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Takashi Seto,
Katsuyuki Kiura,
Makoto Nishio,
Kazuhiko Nakagawa,
Makoto Maemondo,
Akira Inoue,
Toyoaki Hida,
Nobuyuki Yamamoto,
Hiroshige Yoshioka,
Masao Harada, Yuichiro Ohe,
Naoyuki Nogami,
Kengo Takeuchi,
Tadashi Shimada,
Tomohiro Tanaka,
Tomohide Tamura
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ABSTRACT: 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. FUNDING: Chugai Pharmaceutical Co, Ltd.
The lancet oncology 04/2013; · 14.47 Impact Factor
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ABSTRACT: BACKGROUND: The safety and efficacy of combination of platinum agents plus etoposide for patients with small cell lung cancer (SCLC) with pre-existing interstitial lung disease (ILD) is uncertain. PATIENTS AND METHODS: Fifty-two patients received platinum agents plus etoposide as first-line chemotherapy for SCLC with pre-existing ILD. The clinical characteristics, treatment outcome and survival of these patients were retrospectively reviewed. RESULTS: During first-line chemotherapy, only one (2%) out of the 52 patients developed an acute exacerbation of ILD. The median number of treatment cycles was four. The overall response rate was 69%. The median progression-free survival period was 4.5 months. The median survival time was 9.4 months. Thirty-three patients (63%) received at least one subsequent chemotherapy regimen, and five of these patients developed acute exacerbation of ILD. CONCLUSION: The combination of platinum agents plus etoposide is feasible and effective in SCLC patients with pre-existing ILD, compared with regimens after second-line chemotherapy.
Anticancer research 03/2013; 33(3):1175-1179. · 1.73 Impact Factor
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ABSTRACT: OBJECTIVE: A generic cisplatin formulation has replaced the brand-name formulation since November 2003 in our hospital. We retrospectively assessed the renal toxicity caused by the brand-name and generic cisplatin formulations. METHODS: The medical records of patients with thoracic malignancy who were treated at our hospital between November 2000 and April 2008 were reviewed. In total, 1296 eligible patients received 80 mg/m(2) of cisplatin: 499 patients were treated with the brand-name cisplatin formulation before November 2003 (Group 1) and 797 patients were treated with the generic formulation after November 2003 (Group 2). We compared the maximum serum creatinine level after chemotherapy in the two groups. RESULTS: The patient characteristics, including age, sex and performance status, and pretreatment serum creatinine levels were well balanced between the two groups. More patients received four cycles of chemotherapy in Group 2 (P < 0.0001). The median (range) of the maximum serum creatinine levels during all the chemotherapy cycles were 1.1 (0.5-4.1) mg/dl and 1.1 (0.5-4.4) mg/dl in Groups 1 and 2, respectively (P = 0.0237). The incidence of grade 0 serum creatinine elevations decreased from 47% to 39%, while that of grade 1 serum creatinine elevations increased from 32% to 41% (P = 0.0094). The incidence rates of grade 2 or 3 serum creatinine elevations were similar (21 vs. 20%). The time to serum creatinine elevation was also similar in Groups 1 and 2 (P = 0.161). CONCLUSION: Although grade 1 maximum serum creatinine level was more common in the generic cisplatin formulation group, this was attributed to the larger number of patients receiving four cycles of chemotherapy in this group.
