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Sugawara S.,Sendai Kousei Hospital | Oizumi S.,Hokkaido University | Minato K.,Gunma Prefectural Cancer Center | Harada T.,JCHO Hokkaido Hospital | And 15 more authors.
Annals of Oncology | Year: 2015

Background: The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation. Patients and methods: Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/ pemetrexed [area under the curve (AUC) = 6 and 500 mg/m2; 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety. Results: All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [hazard ratio (HR) 0.71 (0.42-1.20), P = 0.20]. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively [HR 0.51 (0.26-0.99); P = 0.042]. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients). Conclusion: This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Kubota K.,Nippon Medical School | Hida T.,Aichi Cancer Center Hospital | Ishikura S.,Juntendo University | Mizusawa J.,Data Center | And 16 more authors.
The Lancet Oncology | Year: 2014

Background: Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC. Methods: We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20-70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m2 on days 1-3; intravenous cisplatin 80 mg/m2 on day 1) plus AHTRT (1·5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1:1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m2 on days 1, 8, 15; intravenous cisplatin 60 mg/m2 on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00144989, and the UMIN Clinical Trials Registry, number C000000095. Findings: 281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3·2 years (95% CI 2·4-4·1). In the irinotecan and cisplatin group, median overall survival was 2·8 years (95% CI 2·4-3·6); overall survival did not differ between the two groups (hazard ratio 1·09 [95% CI 0·80-1·46], one-sided stratified log-rank p=0·70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group). Interpretation: Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC. Funding: National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan. © 2014 Elsevier Ltd.


Maemondo M.,Miyagi Cancer Center | Maemondo M.,Tohoku University | Minegishi Y.,Nippon Medical School | Inoue A.,Nippon Medical School | And 11 more authors.
Journal of Thoracic Oncology | Year: 2012

INTRODUCTION:: Recent studies have demonstrated that first-line treatment with gefitinib, an epidermal growth factor receptor (EFGR)-targeted tyrosine kinase inhibitor, is significantly superior to standard chemotherapy for advanced non-small-cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Meanwhile, the efficacy of gefitinib therapy among elderly populations diagnosed with EGFR-mutated NSCLC has not yet been elucidated. The purpose of this study was to investigate the efficacy and feasibility of gefitinib for chemotherapy-naive patients aged 75 or older with NSCLC harboring EGFR mutations; generally, these patients have no indication for treatment with platinum doublets. METHODS:: Chemotherapy-naive patients aged 75 years or older with performance status 0 to 1 and advanced NSCLC harboring EGFR mutations, as determined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, were enrolled. The enrolled patients received 250 mg/day of gefitinib orally. RESULTS:: Between January 2008 and May 2009, 31 patients were enrolled, all of whom were eligible. The median age was 80 (range, 75-87) years. Twenty-five patients (81%) were women, and 30 patients (97%) had adenocarcinoma. The overall response rate was 74% (95% confidence interval, 58%-91%), and the disease control rate was 90%. The median progression-free survival was 12.3 months. The common adverse events were rash, diarrhea, and liver dysfunction. One treatment-related death because of interstitial lung disease occurred. CONCLUSIONS:: This is the first study that verified safety and efficacy of first-line treatment with gefitinib in elderly patients having advanced NSCLC with EGFR mutation. Considering its strong antitumor activity and mild toxicity, first-line gefitinib may be preferable to standard chemotherapy for this population. Copyright © 2012 by the International Association for the Study of Lung Cancer.


Watanabe S.,Niigata University | Minegishi Y.,Infections Disease and Oncology | Yoshizawa H.,Niigata University | Maemondo M.,Miyagi Cancer Center | And 8 more authors.
Journal of Thoracic Oncology | Year: 2014

INTRODUCTION:: In non-small-cell lung cancer, an exon 19 deletion and an L858R point mutation in the epidermal growth factor receptor (EGFR) are predictors of a response to EGFR-tyrosine kinase inhibitors. However, it is uncertain whether other uncommon EGFR mutations are associated with sensitivity to EGFR-tyrosine kinase inhibitors. METHODS:: A post-hoc analysis to assess prognostic factors was performed with the use of patients with EGFR mutations (exon 19 deletion, L858R, G719X, and L861Q) who were treated with gefitinib in the NEJ002 study, which compared gefitinib with carboplatin-paclitaxel as the first-line therapy. RESULTS:: In the NEJ002 study, 225 patients with EGFR mutations received gefitinib at any treatment line. The Cox proportional hazards model indicated that performance status, response to chemotherapy, response to gefitinib, and mutation types were significant prognostic factors. Overall survival (OS) was significantly shorter among patients with uncommon EGFR mutations (G719X or L861Q) compared with OS of those with common EGFR mutations (12 versus 28.4 months; p = 0.002). In the gefitinib group (n = 114), patients with uncommon EGFR mutations had a significantly shorter OS (11.9 versus 29.3 months; p < 0.001). By contrast, OS was similar between patients with uncommon mutations and those with common mutations in the carboplatin-paclitaxel group (n = 111; 22.8 versus 28 months; p = 0.358). CONCLUSIONS:: The post-hoc analyses clearly demonstrated shorter survival for gefitinib-treated patients with uncommon EGFR mutations compared with the survival of those with common mutations and suggest that the first-line chemotherapy may be relatively effective for non-small-cell lung cancer with uncommon EGFR mutations. © 2013 by the International Association for the Study of Lung Cancer.


