Publications by authors named "Koichi Minato"

69 Publications

Efficacy and Safety of Anti-Programed Death-1 Blockade in Previously Treated Large-Cell Neuroendocrine Carcinoma.

Chemotherapy 2021 Apr 7:1-7. Epub 2021 Apr 7.

Department of Respiratory Medicine, Comprehensive Cancer Center, Saitama Medical University International Medical Center, Kawagoe, Japan.

Background: Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a rare tumor with an aggressive clinical course. However, there is limited knowledge of its treatment strategy. This retrospective study aimed to assess the efficacy and safety of anti-programed death-1 (PD-1) blockade monotherapy in previously treated advanced LCNEC.

Methods: Eleven patients with previously treated advanced LCNEC who received immune checkpoint inhibitor monotherapy between January 2015 and November 2020 were retrospectively analyzed for efficacy and safety.

Results: Of a total of 11 patients (median [range] age, 66 [37-79] years; 8 men [73%] and 3 women [27%]), 8 patients had performance status (PS) 0-1 [73%] and 3 patients had PS 2 [27%]; 9 patients received 1 prior chemotherapy [82%] and 2 patients received 2 prior chemotherapies [18%]. The median follow-up duration was 4.6 months. Although PD-1 blockade was administered at median cycles of 3 (range, 1-12), overall response rate, median progression-free survival, and median overall survival were 9.1%, 2.7 months, and 4.6 months, respectively. Any adverse events were observed in 9 patients (82%), including 1 patient with grade 3 pneumonitis as a serious adverse event.

Conclusion: Anti-PD-1 blockade monotherapy as a subsequent line for previously treated advanced LCNEC exhibited usefulness and tolerability and was identified as a valid treatment option.
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http://dx.doi.org/10.1159/000514841DOI Listing
April 2021

Low-Dose Olanzapine Plus Granisetron and Dexamethasone for Carboplatin-Induced Nausea and Vomiting in Patients with Thoracic Malignancies: A Prospective Multicenter Phase II Trial.

Oncologist 2021 Apr 3. Epub 2021 Apr 3.

Department of Cardiology and Respiratory Medicine, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan.

Background: Olanzapine is an inexpensive and durable agent for the treatment of chemotherapy-induced nausea and vomiting and is also superior to neurokinin-1 receptor antagonists in the control of nausea. This study aimed to investigate the efficacy and safety of a low dose of 5 mg olanzapine plus granisetron and dexamethasone for treatment of carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic malignancies.

Materials And Methods: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four centers in Japan. Registered patients were scheduled to receive area under the curve (AUC) ≥5 mg/mL per minute of CBDCA and had never received moderately to highly emetogenic chemotherapy. Patients received olanzapine 5 mg/day orally after supper for 4 days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the overall phase (0-120 hours).

Results: Between February 2018 and June 2020, 51 patients were enrolled, and 50 patients were evaluated. The CR rates in the overall (0-120 hours), acute (0-24 hours), and delayed phases (24-120 hours) were 94.0%, 100%, and 94.0%, respectively. No grade 3 or higher adverse effects of olanzapine were observed.

Conclusion: Prophylactic antiemetic therapy with a low dose of 5 mg olanzapine plus granisetron and dexamethasone showed durable efficacy with an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic malignancies receiving an AUC ≥5 mg/mL per minute of CBDCA-based regimen. Clinical trial identification number: UMIN000031267.

Implications For Practice: The results of this phase II trial indicated that the prophylactic administration of low-dose of 5 mg olanzapine combined with granisetron and dexamethasone has promising activity with acceptable safety profile in patients with thoracic malignancy receiving high-dose carboplatin chemotherapy.
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http://dx.doi.org/10.1002/onco.13772DOI Listing
April 2021

Randomized Phase III Study of Irinotecan Plus Cisplatin Versus Etoposide Plus Cisplatin for Completely Resected High-Grade Neuroendocrine Carcinoma of the Lung: JCOG1205/1206.

J Clin Oncol 2020 12 2;38(36):4292-4301. Epub 2020 Nov 2.

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

Purpose: To verify the superiority of irinotecan plus cisplatin over etoposide plus cisplatin as postoperative adjuvant chemotherapy for patients with pathologic stage I-IIIA, completely resected, high-grade neuroendocrine carcinoma (HGNEC) of the lung.

Methods: This was a randomized, open-label, phase III study on patients with completely resected stage I-IIIA HGNEC of the lung. They were randomly assigned to receive either etoposide (100 mg/m, days 1-3) plus cisplatin (80 mg/m, day 1) or irinotecan (60 mg/m, days 1, 8, 15) plus cisplatin (60 mg/m, day 1) up to four cycles. The primary end point was relapse-free survival (RFS) in the intention-to-treat population. This trial was registered with the Japan Registry of Clinical Trials (jRCTs031180216).

Results: Between April 2013 and October 2018, 221 patients were enrolled (etoposide plus cisplatin arm, 111 patients; irinotecan plus cisplatin arm, 110 patients). In the second interim analysis, early termination of the trial was recommended because of futility. At a median follow-up of 24.1 months, the 3-year RFS was 65.4% for etoposide plus cisplatin and 69.0% for irinotecan plus cisplatin, with a hazard ratio of 1.076 (95% CI, 0.666 to 1.738; one-sided log-rank = .619). Grade 3-4 adverse events were more frequent in the etoposide plus cisplatin arm, with febrile neutropenia (20% of 109 patients 4% of 107 patients) and neutropenia (97% 36%) being the most common. Meanwhile, grade 3-4 anorexia (6% 11%) and diarrhea (1% 8%) were more frequently observed in the irinotecan plus cisplatin arm.

Conclusion: Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving RFS in patients with completely resected HGNEC; thus, etoposide plus cisplatin remains the standard treatment.
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http://dx.doi.org/10.1200/JCO.20.01806DOI Listing
December 2020

Prognostic value of morphological characteristics assessed by CT scan in patients with non-small cell lung cancer treated with nivolumab.

Thorac Cancer 2020 12 12;11(12):3521-3527. Epub 2020 Oct 12.

Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan.

Background: Nivolumab is known to demonstrate superior overall survival compared with docetaxel in pretreated non-small cell lung cancer (NSCLC) patients. Programmed death-ligand 1 (PD-L1) expression is reported to predict the outcome of treatment by nivolumab in lung cancer patients. However, the significance of the morphological characteristics of chest computed tomography (CT) as predictors of nivolumab efficacy for advanced NSCLC patients remains unknown.

