National Shikoku Cancer Center

Matsuyama-shi, Japan

National Shikoku Cancer Center

Matsuyama-shi, Japan
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Niho S.,National Cancer Center Hospital East | Kunitoh H.,National Cancer Center Hospital | Nokihara H.,National Cancer Center Hospital | Horai T.,Cancer Institute Hospital | And 18 more authors.
Lung Cancer | Year: 2012

Purpose: This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods: Chemonaïve patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results: After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p= 0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p= 0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p= 0.9526). No new safety signals were detected. Conclusion: Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338). © 2011 Elsevier Ireland Ltd.

Toi M.,Kyoto University | Iwata H.,Aichi Cancer Center Hospital | Yamanaka T.,Institute for Clinical Research | Masuda N.,Osaka National Hospital | And 8 more authors.
Cancer | Year: 2010

BACKGROUND: The 21-gene signature has been intensively studied and incorporated into major guidelines for treatment decision in early breast caner. However, it remains to be examined whether this system is applicable to Asian populations. METHODS: The authors collected 325 tumor tissues from estrogen receptor (ER)-positive primary breast cancer patients who had undergone surgery and were treated with tamoxifen between 1992 and 1998. The tissues were analyzed for the 21-gene signature, and the patients were classified into groups of low, intermediate, or high risk based on the Recurrence Score. RESULTS: A total of 280 patients were eligible, with adequate reverse transcription polymerase chain reaction profiles for the Recurrence Score. Of those, 200 and 80 patients had lymph nodenegative and lymph node-positive disease, respectively. The proportions of lymph node-negative patients categorized as being at low, intermediate, or high risk were 48%, 20%, and 33%, respectively. In lymph node-negative patients, the Kaplan-Meier estimates of the distant recurrence rate at 10 years were 3.3% (95% confidence interval [95% CI], 1.1-10.0%), 0%, and 24.8% (95% CI, 15.7-37.8%) for those in the low-risk, intermediate-risk, and high-risk groups, respectively. The risk of distant recurrence in the low-risk group was significantly lower than that in the highrisk group when the entire Kaplan-Meier plots were compared (P < .001, log-rank test). There was a significant difference for overall survival between the low-risk and the high-risk groups (P = .008, log-rank test). CONCLUSIONS: This is the first report to show that the 21-gene signature has value in providing prognostic information in Asian populations with ER-positive, lymph node-negative breast cancer. © 2010 American Cancer Society.

Toita T.,University of Ryukyus | Kato S.,Japan National Institute of Radiological Sciences | Niibe Y.,Kitasato University | Ohno T.,Gunma University | And 16 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To determine the efficacy of a definitive radiotherapy protocol using high-dose-rate intracavitary brachytherapy (HDR-ICBT) with a low cumulative dose schedule in nonbulky early-stage cervical cancer patients, we conducted a prospective multi-institutional study. Methods and Materials: Eligible patients had squamous cell carcinoma of the intact uterine cervix, Federation of Gynecologic Oncology and Obstetrics (FIGO) stages Ib1, IIa, and IIb, tumor size <40 mm in diameter (assessed by T2-weighted magnetic resonance imaging), and no pelvic/para-aortic lymphadenopathy. The treatment protocol consisted of whole-pelvis external beam radiotherapy (EBRT) of 20 Gy/10 fractions, pelvic EBRT with midline block of 30 Gy/15 fractions, and HDR-ICBT of 24 Gy/4 fractions (at point A). The cumulative biologically effective dose (BED) was 62 Gy 10 (α/β = 10) at point A. The primary endpoint was the 2-year pelvic disease progression-free (PDPF) rate. All patients received a radiotherapy quality assurance review. Results: Between September 2004 and July 2007, 60 eligible patients were enrolled. Thirty-six patients were assessed with FIGO stage Ib1; 12 patients with stage IIa; and 12 patients with stage IIb. Median tumor diameter was 28 mm (range, 6-39 mm). Median overall treatment time was 43 days. Median follow-up was 49 months (range, 7-72 months). Seven patients developed recurrences: 3 patients had pelvic recurrences (2 central, 1 nodal), and 4 patients had distant metastases. The 2-year PDPF was 96% (95% confidence interval [CI], 92%-100%). The 2-year disease-free and overall survival rates were 90% (95% CI, 82%-98%) and 95% (95% CI, 89%-100%), respectively. The 2-year late complication rates (according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer of Grade ≥1) were 18% (95% CI, 8%-28%) for large intestine/rectum, 4% (95% CI, 0%-8%) for small intestine, and 0% for bladder. No Grade ≥3 cases were observed for genitourinary/gastrointestinal late complications. Conclusions: These results suggest that definitive radiotherapy using HDR-ICBT with a low cumulative dose schedule (BED, 62 Gy 10 at point A) can provide excellent local control without severe toxicity in nonbulky (<4-cm) early-stage cervical cancer. Copyright © 2012 Elsevier Inc. Printed in the USA. All rights reserved.