Japanese Journal of Clinical Oncology 02/2013; · 1.78 Impact Factor
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Toshihiro Shiozawa,
Genichiro Ishii,
Koichi Goto,
Kanji Nagai,
Sachiyo Mimaki,
Shotaro Ono,
Seiji Niho,
Satoshi Fujii, Yuichiro Ohe,
Katsuya Tsuchihara,
Atsushi Ochiai
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ABSTRACT: Adenosquamous carcinoma of the lung (Ad-Sq) is an uncommon subtype with poor prognosis. We analyzed the clinicopathological characteristics of Ad-Sq, focusing the correlation between Epidermal Growth Factor Receptor (EGFR) mutation and clinicopathological factors. A total of 67 cases were selected from September 1992 to May 2011. EGFR mutational analysis (n = 59) was performed by direct sequence. We also performed immunohistochemical staining for EGFR mutated cases using the two mutation-specific antibodies for deletion and L858R. Postoperative 3-year survival rate of Ad-Sq was 58.7%, statistically worse in comparison with adenocarcinoma (58.7% vs. 78.1%, P = 0.038). Twenty-four percent (14/59) were positive for EGFR mutations. Patients who had never been smokers and who were lymphatic permeation positive were seen more frequently in the mutation positive group (P = 0.035, 0.027, respectively). Moreover, the EGFR mutated group tended to have a more positive prognosis than negative. Focusing on the pathological features, the lepidic growth pattern was more frequently seen in the positive group (P = 0.018). Immunoreactivity for the DEL-specific and L858-specific antibody were observed in both adenocarcinoma and squamous cell carcinoma components. Our study demonstrated that EGFR mutated Ad-Sq had similar clinicopathological features as EGFR mutated adenocarcinoma.
Pathology International 02/2013; 63(2):77-84. · 1.62 Impact Factor
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ABSTRACT: Cancer-initiating cell (CIC) hypothesis suggests that CICs may be responsible for the generation of tumors that recapitulate the histology of the primary tumor at distant sites. We investigated the distribution of CIC markers (podoplanin (PDPN), CD44, and p63) positive cells of lung squamous cell carcinoma (SqCC) within primary and matched lymph node (LN) metastatic tumors to confirm this hypothesis (n = 113). In 61 cases, the PDPN-positive cells were localized in more peripheral areas of the tumor nests than the CD44- and p63-positive cells. This distribution pattern corresponded to a 'hierarchical distribution (HD)' reported previously. Among the cases with HD-(+) primary tumors (n = 61), the number showing HD-(+) LN metastatic tumors was 31 (51%), while among the cases with HD-(-) primary tumors (n = 52), the number showing HD-(+) LN metastatic tumors was 7 (13%) (p < 0.01). Primary and matched pulmonary metastatic (PM) tumors were also analyzed (n = 31), and a significant relationship of the HD pattern between them was also detected (p = 0.01). These results indicate that PDPN-positive cells might reflect the most immature cells in the differentiation process of metastatic SqCC and might generate metastatic tumors that recapitulate the histologic heterogeneity of the primary tumor.
Pathology International 02/2013; 63(2):94-101. · 1.62 Impact Factor
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ABSTRACT: BACKGROUND: Severe hematological toxicity has been frequently observed during amrubicin monotherapy for patients with lung cancer despite the favorable anti-tumor response. The purpose of this retrospective study was to identify pretreatment factors associated with severe hematological toxicity. METHODS: The medical records of lung cancer patients treated with amrubicin monotherapy were reviewed, and univariate and multivariate analyses were conducted. RESULTS: From January 2003 to December 2006, the medical records of 103 patients were extracted. Grade 4 neutropenia was frequently observed in females (male, 66% and female, 90%, P = 0.036 in a univariate analysis). In a multivariate analysis, female gender (P = 0.019), body weight loss (P = 0.021) and amrubicin dose (P = 0.028) were significantly correlated with Grade 4 neutropenia. CONCLUSION: Gender could be considered as one of the important predictive factors associated with Grade 4 neutropenia in patients receiving amrubicin monotherapy.