Methods: We performed a multicenter retrospective trial from April 2013 to March 2017, to assess the significance of CT morphological characteristics as predictors of nivolumab efficacy for advanced NSCLC patients. A total of 78 NSCLC patients pretreated with nivolumab were enrolled. A chest radiologist used chest CT to assess the following morphological characteristics of each patient's main tumor and intrathoracic status prior to nivolumab treatment; interstitial septal thickening, peritumoral ground-glass opacity, spiculated margin, air bronchogram, cavity or necrosis, adjacent organ invasion, bulky lymph node, and accumulation of small lymph nodes. Logistic regression and Cox proportional hazards regression models were used to analyze outcomes.

Results: A total of 60 (77%) patients were male and 72 (92%) had a performance status (PS) of 0 or 1. The objective response rates of male patients and heavy smokers were significantly higher than those of female patients and light or never smokers, respectively. Multivariate analysis identified light or never smoking, poor PS, histological type of squamous cell carcinoma, and interstitial septal thickening as independent negative predictors of progression free survival (PFS).

Conclusions: Interstitial septal thickening was a significant and independent predictor of PFS in NSCLC patients treated with nivolumab.

Key Points: SIGNIFICANT FINDINGS OF THE STUDY: Interstitial septal thickening is an independent predictor of progression free survival in non-small lung cancer patients treated with nivolumab.

What This Study Adds: The current study reveals the significance of morphological characteristics obtained via chest computed tomography as a predictor of nivolumab efficacy for advanced non-small cell lung cancer patients.
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http://dx.doi.org/10.1111/1759-7714.13695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705921PMC
December 2020

Five-year follow-up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non-small cell lung cancer: pooled analysis of the ONO-4538-05 and ONO-4538-06 studies.

Jpn J Clin Oncol 2021 Jan;51(1):106-113

Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.

Background: Two phase II studies in Japan examined the efficacy and safety of nivolumab, a programmed cell death 1 receptor inhibitor, in patients with advanced squamous and non-squamous non-small cell lung cancer (ONO-4538-05 and ONO-4538-06). We examined the long-term efficacy and safety of nivolumab in these patients treated for up to 5 years.

Methods: Patients with squamous (N = 35) or non-squamous (N = 76) non-small cell lung cancer received nivolumab (3 mg/kg every 2 weeks) until disease progression/death. Overall survival and progression-free survival were assessed at 5 years after starting treatment in separate and pooled analyses. Safety was evaluated in terms of treatment-related adverse events.

Results: A total of 17 patients were alive at the database lock (26 July 2019). The median overall survival (95% confidence interval) and 5-year survival rate were 16.3 (12.4-25.2) months and 14.3% in squamous patients, 17.1 (13.3-23.0) months and 19.4% in non-squamous patients and 17.1 (14.2-20.6) months and 17.8% in the pooled analysis, respectively. Programmed death ligand-1 expression tended to be greater among 5-year survivors than in non-survivors (P = 0.0703). Overall survival prolonged with increasing programmed death ligand-1 expression, with 5-year survival rates of 11.8, 21.8 and 41.7% in patients with programmed death ligand-1 expression of <1, ≥1-<50 and ≥50%, respectively. Treatment-related adverse events in ≥10% of patients (pooled analysis) included rash (15.3%), malaise (14.4%), decreased appetite (14.4%), pyrexia (14.4%) and nausea (10.8%).

Conclusions: Long-term survival with nivolumab was observed in patients with squamous or non-squamous non-small cell lung cancer. No new safety signals were reported after ≥5 years of follow-up.
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http://dx.doi.org/10.1093/jjco/hyaa157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767981PMC
January 2021

Post-progression survival is strongly linked to overall survival in refractory small-cell lung cancer patients who received amrubicin.

J Cancer Res Ther 2020 Jul-Sep;16(4):764-770

Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ohta, Gunma 373-8550; Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan.

Background: The benefits of second-line chemotherapy on the overall survival (OS) of small-cell lung cancer (SCLC) patients might be confounded by subsequent therapies. In this study, we aimed to determine the influence of progression-free survival (PFS) and postprogression survival (PPS) on OS after second-line chemotherapy in patients with refractory SCLC treated with amrubicin monotherapy.

Materials And Methods: We analyzed the data of 35 patients with refractory SCLC who were treated with amrubicin monotherapy as second-line chemotherapy between July 2005 and December 2015. The correlations of PFS and PPS with OS were statistically analyzed at the individual level using Spearman's rank correlation and linear regression analyses.

Results: The correlation between PPS and OS was strong (r = 0.88, P < 0.05, R = 0.87), while that between PFS and OS was weak (r = 0.60, P < 0.05, R = 0.15). The number of regimens administered after disease progression postsecond-line chemotherapy was significantly associated with PPS (P = 0.003).

Conclusions: OS is more strongly linked to PPS than to PFS in refractory SCLC patients who undergo amrubicin monotherapy as a second-line treatment. These results suggest that treatments administered after second-line chemotherapy affect the OS of refractory SCLC patients treated with amrubicin monotherapy.
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http://dx.doi.org/10.4103/jcrt.JCRT_1170_16DOI Listing
November 2020

Metachronous bilateral breast metastases of a lung neuroendocrine tumor: A case report.

Mol Clin Oncol 2020 Nov 20;13(5):53. Epub 2020 Aug 20.

Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ota, Gunma 373-8550, Japan.

Breast metastases of primary lung neuroendocrine tumors are rarely reported. The current report presents the case of a 41-year old female with no history of smoking who initially underwent surgery for a breast fibroadenoma, during which a neuroendocrine tumor of the right lung was detected via chest X-ray. The patient underwent surgery for the tumor and developed right breast nodules after adjuvant chemotherapy. Histological and immunohistochemical examinations of biopsies from these nodules indicated breast metastasis of the primary lung neuroendocrine tumor. The patient underwent mastectomy of the right breast but subsequently developed metastases in the left breast, for which local radiotherapy was administered. The observed metachronous bilateral breast metastases indicated that the contralateral breast should be considered during an investigation of metastasis.
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http://dx.doi.org/10.3892/mco.2020.2123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453391PMC
November 2020

Efficacy and safety of S-1 monotherapy in previously treated elderly patients (aged ≥75 years) with non-small cell lung cancer: A retrospective analysis.

