[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to evaluate the interfractional prostate motion of patients immobilized in the prone position using a thermoplastic shell. A total of 24 patients with prostate calcifications detectable using a kilo-voltage X-ray image-guidance system (ExacTrac X-ray system) were examined. Daily displacements of the calcification within the prostate relative to pelvic bony structures were calculated by the ExacTrac X-ray system. The average displacement and standard deviation (SD) in each of the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were calculated for each patient. Based on the results of interfractional prostate motion, we also calculated planning target volume (PTV) margins using the van Herk formula and examined the validity of the PTV margin of our institute (a 9-mm margin everywhere except posteriorly, where a 6-mm margin was applied). In total, 899 data measurements from 24 patients were obtained. The average prostate displacements ± SD relative to bony structures were 2.8 ± 3.3, -2.0 ± 2.0 and 0.2 ± 0.4 mm, in the SI, AP and LR directions, respectively. The required PTV margins were 9.7, 6.1 and 1.4 mm in the SI, AP and LR directions, respectively. The clinical target volumes of 21 patients (87.5%) were located within the PTV for 90% or more of all treatment sessions. Interfractional prostate motion in the prone position with a thermoplastic shell was equivalent to that reported for the supine position. The PTV margin of our institute is considered appropriate for alignment, based on bony structures.
Journal of Radiation Research 07/2013; · 1.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose
To analyze initial recurrence patterns in patients with newly diagnosed glioblastoma after radiotherapy plus concurrent and adjuvant temozolomide, and to investigate cumulative recurrence patterns after salvage treatment, including surgery, stereotactic radiotherapy, and chemotherapy.
Twenty-one patients with glioblastoma that recurred after concurrent temozolomide and localized radiotherapy were retrospectively analyzed (11 male, 10 female; median age, 57 years; range, 27–74). Disease progression was assessed by new response criteria proposed by the Response Assessment in Neuro-Oncology Working Group of the American Society of Clinical Oncology. The pattern of recurrence was determined by relationships between locations of recurrent tumors and irradiated doses. Central, in-field, marginal, and out-field recurrences were defined relative to the prescribed isodose line. Distant recurrence was operationally defined as subependymal or disseminated disease. Initial and cumulative patterns of recurrence were evaluated in each patient.
The median follow-up of the recurrent patients was 501 (range, 217–1815) days after initial surgery. Initial recurrences were central in 14 patients (66.7%), in-field in four patients (19.0%), marginal in no patient (0%), out-field in two patients (9.5%), and distant in four patients (19.0%). One patient had both central and in-field recurrences simultaneously, and two had both central and distant recurrences. In the analysis of cumulative recurrence patterns, five patients, who had no scans after initial recurrences, were excluded and the remaining 16 were included. Cumulative recurrences were central in 11 patients (68.8%), in-field in five patients (31.3%), marginal in three patients (18.8%), out-field in five patients (31.3%), and distant in 14 patients (87.5%). Regarding salvage treatments, 11 (52.4%), 11 (52.4%) and 17 (81.0%) patients underwent surgery, stereotactic radiotherapy and chemotherapy, respectively. Eighteen (85.7%) patients had died at the time of analysis, and 16 of them (88.9%) had suffered distant recurrences, which could have been the immediate causes of death.
Recurrence patterns of glioblastoma after radiotherapy plus concomitant and adjuvant temozolomide were mainly central at first, and distant recurrences were often detected during the clinical course. Much better local control and prevention of distant recurrence, including effective salvage treatment, seem to be important.
[Show abstract][Hide abstract] ABSTRACT: We investigated whether intraoperative radiotherapy (IORT) during curative surgery for esophageal carcinoma is useful or not. The cases of 117 patients diagnosed with thoracoabdominal esophageal carcinoma who underwent curative surgery between 1986 and 2007 were reviewed: 72 patients received IORT (IORT group) and 45 did not (non-IORT group). Upper abdominal lymphadenectomy was performed in 115 patients (98.5%). Seventy patients (59.8%) received chemotherapy and 80 patients (68.4%) received external radiotherapy. IORT encompassed the upper abdominal lymph node area. A single-fraction dose of 20-30 Gy was delivered using high-energy electrons. Median follow-up duration for patients was 7.4 years. The 5-year overall survival rate did not significantly differ between the IORT and non-IORT groups. However, the 5-year abdominal control rate was significantly higher in the IORT group (89.2%) than in the non-IORT group (72.9%; P = 0.022). We next focused on a patient subgroup with a primary lesion in the lower thoracic or abdominal esophagus or measuring >6 cm in length since this subgroup is probably at high risk of upper abdominal lymph node metastasis. Of the 117 patients, 75 belonged to this subgroup, and among them 45 received IORT. Both univariate and multivariate analysis revealed the survival rate was significantly higher in patients who received IORT than in those who did not (P = 0.033 univariate; 0.026 multivariate). There were no obvious perioperative complications solely attributed to IORT. IORT for esophageal carcinoma will likely be effective for patients with a primary lesion in the lower thoracic or abdominal esophagus, or with a long lesion.