Japanese Journal of Clinical Oncology 10/2012; · 1.78 Impact Factor
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Tomoko Ogawa,
Seiji Niho,
Shunji Nagai,
Takashi Kojima,
Yoshiko Nishimura, Yuichiro Ohe,
Naoki Kondo,
Takuhiro Yamaguchi,
Kazushi Endo,
Keishiro Izumi,
Hironobu Minami
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ABSTRACT: OBJECTIVE: The aim of this study was to assess the tolerability of cisplatin (CDDP) in patients with moderate renal dysfunction. METHODS: To investigate the relationship between CDDP dose and nephrotoxicity, a retrospective chart review was conducted of patients with a creatinine clearance (Ccr) of 30-60 mL/min. Subjects were classified into three groups according to the CDDP dose, as determined by the physician, and the nephrotoxicity among these groups was compared. Additionally, we investigated the correlation coefficients between maximum serum creatinine (Scr) level or minimum estimated glomerular filtration rate (eGFR) and baseline Ccr. RESULTS: Fifty-six patients were included in this study. Among these patients, 13 patients received 30-40 mg/m(2) CDDP (group I), 18 patients received 40-70 mg/m(2) (group II), and 25 patients received 70-80 mg/m(2) (group III). No significant difference in nephrotoxicity was observed (median Scr 1.53, 1.61, and 1.53 mg/dL, respectively), and no correlation was observed between baseline Ccr and maximum Scr (r = 0.004, p = 0.979) or minimum eGFR (r = 0.21, p = 0.119). Only two patients (3.5 %) experienced grade 3 or 4 Scr elevation-one patient with a Ccr of 52.6 mL/min received 60 mg/m(2) CDDP, and the other patient with a Ccr of 52.1 mL/min received 70 mg/m(2) of CDDP. Hemodialysis was not observed. CONCLUSION: CDDP was tolerated at doses of 35-80 mg/m(2) among patients with moderate renal impairment. Empiric dose reduction might create a risk of under-treatment.
International Journal of Clinical Oncology 10/2012; · 1.41 Impact Factor
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ABSTRACT: This study evaluated the safety and efficacy of combined zoledronic acid, cisplatin and docetaxel in patients with non-small cell lung cancer (NSCLC) with bone metastases.
Cisplatin 80 mg/m(2) and docetaxel 60 mg/m(2) with zoledronic acid 4 mg were given intravenously on day 1 every 3-4 weeks. The primary endpoint was feasibility of concomitant administration of zoledronic acid and cisplatin.
Thirty-five chemonaïve patients were enrolled. The median number of treatment cycles was four, and two or more cycles were administered in 29 (83%) patients without severe toxicity. No grade 3 or 4 renal toxicity was observed. The objective response rate was 29% and the 1-year survival rate was 37%. The pain score improved in 77% of the patients after six weeks.
The combination of zoledronic acid, cisplatin and docetaxel is well-tolerated with acceptable renal toxicity, and has modest activity as a first-line treatment of NSCLC patients with bone metastases.
Anticancer research 09/2012; 32(9):4131-5. · 1.73 Impact Factor
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ABSTRACT: BACKGROUND: Pemetrexed has radiosensitizing potential when evaluated in vitro in combination with platinum-containing compounds and radiation. We determined the recommended dose (RD) of thoracic radiotherapy (TRT) with a concurrent chemotherapy combination of pemetrexed and cisplatin in Japanese patients with nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients were histologically confirmed as having locally advanced nonsquamous NSCLC. Study treatment consisted of 2 phases: concurrent chemoradiation and consolidation. In the concurrent chemoradiation phase, all patients received pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) on day 1 of a 21-day interval for 3 cycles. The first 6 patients were given 60 Gy concurrently at level 1 dose (L1D). If dose-limiting toxicity (DLT) occurred in < 2 patients at L1D, radiation was escalated to 66 Gy (level 2 dose [L2D]). RESULTS: Eighteen patients were treated and completed chemoradiotherapy; 12 completed the consolidation phase. In the concurrent chemoradiation phase, 1 patient experienced 2 DLTs [grade 3 anorexia and diarrhea] at L1D. Because no DLT was observed at L2D, it was determined to be the RD. Common toxicities ≥ grade 3 were neutropenia and leukopenia. At L1D, 1 patient each experienced grade 2 and grade 3 pneumonitis, and 2 patients experienced grade 2 esophagitis. Six patients experienced grade 2 pneumonitis and 3 patients experienced grade 2 esophagitis at L2D. Fifteen patients achieved partial response (PR), 2 had stable disease (SD), and 1 had progressive disease (PD). CONCLUSION: Expected toxicities from concurrent chemoradiation were not worsened with concurrent TRT at a total dose of 66 Gy combined with pemetrexed in Japanese patients with locally advanced (LA) nonsquamous NSCLC.