Thorac Cancer 2020 10 26;11(10):2867-2876. Epub 2020 Aug 26.

Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ota, Japan.

Background: S-1 monotherapy is effective and feasible for previously treated patients with advanced non-small cell lung cancer (NSCLC). However, it is not clear whether its effectiveness and tolerability in elderly patients are equivalent to those in younger patients. Hence, this study aimed to evaluate the efficacy and feasibility of S-1 monotherapy in elderly patients with NSCLC who had previously received other treatments.

Methods: We included 96 elderly patients (aged ≥75 years) with advanced NSCLC treated with S-1 alone as a subsequent-line treatment at 12 medical facilities between January 2005 and March 2018 in this study. The baseline characteristics of the patients, response to S-1 monotherapy, and adverse events (AEs) were investigated, retrospectively.

Results: A total of 68 male and 28 female patients (median age, 78 [range: 75-86] years) were analyzed. In elderly patients who were treated with S-1 monotherapy as a subsequent-line treatment, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 8.3%, 43.8%, 3.4 months, and 9.6 months, respectively. Observed AEs included anorexia, anemia, nausea, fatigue, reduced platelet count, and skin hyperpigmentation. Treatment-related death was observed in one patient because of pneumonitis. In patients who experienced no progressive disease, subsequent-line S-1 alone was associated with longer PFS and OS.

Conclusions: S-1 monotherapy is effective and feasible as a subsequent-line treatment in elderly patients who were previously treated for NSCLC, and it produces results. S-1 monotherapy could be one of the treatment choices for elderly patients with previously treated NSCLC.
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http://dx.doi.org/10.1111/1759-7714.13622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529563PMC
October 2020

Phase II Study of Weekly Nanoparticle Albumin-Bound Paclitaxel as Second- or Third-Line Therapy in Patients with Advanced Non-Small Cell Lung Cancer.

Chemotherapy 2020 16;65(1-2):21-28. Epub 2020 Jul 16.

Department of Respiratory Medicine, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.

Introduction: Treatment outcomes in patients with advanced non-small cell lung cancer (NSCLC) are poor due to limited treatment options.

Objective: We conducted a multicenter, single-arm phase II study to prospectively assess the efficacy and safety of weekly nab-PTX in patients with advanced NSCLC with failed cytotoxic chemotherapy.

Methods: Patients with advanced NSCLC having adequate organ functions with a performance status of 0-1 were enrolled. A 100 mg/m2 dose of nab-paclitaxel was administered on days 1, 8, and 15 of a 28-day cycle. Primary endpoint was the objective response rate (ORR). Secondary endpoints were disease control rate (DCR), toxicity profile, progression-free survival (PFS), and overall survival (OS).

Results: Between September 2013 and May 2016, 35 patients were enrolled. The ORR was 31.4%, and the DCR was 74.3%. The median PFS was 3.6 months, and the median OS was 11.4 months. The most common grade 3 or 4 toxicities included neutropenia (54.3%), leukopenia (42.9%), and anemia (11.4%). Two patients discontinued chemotherapy due to pneumonitis.

Conclusions: Nab-PTX may be a later-line chemotherapeutic option for previously treated advanced NSCLC.
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http://dx.doi.org/10.1159/000508715DOI Listing
May 2021

Proton magnetic resonance spectroscopy of lung cancer .

Radiol Case Rep 2020 Jul 22;15(7):1099-1102. Epub 2020 May 22.

Thoracic Surgery, Gunma Prefectural Cancer Center, Ota, Gunma, Japan.

Proton magnetic resonance spectroscopy (H-MRS) has demonstrated that , lung cancer has higher lactate and choline signals than those of normal tissues. The detection of these metabolites in lung cancer by H-MRS would be useful for clinical diagnoses of lung cancer. We report the detection of lactate and choline in lung cancer by H-MRS in a 41-year-old Asian man who was diagnosed with pT4N0M0 ⅢA stage, right upper lobe lung adenocarcinoma. A lactate-lipid peak was observed near 1.33 ppm in the spectrum of lung cancer at TE  =  30 ms, and it was inverted at TE  =  135 ms, indicating that a lactate signal is contained in the lactate-lipid peak. A choline peak was also observed near 3.2 ppm in the spectrum with fat suppression at TE  =  135 ms. An accumulation of similar cases will help determine the appropriate applications of H-MRS for lung cancer.
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http://dx.doi.org/10.1016/j.radcr.2020.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256246PMC
July 2020

Efficacy and safety of immune checkpoint inhibitor monotherapy in pretreated elderly patients with non-small cell lung cancer.

Cancer Chemother Pharmacol 2020 04 19;85(4):761-771. Epub 2020 Mar 19.

Department of Respiratory Medicine, Comprehensive Cancer Center, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.

Purpose: Immune checkpoint inhibitors (ICIs) are an effective subsequent-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether the efficacy and safety of subsequent-line ICI monotherapy in elderly patients (aged ≥ 75 years) are similar to that in non-elderly patients. Therefore, we aimed to investigate the efficacy and safety of ICI monotherapy in pretreated elderly patients with NSCLC.

Methods: Between January 2016 and February 2018, 131 elderly patients with advanced NSCLC who received subsequent-line ICI monotherapy at 13 Japanese institutions were enrolled in this study. Baseline characteristics, the efficacy of ICI treatment, and adverse events were evaluated.

Results: Ninety-eight men and 33 women (median age 77 [range 75-87] years) were enrolled. Among those who received subsequent-line ICI monotherapy, the overall response, disease control rates, median progression-free survival (PFS), and overall survival (OS) were 27.4%, 61.8%, 4.5 months, and 16.0 months, respectively. Adverse events such as anorexia, fatigue, pneumonitis, and hypothyroidism were observed. There were two treatment-related deaths due to pneumonitis and thrombocytopenia. Subsequent-line ICI monotherapy in patients with good performance status (PS), receiving steroids for immune-related adverse events (irAEs), and exhibiting partial response (PR) was associated with improved PFS, as well as OS in patients with good PS and PR.

Conclusions: Subsequent-line ICI monotherapy in elderly patients, with previously treated NSCLC, was effective, safe and showed outcomes equivalent to those in non-elderly patients. Immunotherapy provides a survival benefit for elderly patients, who exhibit its efficacy and a favorable general condition.
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http://dx.doi.org/10.1007/s00280-020-04055-7DOI Listing
April 2020

Prospective Feasibility Study of Amrubicin and Bevacizumab Therapy for Patients With Previously Treated Advanced NSCLC.