Takiguchi Y.,Chiba University | Seto T.,National Kyusyu Cancer Center | Ichinose Y.,National Kyusyu Cancer Center | Nogami N.,National Shikoku Cancer Center | And 8 more authors.
Journal of Thoracic Oncology | Year: 2011

BACKGROUND: Standard second-line chemotherapies for non-small cell lung cancer (NSCLC) have been established but have limited clinical relevance. S-1 is a recently developed agent with potential activity against NSCLC. METHODS: Patients with confirmed NSCLC recurrence after previous single- or two-regimen chemotherapy with platinum, performance status of 0 to 1, adequate organ functions, and measurable lesions were treated with S-1 (60 mg/m2/d, twice a day) on days 1 to 14 and gemcitabine (1000 mg/m2) on days 8 and 15, which were repeated every 3 weeks until tumor progression. RESULTS: Treatment was administered for a median of 4 courses (range, 1-13) over a median of 125-day period in 34 patients. The overall response rate was 23.5% (no complete response and eight partial response; 95% confidence interval: 9.1-38.0%). The median progression-free and overall survival times were 6.6 and 19.9 months, respectively. The 1- and 2-year survival rates were 58.8 and 30.9%, respectively. Toxicity was mild during the entire treatment period, except for three grade 3 interstitial pneumonia. CONCLUSION: The primary end point was met with the relatively high overall response rate. Randomized phase III studies for elucidating survival outcome of the regimen are warranted. Copyright © 2010 by the International Association for the Study of Lung Cancer.

Tokumaru S.,Saga University | Toita T.,University of Ryukyus | Oguchi M.,Cancer Institute Hospital | Ohno T.,Gunma University | And 16 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To investigate pelvic insufficiency fractures (IF) after definitive pelvic radiation therapy for early-stage uterine cervical cancer, by analyzing subjects of a prospective, multi-institutional study. Materials and Methods: Between September 2004 and July 2007, 59 eligible patients were analyzed. The median age was 73 years (range, 37-84 years). The International Federation of Gynecologic Oncology and Obstetrics stages were Ib1 in 35, IIa in 12, and IIb in 12 patients. Patients were treated with the constant method, which consisted of whole-pelvic external-beam radiation therapy of 50 Gy/25 fractions and high-dose-rate intracavitary brachytherapy of 24 Gy/4 fractions without chemotherapy. After radiation therapy the patients were evaluated by both pelvic CT and pelvic MRI at 3, 6, 12, 18, and 24 months. Diagnosis of IF was made when the patients had both CT and MRI findings, neither recurrent tumor lesions nor traumatic histories. The CT findings of IF were defined as fracture lines or sclerotic linear changes in the bones, and MRI findings of IF were defined as signal intensity changes in the bones, both on T1- and T2-weighted images. Results: The median follow-up was 24 months. The 2-year pelvic IF cumulative occurrence rate was 36.9% (21 patients). Using Common Terminology Criteria for Adverse Events version 3.0, grade 1, 2, and 3 IF were seen in 12 (21%), 6 (10%), and 3 patients (5%), respectively. Sixteen patients had multiple fractures, so IF were identified at 44 sites. The pelvic IF were frequently seen at the sacroileal joints (32 sites, 72%). Nine patients complained of pain. All patients' pains were palliated by rest or non-narcotic analgesic drugs. Higher age (>70 years) and low body weight (<50 kg) were thought to be risk factors for pelvic IF (P=.007 and P=.013, Cox hazard test). Conclusions: Cervical cancer patients with higher age and low body weight may be at some risk for the development of pelvic IF after pelvic radiation therapy. © 2012 Elsevier Inc.