Clinical Lung Cancer 05/2012; · 2.94 Impact Factor
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Shinji Atagi,
Masaaki Kawahara,
Akira Yokoyama,
Hiroaki Okamoto,
Nobuyuki Yamamoto, Yuichiro Ohe,
Toshiyuki Sawa,
Satoshi Ishikura,
Taro Shibata,
Haruhiko Fukuda,
Nagahiro Saijo,
Tomohide Tamura
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ABSTRACT: It is unknown whether combined chemoradiotherapy improves overall survival in elderly patients with locally advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether radiotherapy plus carboplatin results in longer survival than radiotherapy alone in elderly patients with NSCLC.
This was a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Patients older than 70 years with unresectable stage III NSCLC were randomly assigned to chemoradiotherapy (60 Gy plus concurrent low-dose carboplatin [30 mg/m(2) per day, 5 days a week for 20 days]) or radiotherapy alone, using a minimisation method with biased-coin assignment balancing on Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), stage (IIIA vs IIIB), and institution. The primary endpoint was overall survival, which was analysed for the eligible population and stratified by ECOG performance status, stage, and institution. The trial was stopped early as a result of the second planned interim analysis. This study is registered with UMIN Clinical Trials Registry, number C000000060, and ClinicalTrials.gov, number NCT00132665.
200 patients were enrolled from Sept 1, 2003 to May 27, 2010: 100 in the chemoradiotherapy group and 100 in the radiotherapy group. The second planned interim analysis was done 10 months after completion of patient accrual. At this time, median follow-up for censored cases was 19·4 months (IQR 10·3-33·5). In accordance with the prespecified stopping rule, the JCOG data and safety monitoring committee recommended early publication of this trial because the difference in overall survival favoured the chemoradiotherapy group. Median overall survival for the chemoradiotherapy and radiotherapy alone groups were 22·4 months (95% CI 16·5-33·6) and 16·9 months (13·4-20·3), respectively (hazard ratio 0·68, 95·4% CI 0·47-0·98, stratified log-rank test one-sided p value=0·0179). More patients had grade 3-4 haematological toxic effects in the chemoradiotherapy group than in the radiotherapy alone group, including leucopenia (61 [63·5%] vs none), neutropenia (55 [57·3%] vs none), and thrombocytopenia (28 [29·2%] vs two [2·0%]). Grade 3 infection was more common with chemoradiotherapy (12 patients [12·5%]) than with radiotherapy (four patients [4·1%]). Incidences of grade 3-4 pneumonitis and late lung toxicity were similar between groups. There were seven treatment-related deaths: three of 100 patients (3·0%) in the chemoradiotherapy group and four of 100 (4·0%) in the radiotherapy group.
For a select group of elderly patients with locally advanced NSCLC, combination chemoradiotherapy provides a clinically significant benefit over radiotherapy alone, and should be considered for this population.
Ministry of Health, Labour, and Welfare of Japan.
The lancet oncology 05/2012; 13(7):671-8. · 14.47 Impact Factor
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ABSTRACT: Interstitial lung disease (ILD) is an adverse drug reaction (ADR) of concern in Japanese patients with non-small-cell lung cancer (NSCLC) receiving erlotinib. To investigate erlotinib safety and efficacy in Japanese patients, a large-scale surveillance study was implemented.
All patients with recurrent/advanced NSCLC receiving erlotinib in Japan were enrolled (December 2007-October 2009). During the 12-month observation period, adverse-event data were collected; any adverse event where erlotinib could not be excluded as a causative factor was termed an ADR. An independent review committee assessed ILD-like events. Overall survival and progression-free survival were also assessed. Interim data were analyzed for patients registered before June 30, 2008.
In total, 10,708 patients were enrolled, 3743 by June 30, 2008, with data available for 3488 patients. Overall ADR incidence was 81.8% (mostly grade 1/2); skin disorders (68.5%) including rash (63.0%) were most common. However, 81.8% of patients who experienced rash recovered or improved. ILD-like events, diagnosed by local physicians, were reported in 189 patients. The independent review committee confirmed ILD (all grades) in 158 patients (4.5% of interim population) with a mortality rate of 1.6% (55 patients). Significant ILD risk factors included concomitant or previous ILD, smoking history, concomitant or previous lung infection, and Eastern Cooperative Oncology Group performance status 2 to 4. Median overall survival and progression-free survival were 260 and 64 days, respectively.