Anticancer Res 2020 Mar;40(3):1571-1578

Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan.

Background/aim: The efficacy of the combination of amrubicin and bevacizumab against advanced non small-cell lung cancer (NSCLC), as a second or third-line treatment, was evaluated.

Patients And Methods: Amrubicin was administered for 3 days to patients with previously treated advanced NSCLC, whereas bevacizumab was administered on day 1 of each cycle; this regimen was repeated every 3 weeks.

Results: Among the 16 patients, an overall response rate of 12.5% (for two patients) was achieved, and the overall disease control rate was 93.7%. Progression free survival and overall survival were 8.5 and 16.6 months, respectively. Grade 3 or 4 haematological toxicities were leukopenia, neutropenia, and febrile neutropenia. Grade 3 proteinuria and infection were the non haematological adverse events.

Conclusion: The combination of amrubicin and bevacizumab is a promising regimen in the second or third-line treatment for advanced non-squamous NSCLC; however, physicians must recognise the risk of proteinuria related with this regimen.
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http://dx.doi.org/10.21873/anticanres.14104DOI Listing
March 2020

A phase I and extension study of S-1 and carboplatin for previously untreated patients aged 75 years or more with advanced non-small cell lung cancer -TCOG 1101.

Int J Clin Oncol 2020 May 14;25(5):867-875. Epub 2020 Feb 14.

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

Purpose: Combination carboplatin and S-1 is active in the treatment of non-small cell lung cancer (NSCLC). However, data on this combination for elderly patients with NSCLC are insufficient.

Methods: Eligibility criteria were no prior chemotherapy, Stage IIIB or IV NSCLC, performance status 0-1, age ≥ 75 years, and adequate hematological, hepatic, and renal functions. Carboplatin was administered on day 1 and S-1 was administered orally, twice a day, between days 1 and 14, repeated every 3 weeks. In phase I, the primary purpose was determination of the recommended dose. Starting doses of carboplatin and S-1 were area under the curve (AUC) of 4 and 80 mg/m/day, respectively. In the extension study, the effects and tolerability of this combination therapy of recommended dose were confirmed.

Results: A total of 10 patients were entered into phase I and 14 patients were entered into the extension study. The recommended doses for this drug combination are AUC 5 for carboplatin and 80 mg/m/day every 3 weeks for S-1. With carboplatin and S-1 combination therapy at the recommended dose, the response rate was 30.0% [95% confidence interval (CI) 12-54%] and the disease control rate was 90.0% (95% CI 68-99%). Thrombocytopenia and neutropenia were major adverse events.

Conclusions: The recommended doses for this combination therapy are carboplatin AUC 5 and S-1 80 mg/m/day every 3 weeks, and this combination is effective with tolerable toxicities for advanced NSCLC patients ≥ 75 years old.
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http://dx.doi.org/10.1007/s10147-020-01629-6DOI Listing
May 2020

Prognostic Significance of Glucose Metabolism as GLUT1 in Patients with Pulmonary Pleomorphic Carcinoma.

J Clin Med 2020 Feb 3;9(2). Epub 2020 Feb 3.

Department of Innovative Immune-Oncology Therapeutics, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.

Glucose metabolism is necessary for tumor progression, metastasis, and survival in various human cancers. Glucose transporter 1 (GLUT1), in particular, plays an important role in the mechanism of ¹⁸F-FDG (2-[¹⁸F]-fluoro-2-deoxy-d-glucose) within tumor cells. However, little is known about the clinicopathological significance of GLUT1 in patients with pulmonary pleomorphic carcinoma (PPC). Adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, poorly differentiated carcinoma, large cell carcinoma, and others were identified as epithelial components, and spindle-cell type, giant-cell type, and both spindle- and giant-cell types were identified as sarcomatous components. This study was performed to determine the prognostic impact of GLUT1 expression in PPC. Patients with surgically resected PPC (n = 104) were evaluated by immunohistochemistry analysis to detect GLUT1 expression and determine the Ki-67 labeling index using specimens of the resected tumors. GLUT1 was highly expressed in 48% (50/104) of all patients, 42% (20/48) of the patients with an adenocarcinoma component, and 53% (30/56) of the patients with a nonadenocarcinoma component. High expression of GLUT1 was significantly associated with advanced stage, vascular invasion, pleural invasion, and tumor cell proliferation as determined by Ki-67 labeling. GLUT1 expression and tumor cell proliferation were significantly correlated according to the Ki-67 labeling in all patients (Spearman's rank; r = 0.25, < 0.01). In multivariate analysis, GLUT1 was identified as a significant independent marker for predicting a poor prognosis. GLUT1 is an independent prognostic factor for predicting the poor prognosis of patients with surgically resected PPC.
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http://dx.doi.org/10.3390/jcm9020413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074371PMC
February 2020

Efficacy and safety of first-line pembrolizumab monotherapy in elderly patients (aged ≥ 75 years) with non-small cell lung cancer.

J Cancer Res Clin Oncol 2020 Feb 18;146(2):457-466. Epub 2019 Dec 18.

Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama University Hospital, Hidaka, Saitama, Japan.

Purpose: Pembrolizumab is an effective front-line treatment for advanced non-small cell lung cancer (NSCLC) in patients expressing high levels of programmed death-ligand 1 (PD-L1). However, it is unclear whether first-line pembrolizumab has similar efficacy among elderly (aged ≥ 75 years) and younger patients. This study aimed to investigate the safety and efficacy of front-line pembrolizumab monotherapy in older adults with NSCLC expressing high PD-L1.

Methods: A total of 128 patients with advanced NSCLC expressing high PD-L1, including 47 older adults, received first-line pembrolizumab monotherapy at ten institutions in Japan, between February 2017 and February 2018. Data related to patient characteristics, efficacy of pembrolizumab therapy, and the type and severity of adverse events were recorded.

Results: Overall, 47 patients [40 men and 7 women; median age 79 (range 75-88) years] were included in our analysis. In patients who received first-line pembrolizumab monotherapy, overall response, disease control rates, median progression-free survival (PFS), and median overall survival (OS) were 53.1%, 74.4%, 7.0 months, and not reached, respectively. Common adverse events included anorexia, fatigue, skin rash, and hypothyroidism. Two treatment-related deaths were noted, due to pneumonitis and infection. First-line pembrolizumab monotherapy was associated with improved PFS in patients with non-progressive disease (PD). In patients with non-PD and good performance status (PS), pembrolizumab monotherapy improved OS.