Inoue A.,Tohoku University | Kobayashi K.,International University of Japan | Maemondo M.,Miyagi Cancer Center | Sugawara S.,Sendai Kousei Hospital | And 15 more authors.
Annals of Oncology | Year: 2013

Background: NEJ002 study, comparing gefitinib with carboplatin (CBDCA) and paclitaxel (PTX; Taxol) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival (PFS). Subsequent analysis was carried out mainly regarding overall survival (OS). Materials and methods: For all 228 patients in NEJ002, survival data wereupdated in December, 2010. Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated. Results: The median survival time (MST) was 27.7 months for the gefitinib group, and was 26.6 months for the CBDCA/PTX group (HR, 0.887; P = 0.483). The OS of patientswho received platinum throughout their treatment(n = 186) was not statistically different from that of patients who never received platinum (n = 40). The MST of patients treated with gefitinib, platinum, and pemetrexed (PEM) or docetaxel (DOC, Taxotere; n = 76) was around 3 years. Conclusions: No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study,probably due to a high crossover use of gefitinib in the CBDCA/PTX group. Considering the many benefits and the risk of missing anopportunity to use the most effective agent for EGFR-mutated NSCLC, the first-line gefitinib is strongly recommended. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Seto T.,National Hospital Organization Kyushu Cancer Center | Kiura K.,Okayama University | Nishio M.,Cancer Institute Hospital | Nakagawa K.,Kinki University | And 12 more authors.
The Lancet Oncology | Year: 2013

Background: Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor. Methods: In this multicentre, single-arm, open-label, phase 1-2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264. Findings: Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20-300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93·5%, 95% CI 82·1-98·6) including two complete responses (4·3%, 0·5-14·8) and 41 partial responses (89·1%, 76·4-96·4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. Interpretation: CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC. © 2013 Elsevier Ltd.


Maemondo M.,Miyagi Cancer Center | Inoue A.,Tohoku University | Kobayashi K.,International University of Japan | Sugawara S.,Sendai Kousei Hospital | And 19 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy. METHODS: We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects. RESULTS: In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P = 0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated amino transferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. CONCLUSIONS: First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.) Copyright © 2010 Massachusetts Medical Society.


Hayase E.,National Hospital Organization Hokkaido Cancer Center
[Rinshō ketsueki] The Japanese journal of clinical hematology | Year: 2012

A 76-year-old woman presented with vaginal bleeding and discharge in September 2009. She was admitted to our hospital because a tumor of 5 cm in diameter was found in the vagina in a nearby clinic. She was diagnosed with primary vaginal diffuse large B-cell lymphoma (DLBCL) on biopsy of the tumor because CT, MRI and FDG-PET showed no area of lymphomatous involvement other than the vagina and direct involvement into the bladder. She achieved complete response (CR) after chemotherapy followed by localized radiation therapy, but she had a relapse in the central nervous system (CNS) two months after CR. A study of 57 reported cases of primary vaginal lymphoma suggested that the most common histologic type was DLBCL, and most of patients were in a localized stage and responded well to combination of chemotherapy and radiation therapy. To date, two cases of primary vaginal lymphoma with a relapse in the CNS have been reported. We presumed that direct involvement into the bladder of vaginal lymphoma contributed to the relapse in the CNS in this case.


Shinohara T.,National Hospital Organization Hokkaido Cancer Center | Maeda Y.,National Hospital Organization Hokkaido Cancer Center | Hamada T.,National Hospital Organization Hokkaido Cancer Center | Futakawa N.,National Hospital Organization Hokkaido Cancer Center
Journal of Gastrointestinal Surgery | Year: 2015

Background and Objectives: Indications for the resection of liver metastases from gastric cancers (GLM) remain controversial, and few previous studies have reported subsequent surgical outcomes. Thus, the present retrospective study was designed to clarify the benefits of surgical treatment and identify prognostic factors. Methods: Outcomes of 47 patients with or without hepatectomy for GLM were retrospectively compared. Results: A total of 22 patients received surgical treatment for GLM, and overall 1-, 3-, and 5-year survival rates were 86, 26, and 26 %, respectively, and the median survival time (MST) was 22 months. Among 25 patients who did not receive hepatic surgical treatment, the overall survival rates were 24, 8.0, and 4.0 % at 1-, 3-, and 5-years, respectively, with an MST of 7 months. A significant difference was observed between patients with and without the liver surgical treatment (P < 0.001). Univariate and multivariate analyses of recipients of surgery, only the number of liver metastases (solitary or multiple) was significantly predictive of survival (HR = 0.26, P = 0.029) following hepatic resection for GLM. Conclusions: Surgical treatment of GLM should be considered when complete excision including the primary tumor appears to be possible, particularly in cases of solitary hepatic metastases. © 2015, The Society for Surgery of the Alimentary Tract.


Suzuki H.,National Hospital Organization Hokkaido Cancer Center | Yamashiro K.,National Hospital Organization Hokkaido Cancer Center | Takeda H.,National Hospital Organization Hokkaido Cancer Center | Nojima T.,Kanazawa Medical University | Usui M.,East Hokkaido Hospital
Pathology Research and Practice | Year: 2011

Extra-axial soft tissue chordoma is rare. We report a case of extra-axial soft tissue chordoma of the right wrist in an 87-year-old man. The tumor was large, and the cut surface showed multinodular and myxoid appearance. Microscopically, nests of epithelioid and spindle cells were observed in the myxoid matrix. Vacuolated cells were also observed. The tumor cells were diffusely positive for brachyury and cytokeratin 19 on immunohistochemistry, suggesting that the tumor was extra-axial soft tissue chordoma. Extra-axial chordoma is the same entity as chordoma periphericum (parachordoma), as proposed by Laskowski and Dabska. © 2011 Elsevier GmbH.

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