These interim data support the clinical benefits of erlotinib in Japanese NSCLC patients with no new safety signals. The risk/benefit balance for erlotinib in recurrent/advanced NSCLC remains favorable.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2012; 7(8):1296-303. · 4.55 Impact Factor
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ABSTRACT: The topoisomerase I inhibitors such as irinotecan and topotecan are active agents against small-cell lung cancer that are
effective in treating not only chemotherapy-naïve tumors but also progressed-stage tumors after treatment with cisplatin-based
regimens, because their mechanism of antitumor activity differs from that of the agents included in standard chemotherapy
for small-cell lung cancer. Etoposide plus cisplatin or etoposide plus cisplatin alternating with cyclophosphamide, doxorubicin,
and vincristine is considered the standard regimen for small-cell lung cancer. No new standard combination chemotherapy for
small-cell lung cancer has been developed over the past decade. Irinotecan with cisplatin is now established as a new standard
chemotherapy for extensive-stage small-cell lung cancer based on the results of the Japan Clinical Oncology Group trial. Of
course, confirmation through phase III studies will be extremely important. The Japan Clinical Oncology Group is intensively
investigating other irinotecan-containing regimens and the incorporation of irinotecan into treatment of patients with limited-stage
small-cell lung cancer.
Current Oncology Reports 04/2012; 3(2):170-178. · 2.55 Impact Factor
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ABSTRACT: The predictive factors for the development of brain metastases in patients with stage III non-small-cell lung cancer receiving concurrent chemoradiotherapy remain unclear. Several studies have suggested adenocarcinoma as a predictive factor of brain relapses. In the current analysis, we tried to identify the factors associated with brain metastases in stage III lung adenocarcinoma. The demographic and clinical characteristics, site and date of recurrence, and date of death were reviewed in patients with unresectable stage III lung adenocarcinoma who underwent concurrent platinum-based chemoradiotherapy. In total, 116 patients were identified with a median (range) age of 57 (35-74) years. Of these, 86 (74%) were men, all patients had platinum-based chemotherapy, and 100 (86%) received a total dose of 60 Gy in 30 fractions as definitive thoracic radiotherapy. Of the 95 patients with disease progression or recurrence, 19 (16%) developed brain metastases as the sole site of initial recurrence. A total of 43 (37%) patients developed brain metastases at some time during follow-up. Time to brain metastases was significantly associated with the pretreatment carcinoembryonic antigen (CEA) value, with a hazard ratio (95% confidence interval) of 2.64 (1.39-5.02, P = 0.003). Patients who developed brain metastases as the first recurrent site had marginally better survival (log-rank test, P = 0.066) than those with metastases other than brain. In conclusion, stage III lung adenocarcinoma patients with an elevated CEA value before treatment had a higher risk of developing brain metastases after chemoradiotherapy. Further effort is mandatory to control brain metastases in this patient population by a therapeutic strategy based on the tumor histology and pretreatment CEA value.
Cancer Science 02/2012; 103(4):756-9. · 3.33 Impact Factor
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ABSTRACT: The purpose of this study was to identify the risk factors associated with fatal pulmonary hemorrhage (PH) in patients with locally advanced non-small cell lung cancer (NSCLC), treated with chemoradiotherapy.
The medical records of 583 patients with locally advanced NSCLC, who were treated with chemoradiotherapy between July 1992 and December 2009 were reviewed. Fatal PH was defined as PH leading to death within 24 h of its onset. Tumor cavitation size was defined by the cavitation diameter/tumor diameter ratio and was classified as minimum (< 0.25), minor (≥ 0.25, but < 0.5), and major (≥ 0.5).
Of the 583 patients, 2.1% suffered a fatal PH. The numbers of patients with minimum, minor, and major cavitations were 13, 11, and 14, respectively. Among the 38 patients with tumor cavitation, all 3 patients who developed fatal PH had major cavitations. On multivariate analysis, the presence of baseline major cavitation (odds ratio, 17.878), and a squamous cell histology (odds ratio, 5.491) proved to be independent significant risk factors for fatal PH. Interestingly, all patients with fatal PH and baseline major cavitation were found to have tumors with squamous cell histology, and the occurrence of fatal PH in patients having both risk factors was 33.3%.