Conclusions: Elderly patients with NSCLC expressing high PD-L1 tolerated front-line pembrolizumab monotherapy well. Their survival outcomes were equivalent to those of younger patients. In patients with non-PD, first-line pembrolizumab monotherapy may improve PFS; in conjunction with good PS, it additionally improves OS.
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http://dx.doi.org/10.1007/s00432-019-03072-1DOI Listing
February 2020

Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study.

J Clin Oncol 2020 01 4;38(2):115-123. Epub 2019 Nov 4.

Tohoku University School of Medicine, Sendai, Japan.

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor combined with cytotoxic chemotherapy is highly effective for the treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations; however, little is known about the efficacy and safety of this combination compared with that of standard therapy with EGFR- tyrosine kinase inhibitors alone.

Methods: We randomly assigned 345 patients with newly diagnosed metastatic NSCLC with EGFR mutations to gefitinib combined with carboplatin plus pemetrexed or gefitinib alone. Progression-free survival (PFS), PFS2, and overall survival (OS) were sequentially analyzed as primary end points according to a hierarchical sequential testing method. Secondary end points were objective response rate (ORR), safety, and quality of life.

Results: The combination group demonstrated a better ORR and PFS than the gefitinib group (ORR, 84% 67% [ < .001]; PFS, 20.9 11.9 months; hazard ratio for death or disease progression, 0.490 [ < .001]), although PFS2 was not significantly different (20.9 18.0 months; = .092). Median OS in the combination group was also significantly longer than in the gefitinib group (50.9 38.8 months; hazard ratio for death, 0.722; = .021). The rate of grade ≥ 3 treatment-related adverse events, such as hematologic toxicities, in the combination group was higher than in the gefitinib group (65.3% 31.0%); there were no differences in quality of life. One treatment-related death was observed in the combination group.

Conclusion: Compared with gefitinib alone, gefitinib combined with carboplatin plus pemetrexed improved PFS in patients with untreated advanced NSCLC with EGFR mutations with an acceptable toxicity profile, although its OS benefit requires further validation.
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http://dx.doi.org/10.1200/JCO.19.01488DOI Listing
January 2020

Clinical Significance of Various Drug-Sensitivity Markers in Patients with Surgically Resected Pulmonary Pleomorphic Carcinoma.

Cancers (Basel) 2019 Oct 24;11(11). Epub 2019 Oct 24.

Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan.

Various drug-sensitivity markers are potentially responsible for tumor progression and chemotherapy resistance in cancer patients with both epithelial and sarcomatous components; however, the clinicopathological significance of drug-sensitivity markers in patients with pulmonary pleomorphic carcinoma (PPC) remains unknown. Here, we clarified the prognostic impact of these drug-sensitivity markers in PPC by performing immunohistochemical and clinicopathologic analyses of samples from 105 patients with surgically resected PPC in order to evaluate levels of vascular endothelial growth factor 2 (VEGFR2), stathmin 1 (STMN1), tubulin β3 class III (TUBB3), thymidylate synthetase (TS), topoisomerase II (Topo-II), glucose-regulated protein, and 78 kDa (GRP78)/binding immunoglobulin protein (BiP). We observed the rates of high expression for VEGFR2, STMN1, TUBB3, TS, Topo-II, and GRP78/BiP were 33% (39/105), 35% (37/105), 61% (64/105), 51% (53/105), 31% (33/105), and 51% (53/105) of the samples, respectively. Moreover, multivariate analysis identified VEGFR2 and GRP78/BiP as significant independent markers for predicting worse prognosis. These findings suggested elevated VEGFR2 and decreased GRP78/BiP levels as independent factors for predicting poor outcomes following surgical resection in patients with PPC.
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http://dx.doi.org/10.3390/cancers11111636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895922PMC
October 2019

Post-progression survival is highly linked to overall survival in patients with non-small-cell lung cancer harboring sensitive EGFR mutations treated with first-line epidermal growth factor receptor-tyrosine kinase inhibitors.

Thorac Cancer 2019 12 8;10(12):2200-2208. Epub 2019 Oct 8.

Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ota, Japan.

Background: In patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC), epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment has shown a good response. Subsequent treatments jeopardize the ability to determine the effect of first-line chemotherapy on overall survival (OS). Therefore, using patient-level data, we aimed to study the associations of progression-free survival (PFS) and post-progression survival (PPS) with OS after first-line EGFR-TKI treatment in patients with EGFR-mutated NSCLC.

Methods: Between November 2006 and December 2016, we analyzed 92 patients with EGFR-mutated NSCLC treated with first-line EGFR-TKI. The correlations of PFS and PPS with OS were analyzed for each patient.

Results: Spearman's rank correlation and linear regression analyzes showed that PPS correlated highly with OS (r = 0.85, P < 0.05, R = 0.75), whereas PFS correlated weakly with OS (r = 0.76, P < 0.05, R = 0.50). The best responses after first-line and second-line treatments were significantly associated with PPS.

Conclusions: PPS has a higher impact on OS than PFS in patients with EGFR-mutated NSCLC treated with first-line EGFR-TKIs. These outcomes suggest that the OS in this patient group may be affected by treatments following first-line chemotherapy; however, this remains to be verified in prospective trials.
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http://dx.doi.org/10.1111/1759-7714.13193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885435PMC
December 2019

Hypofractionated carbon-ion radiotherapy for stage I peripheral nonsmall cell lung cancer (GUNMA0701): Prospective phase II study.

Cancer Med 2019 11 18;8(15):6644-6650. Epub 2019 Sep 18.

Gunma University Heavy Ion Medical Center, Maebashi, Gunma, Japan.