Toi M.,Kyoto University | Saji S.,Saitama University | Saji S.,Tokyo Metropolitan Komagome Hospital | Masuda N.,Osaka National Hospital | And 15 more authors.
Cancer Science | Year: 2011

Aromatase inhibitor shows efficacy for hormone receptor positive postmenopausal breast cancer. We evaluated the activity of 24weeks of aromatase inhibition with exemestane for primary breast cancer in a neoadjuvant setting. Patients with stageII/IIIA invasive breast cancer with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive status were eligible. Primary endpoints were objective response rate (ORR) and safety. A steroidal aromatase inhibitor exemestane of 25mg/day was administered for 16weeks with an 8-week extension. Secondary endpoints were rates of breast-conserving surgery (BCS), and change of Ki67 index and ER/PgR expression in central laboratory analyses. Between March 2006 and December 2007, 116 patients were enrolled. Among those, 102 patients completed 24weeks of administration. The ORR was 47% (55/116) at Week16 and 51% (59/116) at Week24, respectively. No serious toxicity was seen. ORR was associated with ER Allred scores but not with PgR scores. The significant reduction in Ki67 index was confirmed. No progression was experienced in tumors with less than 15% Ki67 index. Pathological response was observed in 28 (30%) of 94 evaluated cases. No statistical correlation between pre-treatment Ki67 index and pathological response was detected; however, a trend of correlation was found between the post-treatment preoperative endocrine prognostic index (PEPI), a prognostic score and the pathological response. At diagnosis, 59 patients (51%) would have required mastectomy but 40 patients were converted to BCS, showing an increase in the rate of BCS (77%). The 24-week aromatase inhibition provided preferable clinical benefits with significant reduction in Ki67 index. More precise mechanisms of the response need to be investigated. © 2011 Japanese Cancer Association.

Ijichi N.,Saitama University | Shigekawa T.,Saitama University | Shigekawa T.,Komagome Hospital | Ikeda K.,Saitama University | And 10 more authors.
Hormones and Cancer | Year: 2012

Breast cancer is primarily a hormone-dependent tumor that can be regulated by the status of the steroid hormones estrogen and progesterone. Forkhead box A1 (FOXA1) is a member of the forkhead box transcription factor family and functions as a pioneer factor of the estrogen receptor (ER) in breast cancer. In the present study, we demonstrate that FOXA1 mRNA was upregulated by estrogen and that estrogen receptor-α (ERα) recruitment to ER-binding sites in the vicinity of the FOXA1 gene was increased by estrogen in ERα-positive MCF-7 breast cancer cells. The estrogen-induced FOXA1 upregulation was repressed by 4-hydroxytamoxifen treatment. We also demonstrated that the proliferation and the migration of MCF-7 cells were decreased by FOXA1-specific small interfering RNA (siRNA; siFOXA1). Furthermore, siFOXA1 decreased the estrogen response element-driven transcription and the estrogen-dependent upregulation of ERα target genes in MCF-7 cells. Next, the immunohistochemical analyses of FOXA1 were performed using two groups of breast cancer specimens. The nuclear immunoreactivity of FOXA1 was detected in 80 (74 %) of 108 human invasive breast cancers and was negatively correlated with tumor grade and positively correlated with hormone receptor status, including ERα and progesterone receptor, pathological tumor size, and immunoreactivity of FOXP1, another FOX family transcription factor. FOXA1 immunoreactivity was significantly elevated in the relapse-free breast cancer patients treated with tamoxifen. Notably, the double-positive immunoreactivities of FOXA1 and FOXP1 were significantly associated with a favorable prognosis for the relapse-free and overall survival of patients with tamoxifen-treated breast cancer, with lower P values compared with FOXA1 or FOXP1 immunoreactivity alone. These results suggest that FOXA1 plays an important role in the proliferation and migration of breast cancer cells by modulating estrogen signaling and that the double-positive immunoreactivities of FOXA1 and FOXP1 are associated with a favorable prognosis of tamoxifen-treated breast cancer. © 2012 Springer Science+Business Media, LLC.