Patients at high risk of fatal PH could be identified using a combination of independent risk factors.
BMC Cancer 01/2012; 12:27. · 3.01 Impact Factor
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Tetsuhiko Taira,
Genichiro Ishii,
Kanji Nagai,
Kiyotaka Yoh,
Yusuke Takahashi,
Yuki Matsumura,
Motohiro Kojima,
Hironobu Ohmatsu,
Koichi Goto,
Seiji Niho,
Hiroshi Takashima,
Hiromasa Inoue, Yuichiro Ohe,
Atsushi Ochiai
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ABSTRACT: Tumor budding is morphologically defined as infiltration by small clusters of cancer cells. While the biological properties of budding cells in adenocarcinoma (decreased expression of adhesion molecules and of differentiation markers) have been elucidated, those of the cells in squamous cell carcinoma (SqCC) of the lung still remain to be clarified. We examined the clinicopathological data of 217 patients with SqCC of the lung. Furthermore we evaluated the immunohistochemical properties of the budding cells. Tumor budding was observed in 83 (38.2%) patients. A statistically significant difference was observed in overall 5-year survival rates between the cases showing tumor budding and the cases not showing budding (45.6% vs. 64.0%, p<0.001). As compared with cancer cells forming solid nests, budding cells (BCs) exhibited reduced expression levels of the cellular adhesion molecules (E-cadherin; p=0.004, β-catenin; p=0.002) and increased expression levels of laminin-5γ2 (p=0.001). On the other hand, no significant differences in the staining scores for differentiation markers (p63 and podoplanin) were found between BCs and cancer cells forming nests. Multivariate analysis revealed that tumor budding was a significant independent prognostic factor in patients with SqCC of the lung (p=0.022). Tumor budding is an independent adverse prognostic factor in patients with SqCC of the lung. Although budding cells in SqCC exhibited reduced expression levels of the cellular adhesion molecules, the expression levels of specific differentiation markers were retained, suggesting that the budding mechanism in SqCC may differ, at least in part, from that in adenocarcinoma.
Lung cancer (Amsterdam, Netherlands) 12/2011; 76(3):423-30. · 3.14 Impact Factor
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ABSTRACT: The aim of the study is to evaluate the current status of treatment-related death (TRD) in lung cancer patients.
We retrospectively analyzed the incidence and risk factors of TRD in lung cancer patients who received chemotherapy and/or thoracic radiotherapy using logistic regression analyses.
Between January 2001 and December 2005, 1225 (222 small cell and 1003 non-small cell lung cancers) patients received chemotherapy and/or thoracic radiotherapy as the initial treatment. Of these, 43 patients receiving chemotherapy followed by thoracic radiotherapy were included into both the chemotherapy-alone and radiotherapy-alone groups. There were a total of 23 (1.9%) TRDs. Chemotherapy-related deaths occurred in 7 of 927 (0.8%) patients, including 4 from drug-induced lung injury, 2 from pneumonia, and 1 from unknown cause. Concurrent chemoradiotherapy-related deaths occurred in 12 of 245 (4.9%) patients, including 11 from radiation pneumonitis and 1 from pneumonia. Thoracic radiotherapy-related deaths occurred in 4 of 96 (4.2%) patients. The incidence of chemotherapy-related death was correlated with poor performance status (odds ratio [OR]: 11.4, 95% confidence interval [CI]: 3.53-37.1), the presence of hypoxia (OR: 19.3, CI: 6.06-61.7), hyponatremia (OR: 45.5, CI: 13.4-154), and treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (OR: 8.56, CI: 2.48-29.5), whereas the incidence of concurrent chemoradiotherapy-related death was correlated with pulmonary fibrosis (OR: 22.2, CI: 5.61-87.8). Radiotherapy results were not analyzed because there were too few patients.