Journal of Radiation Research 08/2012; · 1.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study aimed to analyze outcomes of hypofractionated stereotactic radiotherapy (HFSRT) delivered in five fractions to metastatic brain tumors. Between June 2008 and June 2011, 39 consecutive patients with 46 brain metastases underwent HFSRT at Kyoto University Hospital. Selection criteria included high risk factors such as eloquent location, history of whole-brain radiotherapy (WBRT), or large tumor size. Given these factors, fractionated schedules were preferable in terms of radiobiology. The prescribed dose at the isocenter was basically 35 Gy in five fractions. Brainstem lesions with a history of WBRT were treated with 20-25 Gy in five fractions. Planning target volume was covered by the 80 % isodose line of the prescribed dose to the isocenter. Local-control probability and overall survival were estimated using the Kaplan-Meier method. For the analysis of local control, the response criteria were defined as follows: complete response (CR) was defined as no visible gross tumor or absence of contrast enhancement, partial response (PR) as more than a 30 % decrease in size, progressive disease as more than a 20 % increase in size, and stable disease (SD) as all other responses. Local control was defined as a status of CR, PR, or SD. Only patients with at least 3 months or longer follow-up (21 patients, 27 tumors) were included in the analysis. Median age and Karnofsky performance status were 59 years (range, 39-84 years) and 90 (range, 40-100), respectively. Tumor volumes and maximum diameters ranged from 0.08 to 15.38 cm(3) (median, 3.67 cm(3)) and from 3 to 34 mm (median, 18 mm), respectively. The median follow-up period was 329 days (range, 120-1,321 days). Local-control probabilities at 6 and 12 months were 92.1 and 86.7 %, respectively. Overall survival after HFSRT at 6 and 12 months was 85.4 and 64.5 %, respectively. Grade 3 radiation necrosis was observed in one patient according to the Common Terminology Criteria for Adverse Events version 3.0. The patient was successfully managed conservatively. HFSRT for metastatic brain tumors yields high local-control probabilities without increasing severe adverse events despite high risk factors.
Journal of Neuro-Oncology 06/2012; 109(2):425-32. · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The outcomes of three-dimensional conformal radiation therapy (3D-CRT) combined with neoadjuvant hormonal therapy (NAHT) in Japanese patients with T1c-T2N0M0 prostate cancer, with initiation of salvage hormonal therapy (SHT) at a relatively early phase, were analyzed. METHODS: Fifty-nine Japanese patients with T1c-T2N0M0 prostate cancer who received radical 3D-CRT between January 1999 and January 2003 were evaluated. The median age, initial prostate-specific antigen (PSA) level, and duration of NAHT were: 72 years, 9.4 ng/ml, and 6 months, respectively. Seventy Gy was given in 35 fractions confined to the prostate ± seminal vesicles. AHT was not administered after 3D-CRT in any patients. RESULTS: The median follow-up period was 89 months. The median PSA value at the time of initiation of SHT was 4.7 ng/ml (range 0.1-21.6 ng/ml). The overall, disease-specific, PSA failure-free (based on the Phoenix definition), and SHT-free survival rates at 8 years were 82.8% (95% confidence interval [CI] 72.4-93.2), 100%, 62.4% (47.1-77.8), and 82.6% (71.3-94.0), respectively. Only one patient developed grade 3 late toxicity. CONCLUSIONS: The PSA control rates in our series of Japanese patients with stage T1c-T2N0M0 prostate cancer treated with the standard dose of 3D-CRT combined with NAHT seemed at least comparable to those reported from Western countries; as well, the patients had excellent outcomes. The present outcomes can be used as basic data for evaluating the impact of dose escalation with intensity-modulated radiation therapy for Japanese patients with prostate cancer in the future.
International Journal of Clinical Oncology 10/2011; · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The outcomes of patients with localized or locally advanced prostate cancer treated with external-beam radiotherapy are not well known in Japan.
Thirty-four institutions combined data on 679 patients with localized or locally advanced prostate cancer treated with a total dose >/=60 Gy between 1995 and 2002.