This phase II study's aim was to confirm the efficacy and safety of hypofractionated carbon-ion radiotherapy in patients with stage I peripheral nonsmall cell lung cancer (NSCLC). The study encompassed 37 patients with histologically proven peripheral stage I NSCLC in the period June 2010-March 2015. All underwent the planned full dose of carbon-ion radiotherapy, administered with relative biological effectiveness of 52.8 Gy and 60 Gy (divided into four fractions over 1 week) for T1 and T2a tumors, respectively. The 2-year local control rate was set as the primary endpoint, while overall survival, progression-free survival, and the incidence rates of acute and late adverse events were secondary endpoints. The patients were followed up for 56.3 months overall and 62.2 months in the surviving patients, respectively. The actuarial local control rates were 91.2% after 2 years, and 88.1% after 5 years. No differences were found between the T1 and T2a tumors in the 5-year local control rate (90.9% vs 86.7%, P = .75). The actuarial overall survival rates achieved 91.9% for 2-year and 74.9% for 5-year period. T1 tumors showed actuarial 5-year overall survival rates of 80%, compared to 66.7% in T2a tumors. Two patients with T2a tumors and either severe emphysema or bronchiectasis experienced lung toxicity ≥ grade 2, in contrast to T1 patients who only experienced mild toxicities (lower than grade 2). The findings suggest that carbon-ion radiotherapy is effective and safe for peripheral stage I NSCLC; however, further clinical evaluations are needed to confirm its therapeutic efficacy. Trial registration: UMIN000003797. Registered 21 June 2010, prospectively registered.
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http://dx.doi.org/10.1002/cam4.2561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825999PMC
November 2019

Multicenter study of zoledronic acid administration in non-small-cell lung cancer patients with bone metastasis: Thoracic Oncology Research Group (TORG) 1017.

Mol Clin Oncol 2019 Oct 23;11(4):349-353. Epub 2019 Jul 23.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Kanagawa 240-8555, Japan.

Skeletal-related events (SREs) may occur at the time of first diagnosis in 20-30% of lung cancer patients with bone metastases. Several clinical trials have shown that zoledronic acid (ZA) is effective for decreasing SREs. The main objective of the present study was to discuss clinical data of ZA and compare the frequency of SREs with previous reports. All patients with non-small-cell lung cancer (NSCLC) with metastatic bone disease who were administered ZA at least twice between January 2008 and December 2009 were eligible for inclusion in the study. In total, 198 consecutive patients were identified. The median duration of ZA administration was 106 days [95% confidence interval (CI), 92-133 days], and the median number of ZA administrations was 4 (range, 2-41). The median time to first SRE in patients who experienced SRE following ZA treatment was 202 days (95% CI, 156-264 days). Among the 78 patients who had already experienced SRE prior to ZA treatment, 35 (45%) experienced SRE subsequently after starting ZA treatment. On the other hand, among the 120 patients without a history of SRE before starting ZA treatment, 42 (35%) experienced SRE after the start of ZA administration (P=0.16). No osteonecrosis of the jaw (ONJ) was reported in any of the patients. The present study revealed that ZA had a certain level of efficacy regardless of the presence or absence of prior SREs. However, the duration of ZA therapy was short in this study; further accumulation of data on the long-term prognosis and incidence rates of ONJ and other late complications of ZA therapy seems to be particularly important.
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http://dx.doi.org/10.3892/mco.2019.1903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713944PMC
October 2019

Multicenter, placebo-controlled, double-blind, randomized study of fosnetupitant in combination with palonosetron for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy.

Cancer 2019 Nov 5;125(22):4076-4083. Epub 2019 Aug 5.

Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.

Background: The current randomized, double-blind, phase 2 study assessed the efficacy and safety profile of a single intravenous administration of fosnetupitant, a neurokinin 1 receptor antagonist prodrug, for the prevention of chemotherapy-induced nausea and vomiting in Japanese patients receiving cisplatin-based chemotherapy.

Methods: Patients scheduled to receive cisplatin (at a dose of ≥70 mg/m )-based regimens were randomly assigned to receive fosnetupitant at a dose of 81 mg or 235 mg or placebo in combination with palonosetron at a dose of 0.75 mg and dexamethasone. The primary endpoint was complete response (CR; no vomiting and no rescue medication) during the overall phase (0-120 hours). The overall CR rate was compared between each dose of fosnetupitant and the placebo group adjusting for the stratification factors of sex and age class (age <55 years vs age ≥55 years). Safety was assessed, with special attention given to events that potentially were suggestive of infusion site reactions.

Results: A total of 594 patients were randomized. Of these, 194 patients, 195 patients, and 195 patients, respectively, in the placebo and fosnetupitant 81-mg and 235-mg dose groups were evaluable for efficacy. The overall CR rate was 54.7% for the placebo group, 63.8% for the fosnetupitant 81-mg dose group (adjusted difference, 9.1%; 95% CI, -0.4% to 18.6% [P = .061]), and 76.8% for the fosnetupitant 235-mg dose group (adjusted difference, 22.0%; 97.5% CI, 11.7% to 32.3% [P < .001]). Safety profiles were comparable between the 3 groups. The incidence of infusion site reactions related to fosnetupitant was ≤1% in each dose group.

Conclusions: Fosnetupitant at a dose of 235 mg provided superior prevention of chemotherapy-induced nausea and vomiting among patients receiving cisplatin-based chemotherapy compared with the control group, and with a satisfactory safety profile.
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http://dx.doi.org/10.1002/cncr.32429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900104PMC
November 2019

Three-year follow-up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non-small cell lung cancer: Pooled analysis of ONO-4538-05 and ONO-4538-06 studies.

Cancer Med 2019 Sep 29;8(11):5183-5193. Epub 2019 Jul 29.

Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.

Background: Nivolumab is a programmed cell death 1 (PD-1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non-squamous (non-SQ) non-small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO-4538-05) and non-SQ (ONO-4538-06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2-42.1) and 22.4% (14.5-32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long-term safety and efficacy in patients with SQ and non-SQ NSCLC by pooling data from these two trials.

Methods: SQ (N = 35) and non-SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan-Meier method. A pooled analysis of SQ and non-SQ patients was also performed.

Results: In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found.

Conclusion: Treatment with nivolumab improved long-term survival and was well tolerated in patients with SQ and non-SQ NSCLC.

Trial Registration: JapicCTI-132072; JapicCTI-132073.
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http://dx.doi.org/10.1002/cam4.2411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718542PMC
September 2019

Clinical trial protocol of doublet therapy and olanzapine for carboplatin-induced nausea and vomiting in patients with thoracic cancer: a multicentre phase II trial.

BMJ Open 2019 07 4;9(7):e028056. Epub 2019 Jul 4.

Department of Cardiology and Respirology, Gifu University Graduate School of Medicine, Gifu, Japan.