TRD occurred in 1.9% of the patients as a result of treatment-related lung injury in the majority of the cases.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2011; 7(1):177-82. · 4.55 Impact Factor
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Seiji Yano,
Tadaaki Yamada,
Shinji Takeuchi,
Keisei Tachibana,
Yuko Minami,
Yasushi Yatabe,
Tetsuya Mitsudomi,
Hidenori Tanaka,
Tatsuo Kimura,
Shinzoh Kudoh, [......],
Jun Yokota,
Hidetaka Uramoto,
Kosei Yasumoto,
Katsuyuki Kiura,
Masahiko Higashiyama,
Makoto Oda,
Haruhiro Saito,
Junji Yoshida,
Kazuya Kondoh,
Masayuki Noguchi
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ABSTRACT: This study was performed to determine the incidence rates of resistance factors, i.e., high-level hepatocyte growth factor (HGF) expression, epidermal growth factor receptor (EGFR) T790M secondary mutation, and MET amplification, in tumors with intrinsic and acquired EGFR tyrosine kinase inhibitor (TKI) resistance in EGFR mutant lung cancer.
Ninety-seven specimens from 93 EGFR mutant lung cancer patients (23 tumors with acquired resistance from 20 patients, 45 tumors with intrinsic resistance from 44 patients [nonresponders], 29 sensitive tumors from 29 patients) from 11 institutes in Japan were analyzed. HGF expression, EGFR T790M secondary mutation, and MET amplification were determined by immunohistochemistry, cycleave real-time polymerase chain reaction, and fluorescence in situ hybridization, respectively.
High-level HGF expression, EGFR T790M secondary mutation, and MET amplification were detected in 61, 52, and 9% of tumors with acquired resistance, respectively. High-level HGF expression was detected in 29% of tumors with intrinsic resistance (nonresponders), whereas EGFR T790M secondary mutation and MET amplification were detected in 0 and 4%, respectively. HGF expression was significantly higher in tumors with acquired resistance than in sensitive tumors (p < 0.001, Student's t test). Fifty percent of tumors with acquired resistance showed simultaneous HGF expression with EGFR T790M secondary mutation and MET amplification.
High-level HGF expression was detected more frequently than EGFR T790M secondary mutation or MET amplification in tumors with intrinsic and acquired EGFR-TKI resistance in EGFR mutant lung cancer in Japanese patients. These observations provide a rationale for targeting HGF in EGFR-TKI resistance in EGFR mutant lung cancer.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2011; 6(12):2011-7. · 4.55 Impact Factor
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Yoshinori Makino,
Noboru Yamamoto,
Hitoshi Sato,
Reiko Ando,
Yasushi Goto,
Chiharu Tanai,
Hajime Asahina,
Hiroshi Nokihara,
Ikuo Sekine,
Hideo Kunitoh, Yuichiro Ohe,
Erika Sugiyama,
Nobuaki Yokote,
Tomohide Tamura,
Hiroshi Yamamoto
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ABSTRACT: The pharmacokinetic (PK)-pharmacodynamic (PD) relationship of amrubicin and its active metabolite, amrubicinol, has only been evaluated using trough levels of these agents since the full PK profiles not yet been clarified so far. This study was performed to analyze the full PK profiles of amrubicin and amrubicinol and to evaluate their toxicity-PK relationships in Japanese patients.
Amrubicin (35-40 mg/m(2)) was administered to 21 lung cancer patients on days 1-3 every 3-4 weeks. Fourteen blood samples were obtained per patient over the course of 3 administration days. The plasma concentrations of amrubicin and amrubicinol were quantitated by HPLC, and the relationships between PK parameters of these compounds and hematological toxicities were evaluated.
The overall PK profiles of amrubicin and amrubicinol were well characterized using a 3-compartment model and a 1-compartment model with a first-order metabolic process, respectively. The major toxicities were hematological. The clearance of amrubicinol was significantly correlated with grade 4 neutropenia (P = 0.01). The percentage decreases in the neutrophil count, hemoglobin level and platelet count were well correlated with the amrubicinol AUC.
The pharmacokinetic profiles of amrubicin and amrubicinol were clarified, and the subsequent PK-PD analyses indicate that the clearance of amrubicinol is the major determinant of neutropenia.
