard-dose EGFR-TKIs.

Cancer Chemother Pharmacol 2015 Jun 29;75(6):1261-6. Epub 2015 Apr 29.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

Background: After initial response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), approximately one-third of patients develop central nervous system (CNS) metastases, including leptomeningeal metastases (LM). To achieve longer survival, control of CNS metastases is important, but therapeutic options are limited for LM after failure of standard-dose EGFR-TKIs.

Methods: We retrospectively evaluated the efficacy and safety of high-dose erlotinib in EGFR-mutant non-small cell lung cancer (NSCLC) patients with refractory LM after failure of standard-dose EGFR-TKIs. Survivals from diagnosis of LM to death were compared in patients with or without high-dose erlotinib.

Results: Between January 2007 and April 2013, we identified 35 patients with EGFR-mutant NSCLC, complicated with LM, and 12 underwent high-dose erlotinib, while the other 23 received only standard-dose EGFR-TKIs. In patients receiving high-dose erlotinib, magnetic resonance imaging response was confirmed in 3 (30 %) of 10 evaluable patients. Median time to CNS progression was 2.3 months (95 % confidence interval [CI] 1.8-5.5 months). Performance status and neurological symptoms improved in 4 (33 %) of 12 and 6 (50 %) of 12 patients, respectively. No severe adverse events (≥grade 3) associated with high-dose erlotinib were observed. Median survival time from diagnosis of LM in patients with high-dose erlotinib was 6.2 months (95 % CI 2.5-8.5 months), and in those without 5.9 months (95 % CI 1.3-7.8 months) (p = 0.94).

Conclusion: High-dose erlotinib suggested its efficacy and safety in some patients with refractory LM. It represents a potential therapeutic option against LM after failure of standard-dose EGFR-TKIs, especially to palliate LM-related neurological symptoms.
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http://dx.doi.org/10.1007/s00280-015-2759-yDOI Listing
June 2015

The safety and efficacy of paclitaxel and carboplatin with or without bevacizumab for treating patients with advanced nonsquamous non-small cell lung cancer with interstitial lung disease.

Cancer Chemother Pharmacol 2014 Dec 23;74(6):1159-66. Epub 2014 Sep 23.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 2 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan,

Purpose: Optimal chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD) is established for paclitaxel and carboplatin, but is otherwise controversial. Therefore, we assessed the efficacy and safety of paclitaxel and carboplatin with or without bevacizumab for treating these patients.

Methods: We analyzed the outcomes of 21 patients with advanced nonsquamous NSCLC with ILD who received paclitaxel and carboplatin without (paclitaxel-carboplatin group; n = 11) or with bevacizumab (paclitaxel-carboplatin-bevacizumab group; n = 10) between April 2008 and October 2013.

Results: The median progression-free survival time of the paclitaxel-carboplatin-bevacizumab group was 5.3 months (95 % CI 0.4-11.6 months) compared with 4.4 months (95 % CI 0.9-6.3 months) for the paclitaxel-carboplatin group (p = 0.060). Their respective median overall survival times were 16.1 months (range 0.4-34.8 months) and 9.7 months (range 2.6-37.0 months) (p = 0.772) with corresponding overall response rates of 40 and 27 % (p = 0.659), respectively. One patient in the paclitaxel-carboplatin-bevacizumab group experienced chemotherapy-related exacerbation of ILD (0/11 vs. 1/10; p = 0.476).

Conclusions: The addition of bevacizumab to paclitaxel and carboplatin may provide an effective and safe treatment option for patients with advanced nonsquamous NSCLC with ILD.
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http://dx.doi.org/10.1007/s00280-014-2590-xDOI Listing
December 2014
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