Introduction: Adding neurokinin-1 receptor antagonist (NKRA) to 5-hydroxytryptamine-3 receptor antagonist and dexamethasone (DEX) improved carboplatin (CBDCA)-induced chemotherapy-induced nausea and vomiting (CINV) in patients with thoracic cancer. NKRAs with high-drug cost are raising medical expenses. Olanzapine (OLZ) is less expensive and can be expected to have an excellent effect on CINV. This phase II trial aimed at evaluating the efficacy and safety of 5 mg OLZ plus granisetron (GRN) and DEX in CBDCA combination therapy with area under curve (AUC) ≥5 mg/mL/min for the prevention of nausea and vomiting in patients with thoracic cancer.

Methods And Analysis: This is an open-label, single-arm, multicentre, phase II trial. Patients who receive CBDCA-based therapies (AUC ≥5) and have never been administered moderate to high emetogenic chemotherapy will be enrolled. All patients will receive a combination of GRN, DEX and OLZ. The primary endpoint is complete response (CR) rate, defined as the absence of emetic episodes and no use of rescue medication for 120 hours after the initiation of CBDCA. Forty-eight patients are required based on our hypothesis that this regimen can improve CR rate from 65% (null hypothesis) to 80% (alternative hypothesis) with a one-sided type I error of 0.1 and a power of 0.8. We set the target sample size at 50 considering dropouts.

Ethics And Dissemination: The study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals.

Trial Registration Number: UMIN000031267.
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http://dx.doi.org/10.1136/bmjopen-2018-028056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615793PMC
July 2019

Intrapericardial carboplatin in the management of malignant pericardial effusion in breast cancer: a pilot study.

Cancer Chemother Pharmacol 2019 09 27;84(3):655-660. Epub 2019 Jun 27.

Division of Respiratory Medicine, Gunma Prefectural Cancer Center, 617-1, Takahayashinishi, Ota, Gunma, 373-8550, Japan.

Purpose: Malignant pericarditis is observed in 5.1-7.0% of all cases of acute pericarditis, and malignant pericardial effusion (MPE) can lead to cardiac tamponade in the later stages of cancer. Breast cancer is the second most common primary cancer associated with MPE, but the efficacy and safety of intrapericardial carboplatin (CBDCA) have never been evaluated in breast cancer. In this study, we assessed the clinical significance of intrapericardial CBDCA following catheter drainage in patients with breast cancer-related MPE.

Methods: A catheter was inserted percutaneously into the pericardial space under echocardiographic guidance. After complete drainage, 150 mg of CBDCA was instilled into the pericardial space through the catheter.

Results: Eight patients with symptomatic breast cancer-related MPE were treated at the Gunma Prefectural Cancer Center, between July 2010 and March 2016. One month after treatment, 100% of MPE was controlled. The median survival time from the recurrence of breast cancer until death or study follow-up was 2336 days (range 293-3937 days), while that from intrapericardial CBDCA administration until death or study follow-up was 552 days (range 35-1673 days). Grade 1 fever, nausea, hypotension, fatigue, and chest discomfort were observed in one patient (12.5%) after intrapericardial CBDCA administration.

Conclusions: We found that intrapericardial administration of CBDCA after catheter drainage appears to be safe and effective in managing breast cancer-associated MPE. As the number of patients in this study was small, further studies are warranted to determine the safety and efficacy of intrapericardial CBDCA in the management of breast cancer-related MPE.
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http://dx.doi.org/10.1007/s00280-019-03897-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682572PMC
September 2019

An Exploratory Randomized Phase II Trial Comparing CDDP Plus S-1 With Bevacizumab and CDDP Plus Pemetrexed With Bevacizumab Against Patients With Advanced Non-squamous Non-small Cell Lung Cancer.

Anticancer Res 2019 May;39(5):2483-2491

Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Background/aim: It remains unclear which chemotherapeutic regimens are better for the addition of bevacizumab. We conducted an exploratory randomized phase II trial comparing first-line S-1 plus cisplatin with bevacizumab and pemetrexed plus cisplatin with bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC).

Patients And Methods: Chemotherapy-naïve patients received S-1 (80 mg/m) from day 1 to day 14 plus cisplatin (80 mg/m) on day 1 with bevacizumab (15 mg/kg) on day 1, followed by maintenance with bevacizumab plus S-1 (SCB) on day 1 every 3 weeks and pemetrexed (500 mg/m) on day 1 plus cisplatin (75 mg/m) on day 1 with bevacizumab (15 mg/kg) on day 1 followed by maintenance bevacizumab plus pemetrexed (PCB) on day 1 every 3 weeks. The expression of thymidylate synthase (TS) was analyzed using immunohistochemistry.

Results: Forty-eight patients were enrolled in this study, and eligible patients were randomly assigned at 1:1 ratio to receive SCB (n=24) or PCB (n=24). The median number of chemotherapy and maintenance therapy for SCB and PCB was 4 (range, 1-6 cycles) and 4 (range, 2-6 cycles), and 5 (range, 0-39 cycles) and 5 (range, 0-28 cycles), respectively. The overall response rate (ORR) for PCB and SCB were 54.2% and 83.3%, respectively (p=0.06). The median progression-free survival (PFS) and overall survival (OS) for PCB and SCB were 406 and 351 days, (p=0.96), and 678 and 1190 days, respectively (p=0.23). The mild adverse events were observed in both regimens. TS expression was more predictive of the chemotherapeutic response in SCB compared to PCB, but not for PFS.

Conclusion: The combination regimen of SCB was identified as having a similar activity and tolerability to that of PCB in patients with advanced non-squamous NSCLC.
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http://dx.doi.org/10.21873/anticanres.13368DOI Listing
May 2019

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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http://dx.doi.org/10.1093/jjco/hyz064DOI Listing
August 2019

A dose-finding randomized Phase II study of oral netupitant in combination with palonosetron .75 mg intravenous for the prevention of chemotherapy-induced nausea and vomiting in Japanese patients receiving highly emetogenic chemotherapy.

Jpn J Clin Oncol 2019 Feb;49(2):121-129

Department of Breast Oncology, Saitama Medical University International Medical Center, Saitama.

Objective: Netupitant is a novel, selective neurokinin-1 receptor antagonist used for prevention of chemotherapy-induced nausea and vomiting, a distressing side effect of chemotherapy. This double-blind, randomized, Phase II study investigated the dose-response of oral netupitant in Japanese patients receiving highly emetogenic chemotherapy.

Methods: Chemotherapy-naïve patients were randomized (1:1:1) to a single oral netupitant 30-, 100- or 300-mg dose before chemotherapy initiation. Patients received concomitant palonosetron (0.75 mg intravenously [i.v.] Day 1) and dexamethasone (9.9 mg i.v. Day 1, 8 mg orally Days 2-4).