Kurokawa Y.,Osaka National Hospital | Sasako M.,Hyogo College of Medicine | Sano T.,Cancer Institute Ariake Hospital | Shibata T.,Clinical Data | And 4 more authors.
British Journal of Surgery | Year: 2011

Background: Extended gastrectomy with para-aortic nodal dissection (PAND) or thorough dissection of mediastinal nodes using a left thoracoabdominal (LTA) approach is an alternative to D2 lymphadenectomy, with variable postoperative results. Methods: Two randomized controlled trials have been conducted to compare D2 lymphadenectomy alone (263 patients) versus D2 lymphadenectomy plus PAND (260), and the abdominal-transhiatal (TH) approach (82) versus the LTA approach (85), in patients with gastric cancer. Prospectively registered secondary endpoints bodyweight, symptom scores and respiratory function were evaluated in the present study. Results: Bodyweight was comparable after D2 and D2 plus PAND, but higher after TH than after LTA procedures at 1 and 3 years. At 1- and 3-year follow-up symptom scores were comparable between D2 and D2 plus PAND. A LTA approach resulted in significantly worse scores than a TH approach in terms of meal volume, return to work, incisional pain and dyspnoea up to 1 year. The decrease in vital capacity was significantly greater after LTA than TH procedures up to 6 months. Conclusion: Bodyweight and postoperative symptoms were not affected by adding PAND to a D2 procedure. A LTA approach aggravated weight loss, symptoms and respiratory functions compared with a TH approach. Registration numbers: NCT00149279, NCT00149266 (). Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Yamamoto N.,Shizuoka Cancer Center | Muraakmi H.,Shizuoka Cancer Center | Nishina T.,National Shikoku Cancer Center | Hirashima T.,Osaka Prefectural Medical Center for Respiratory and Allergic Diseases | And 8 more authors.
Annals of Oncology | Year: 2013

Background: Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ~20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs). Patients and methods: Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid. Results: Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC0-12 compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients. Conclusion: Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

PubMed | National Shikoku Cancer Center
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

16566 Background: Several clinical trials of neoadjuvant chemotherapy for advanced ovarian cancer have been conducted. However, clear cell and mucinous adenocarcinoma should be excluded from the eligible criteria, because these two histological subtypes are resistant to chemotherapy, and the completeness of cytoreduction is the most prognostic factor in survival. In this study, we verified the significance of peritoneal cytology with cell block method and immunohistochemical (IHC) analysis in the pretherapeutic diagnosis of histological subtype in advanced ovarian cancer.Forty-one patients with advanced epithelial ovarian or primary peritoneal cancer, consisting of 8 serous (S), 9 endometrioid (E), 5 clear cell (C), 14 mucinous (M) and 5 mixed epithelial tumors, treated between 1/2006 and 12/2007 were analyzed. In 27 patients, only conventional cytology technique was performed; in 14 patients, cell block preparation method was also used. IHC staining of estrogen receptor (ER), mutant p53, cytokeratin 20 (CK20), vimentin and periodic acid-Schiff stain (PAS) was performed in the cytology and/or cell block specimens.In conventional peritoneal cytology, the incidence of positive cytology was 63.0% (17/27). Adding cell block method and IHC staining increased the incidence of positive cytology (85.7%, 12/14). PAS was positive in 25% S (2/8), 33% E (3/9), 100% C (5/5) and 100% M (14/14); ER in 63% S (5/8), 100% E (9/9), 0% C (0/5) and 36% M (5/14); p53 in 75% S (6/8), 11% E (1/9), 0% C (0/5) and 0% M (0/14); Vimentin in 0% S (0/8), 100% E (9/9), 60% C (3/5) and 36% M (5/14); CK20 in 0% S (0/8), 0% E (0/9), 0% C (0/5) and 29% M (4/14). Using this IHC panel, the percentage of correct pretherapeutic diagnoses of histological subtype is 95.1% (39/41).Peritoneal cytology with cell block method and IHC staining of ER, p53 and PAS makes pretherapeutic diagnosis of histological subtype more accurate, and may be useful for individualizing treatment in advanced ovarian cancer patients. No significant financial relationships to disclose.

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