With a median follow-up of 46 months, the 5-year overall, clinical progression-free, and biochemical relapse-free survival rate were 93.0, 95.3 and 71.9% for all patients, respectively. The 5-year progression-free, and biochemical relapse-free survival rates according to the risk group were 100%, 90.8% in the low-risk group, 98.3%, 75.7% in the intermediate-risk group and 93.6%, 67.6% in the high-risk group, respectively. The multivariate analysis for biochemical relapse-free survival revealed that prostate-specific antigen (relative risk, 1.002; 95% CI, 1.001-1.003; P = 0.0041), Gleason score (relative risk, 1.166; 95% CI, 1.046-1.302; P = 0.0055), T classification (relative risk, 2.897; 95% CI, 1.999-4.230; P = 0.0000), pelvic irradiation (relative risk, 2.042; 95% CI, 1.328-3.273; P = 0.0008), and androgen abletion (relative risk, 0.321; 95% CI, 0.240-0.427; P = 0.0000) were significant prognostic factors. Only 1.1% of patients experienced late morbidity of Grade 3.
Radiotherapy for prostate cancer seemed to be effective, with little risk of normal tissue complications.
Japanese Journal of Clinical Oncology 04/2008; 38(3):200-4. · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypoxia is closely associated with the radioresistance of tumours; therefore, targeting hypoxic areas is very important for cancer therapy. The aim of this study is to establish such a targeting strategy by applying a bacterial cytosine deaminase (BCD)/5-fluorocytosine (5-FC) gene therapy system and to examine whether the strategy enhances the efficacy of radiotherapy in a tumour xenograft. The hypoxia-responsive promoter 5HREp, in which five copies of the hypoxia-response element (HRE) enhance transcription from a cytomegalovirus minimal promoter, was employed to induce the expression of BCD under hypoxic conditions. The adenoviral vector Ad/5HREp-BCD, encoding the gene 5HREp-BCD, robustly induced BCD expression under hypoxic conditions and this led to significant cytotoxicity in combination with 5-FC in vitro. Intratumoral Ad/5HREp-BCD administration resulted in the expression of BCD at the border between normoxic and necrotic regions. The BCD/5-FC gene therapy enhanced the therapeutic effects of both single (12.5 Gy) and fractionated (3 Gy x 5 days) radiotherapy with few side effects and significantly increased tumour growth doubling time by up to 2.4-fold (P<0.01) and 2.5-fold (P<0.05), respectively. All of these results suggest that the present BCD/5-FC gene therapy has the ability to specifically target hypoxic tumour cells and significantly improves the control of tumour growth after radiotherapy.
British Journal of Cancer 07/2007; 96(12):1871-8. · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypoxia-inducible factors, key transcription factors for hypoxia-dependent gene expression, play important roles in angiogenesis and tumor growth. The VHL protein binds to the alpha subunit of (HIF-alpha) for its oxygen-dependent degradation. VHL mutations are found frequently in sporadic RCC. Disruption of VHL results in an abnormal accumulation of HIF-alpha, leading to the upregulation of downstream genes such as the vascular endothelial growth factor gene. We constructed a luciferase reporter vector driven by hypoxia-responsive elements (5HRE/luc) and a therapeutic vector expressing a herpes simplex virus thymidine kinase gene (5HRE/tk). In the transient transfection assay using VHL-deficient 786-O cells, constitutive luciferase expression was detected under both aerobic and hypoxic conditions. In contrast, 786-O cells transfected with a wild-type VHL showed hypoxia-inducible luciferase activity. In in vitro MTS assay, 50% of growth inhibition of 786-O cells stably transfected with 5HRE/tk was achieved with exposure to 0.2 microg/mL of GCV under both aerobic and hypoxic conditions. Xenografts of the stable clone in SCID mice exhibited a marked regression on daily injections of GCV (50 mg/kg) for 10 days. In conclusion, a hypoxia-responsive vector may have therapeutic potential for RCC with VHL mutations.
Cancer Science 06/2005; 96(5):288-94. · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypoxia-inducible factor-1 (HIF-1) is responsible for various gene expressions related to tumor malignancy, such as metastasis, invasion and angiogenesis. Therefore, monitoring HIF-1 activity in solid tumors is becoming increasingly important in clinical and basic studies. To establish a convenient system for visualizing HIF-1 activity in tumor xenografts, we employed a promoter consisting of five copies of hypoxia response elements (5HRE), whose activity depends on HIF-1, and used a derivative of green fluorescence protein (d2EGFP) as a reporter gene. A human melanoma cell line, Be11, which contains the 5HRE-d2EGFP gene, showed fluorescence in response to hypoxia. The fluorescent intensity correlated inversely with the surrounding oxygen tension, and was time-dependent for the hypoxic treatment. Reoxygenation resulted in a rapid decrease in fluorescence due to the signal sequence for protein degradation encoded in d2EGFP, which enabled monitoring of HIF-1 activity in real-time. Heterogeneous fluorescence was observed in the solid tumor of a non-sacrificed tumor-bearing mouse. Immunohistochemical analysis confirmed that d2EGFP-expressing regions overlapped with the ones stained with a hypoxia marker, pimonidazole. These results suggest that the 5HRE-d2EGFP gene is suitable for the real-time imaging of HIF-1-activating cells in vivo, due to the short half-life of the d2EGFP protein as well as the specificity of the 5HRE promoter for HIF-1 activity.