Results: Overall, 402 patients (30 mg: 134; 100 mg: 135; 300 mg: 133) were treated and evaluable for efficacy and safety. The primary endpoint of overall (0-120 h after chemotherapy administration) complete response (CR) rate (no emesis, no rescue medication) was 64.2%, 60.0% and 54.9% in the 30-, 100- and 300-mg arms, respectively, without statistical significance for dose-response. The safety profile of netupitant was comparable in the three arms. The plasma concentrations of netupitant and its metabolites increased with the dose increase from 30 mg to 300 mg.

Conclusions: No dose-response relationship of netupitant in terms of overall CR rate was observed in this study. Netupitant was well tolerated at all doses without clinically harmful safety signals observed.

Clinical Trial Registration: JapicCTI-142 483.
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http://dx.doi.org/10.1093/jjco/hyy161DOI Listing
February 2019

A phase II study of afatinib treatment for elderly patients with previously untreated advanced non-small-cell lung cancer harboring EGFR mutations.

Lung Cancer 2018 12 13;126:41-47. Epub 2018 Oct 13.

Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Objective: The efficacy and safety of afatinib in elderly patients with EGFR-mutated non-small-cell lung cancer (NSCLC) have not been evaluated. This study aimed to assess the efficacy and safety of afatinib in elderly chemotherapy-naive patients with NSCLC harboring sensitive EGFR mutations.

Materials And Methods: We prospectively assessed the clinical effects of afatinib as a first-line treatment for elderly (age ≥70 years) NSCLC patients with EGFR mutations (exon 19 deletion or exon 21 L858R mutation). All patients were initially administered afatinib (30 mg/day).

Results: Between May 2014 and August 2017, 40 patients (13 men, 27 women) with adenocarcinoma were included in our analysis. The median age was 77 years (range, 70-85 years). The dose was reduced in 19 patients. The objective overall response and disease control rates were 72.5% and 100%, respectively, and the median progression-free survival and overall survival were 12.9 months and not reached, respectively. Common adverse events (AEs) included diarrhea, rash/acne, and anemia. Major grade 3 or higher toxicities included diarrhea (12.5%), mucositis (7.5%), and pneumonitis (7.5%). Afatinib treatment was discontinued in 8 patients owing to AEs of elevated amylase (n = 1), liver dysfunction (n = 1), rash/acne (n = 1), nail change (n = 1), anorexia (n = 2), pneumonitis (n = 2), and diarrhea (n = 2). Two patients died due to treatment-related pneumonitis.

Conclusions: This is the first study that verified the efficacy and feasibility of first-line chemotherapy with afatinib at 30 mg/day in elderly patients with advanced NSCLC harboring sensitive EGFR mutations. First-line afatinib of 30 mg/day could be a treatment option in this patient population.
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http://dx.doi.org/10.1016/j.lungcan.2018.10.014DOI Listing
December 2018

Topotecan monotherapy for the treatment of relapsed small cell lung cancer in elderly patients: A retrospective analysis.

Thorac Cancer 2018 12 3;9(12):1699-1706. Epub 2018 Oct 3.

Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ohta, Japan.

Background: Topotecan is one of the most active chemotherapeutic drugs for small cell lung cancer (SCLC). However, its efficacy in elderly patients with SCLC has not been validated. This study evaluated the feasibility and efficacy of topotecan monotherapy in elderly patients with relapsed SCLC.

Methods: Between January 2000 and March 2017, 43 patients aged ≥ 70 years received topotecan monotherapy for relapsed SCLC at four institutions. The clinical outcomes and adverse events of treatment were retrospectively analyzed.

Results: Twenty-nine patients (median age 75 years; range: 70-83 years) had sensitive-type relapse, while 14 (median age 78 years; range: 71-82 years) had refractory relapse. The median number of treatment cycles was two (range: 1-6). The response rate was 7.0% (10.3% and 0% in sensitive and refractory patients, respectively), while the disease control rate was 23.2% (20.6% and 42.8% in sensitive and refractory patients, respectively). Median progression-free survival was 1.9 months in sensitive patients and 1.4 months in refractory patients (P = 0.87). The median survival time from the start of topotecan therapy was 5.5 months in sensitive patients and 4.0 months in refractory patients (P = 0.64). Grade ≥ 3 hematological toxicities were as follows: leukopenia, 37.2%; neutropenia, 51.1%; anemia, 0%; thrombocytopenia, 32.5%; and febrile neutropenia, 9.3%. No treatment-related deaths occurred.

Conclusion: Although hematological toxicities (particularly neutropenia) were severe, topotecan showed favorable disease control in both sensitive and refractory patients. Topotecan may thus be a preferred treatment for elderly patients with relapsed SCLC.
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http://dx.doi.org/10.1111/1759-7714.12884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275829PMC
December 2018

Clinical Impact of Post-Progression Survival on Overall Survival in Elderly Patients with Non-Small-Cell Lung Cancer Harboring Sensitive EGFR Mutations Treated with First-Line EGFR Tyrosine Kinase Inhibitors.

Chemotherapy 2018 14;63(3):181-189. Epub 2018 Aug 14.

Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ota, Japan.

Background/aims: More than 50% of patients with lung cancer are aged > 65 years, and non-small-cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer among both elderly and adult patients. Subsequent therapies confound the capability to discern the effect of first-line chemotherapy on overall survival (OS). Therefore, using individual-level data, our study aimed to determine the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS after first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients with NSCLC harboring sensitive EGFR mutations.

Methods: Between April 2008 and December 2015, we analyzed 68 elderly patients with NSCLC harboring sensitive EGFR mutations and treated with first-line EGFR-TKI. The relationships of PFS and PPS with OS were analyzed at an individual level.

Results: Linear regression analysis showed that PPS was more closely associated with OS (R2 = 0.54) than PFS was (R2 = 0.48). Best response at first-line treatment, performance status at the end of first-line treatment, and administration of EGFR-TKI rechallenge were significantly correlated with PPS.

Conclusions: PPS has a stronger impact on OS than PFS does in elderly patients with NSCLC harboring sensitive EGFR mutations and treated with first-line EGFR-TKI. These results indicate that OS in this patient population may be influenced by treatments subsequent to first-line chemotherapy; however, this remains to be verified in prospective studies.
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http://dx.doi.org/10.1159/000490949DOI Listing
September 2018