Cancer Chemotherapy and Pharmacology 11/2011; 69(4):861-9. · 2.83 Impact Factor
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Yoshihisa Shimada,
Seiji Niho,
Genichiro Ishii,
Tomoyuki Hishida,
Junji Yoshida,
Mitsuyo Nishimura,
Kiyotaka Yoh,
Koichi Goto,
Hironobu Ohmatsu, Yuichiro Ohe,
Kanji Nagai
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ABSTRACT: The overall clinicopathological features or the optimal therapy for large cell neuroendocrine carcinoma (LCNEC) have yet to be defined, because LCNEC has not been studied in the same depth as had small cell lung carcinoma (SCLC) in both clinical and biological standpoints. The aim of this study was to elucidate the clinical features of high-grade neuroendocrine carcinoma (HGNEC)-probable LCNEC diagnosed by biopsy, and compare therapeutic efficacy with patients with SCLC.
We retrospectively examined the chart of total of 25 patients who underwent chemotherapy or chemoradiotherapy as initial therapy for a histologic diagnosis of HGNEC-probable LCNEC, using biopsy samples and compared their data with those of 180 patients with SCLC. We analyzed their responses to chemotherapy and/or radiation therapy and survival outcomes.
In 25 patients with HGNEC-probable LCNEC, 18 patients initially received chemotherapy (17 (94%) of whom received platinum-based chemotherapy) with an overall response rate (ORR) of 61%. The remaining 7 patients received chemoradiotherapy with an ORR of 86%, and 12 of the 25 patients who received second-line chemotherapy had an ORR of 17%. A total of 101 patients with SCLC who initially received chemotherapy had an ORR of 63%, and 79 patients who initially received chemoradiotherapy had an ORR of 98%, and 102 of the 180 patients who received second-line chemotherapy had an ORR of 45%. The 1-year overall survival rate for patients with stage IV HGNEC-probable LCNEC (n=13) and those with ED-SCLC (n=80) was 34% and 49%, respectively (p=0.84).
The overall response rate to initial treatment and the survival outcomes of HGNEC-probable LCNEC were comparable to those of SCLC, but the effectiveness of second-line chemotherapy appeared to differ between the 2 groups.
Lung cancer (Amsterdam, Netherlands) 09/2011; 75(3):368-73. · 3.14 Impact Factor
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Koichi Goto,
Yukito Ichinose, Yuichiro Ohe,
Nobuyuki Yamamoto,
Shunichi Negoro,
Kazuto Nishio,
Yohji Itoh,
Haiyi Jiang,
Emma Duffield,
Rose McCormack,
Nagahiro Saijo,
Tony Mok,
Masahiro Fukuoka
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ABSTRACT: In IPASS (IRESSA Pan-Asia Study), clinically selected patients with pulmonary adenocarcinoma received first-line gefitinib or carboplatin/paclitaxel. This preplanned, exploratory analysis was conducted to increase understanding of the use of surrogate samples, such as serum, versus tumor biopsy samples for determining EGFR mutation status in the Japanese cohort (n = 233).
EGFR mutations were assessed using tumor tissue-derived DNA (n = 91) and circulating free (cf) DNA from pretreatment serum samples (n = 194).
Fewer patients were EGFR mutation positive when assessed using pretreatment cfDNA (23.7%) versus tumor tissue-derived DNA (61.5%). cfDNA results identified no false positives but a high rate of false negatives (56.9%). There was a significant interaction between cfDNA EGFR mutation status and treatment for progression-free survival (PFS) (p = 0.045). PFS was significantly longer and objective response rate (ORR) higher with gefitinib than carboplatin/paclitaxel in the cfDNA EGFR mutation-positive subgroup (PFS: hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.14-0.60; p < 0.001; ORR: odds ratio [OR], 1.71; 95% CI, 0.48-6.09; 75.0% versus 63.6%; p = 0.40). There was a slight numerical advantage in PFS and ORR for gefitinib over carboplatin/paclitaxel in the cfDNA EGFR mutation-negative subgroup, likely due to the high rate of false negatives within this subgroup.
These results merit further investigation to determine whether alternative sources of tumor DNA, such as cfDNA in serum, could be used for determining EGFR mutation status in future; currently, where a sample is available, analysis of tumor material is recommended.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2011; 7(1):115-21. · 4.55 Impact Factor