Journal of Radiation Research 04/2005; 46(1):93-102. · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate the therapeutic effects of hyperthermia in combination with radiotherapy for locoregional recurrence of breast cancer, and to assess the factors related to subsequent local tumor control.
Between March 1981 and February 2001, 85 lesions in 73 patients were treated with local hyperthermia combined with external irradiation. Of 75 evaluable lesions, 41 were previously irradiated. Mean radiation dose to the previously unirradiated area was 59.5 +/- 6.8 Gy (range, 40-70 Gy), while a total dose of 43.0 +/- 12.4 Gy (range, 12-74.4 Gy) was administered to previously irradiated tumors. Hyperthermia was administered once or twice per week. The average number of hyperthermia sessions was 4.5 (2-9).
Complete responses (CRs) were achieved in 56% (23/41) of previously irradiated and 47% (16/34) of unirradiated tumors. There was no significant difference in the CR rate between the two groups. Compared with the response of bulky/nodular tumors, diffuse/multiple small nodular tumors showed a higher CR rate at 4 weeks after treatment. However, at 6 months after treatment, they showed a significantly lower local control rate.
The present findings suggested a significant benefit of local hyperthermia combined with radiotherapy in the treatment of locally recurrent breast cancer, especially for previously irradiated recurrence, by reducing the total irradiation dose. Diffuse/multiple small nodular tumors respond earlier than bulky/large nodular tumors; however, they tend to recur within the treatment field. The purpose of this study was to evaluate the therapeutic effects of hyperthermia in combination with radiotherapy for locoregional recurrence of breast cancer, and to assess the factors related to subsequent local tumor control.
International Journal of Clinical Oncology 07/2004; 9(3):179-83. · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The p53 tumor-suppressor gene is one of the most frequently mutated genes in human cancers, and its genetic alterations may play critical roles in oncogenesis, tumor progression, and angiogenesis. To clarify the influence of the p53 status on hypoxia-inducible gene expression, we first performed transfection assays with a hypoxia-responsive vector carrying 5 hypoxia-responsive elements upstream of the human CMV minimal promoter driving transcription of the luciferase gene in various human tumor cell lines with wild-type (wt) or mutant (mut) p53. As a result, hypoxia responsiveness considerably varied between cell lines, and we could not obtain clear evidence that the hypoxia-inducible factor-1 (HIF-1) mediated gene expression in the wt-p53 cells was lower than that in cells with mut-p53. It is interesting that SaOS2 cells (p53 null) showed the highest luciferase activities under both aerobic and hypoxic conditions among tested cells. Next, to elucidate the effects of endogenous wt- and mut-p53s, a transfection assay and Northern blot analysis for VEGF transcription under hypoxia were performed by using isogenic variants of HT1080 cells differing in their p53 status. The luciferase and the endogenous VEGF mRNA expression were apparently lower in a variant carrying mutations in both p53 alleles than in a parental line harboring wt-p53, implying that some types of mutant p53 constitutively accumulated in cells can decrease both the basal and the hypoxia-induced expressions in addition to wt-p53.
Journal of Radiation Research 07/2004; 45(2):333-9. · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Breast cancer is one of the most common malignancies that metastasize to the brain. Radiation therapy plays a central role in the management of brain metastases.
The medical records of 36 patients with brain metastases from breast cancer who underwent whole-brain radiation therapy (WBRT) at Kyoto University Hospital between 1993 and 2001 were reviewed. The treatment outcomes were analyzed retrospectively.
The median age at the time of diagnosis of brain metastases was 52 years. Only 4 patients (11%) had a single metastasis, while the others had multiple metastases. Uncontrolled extracranial metastases were present in 26 patients at the time of diagnosis of brain metastases. All patients received WBRT at a median dose of 31 Gy. Eight patients received conventional external-beam boost irradiation, and 2 received boost stereotactic radiosurgery (SRS). The overall median survival time was 7.9 months. Uncontrolled extracranial metastases except for bone metastases and old age were significantly associated with a poor survival rate. Twenty-six patients (82%) showed initial response, but 15 developed CNS failure, including 9 patients whose tumor recurred at the original site, 4 patients who developed tumors elsewhere in the brain and 3 patients who exhibited meningeal spread. The median duration of intracranial failure was 5.0 months. Whole-brain dose, and total tumor dose did not affect intracranial control.
Radiation therapy yielded a high initial response, but the duration of effect was limited with external beam irradiation alone. New treatment strategies such as adding SRS need to be studied further.
Breast Cancer 02/2003; 10(4):349-55. · 1.51 Impact Factor