Couch modeling optimization for tomotherapy planning and delivery.

We sought to validate new couch modeling optimization for tomotherapy planning and delivery. We constructed simplified virtual structures just above a default setting couch through a planning support system (MIM Maestro, version 8.2, MIM Software Inc, Cleveland, OH, USA). Based on ionization chamber measurements, we performed interactive optimization and determined the most appropriate physical density of these virtual structures in a treatment planning system (TPS). To validate this couch optimization, Gamma analysis and these statistical analyses between a three-dimensional diode array QA system (ArcCHECK, Sun Nuclear, Melbourne, FL, USA) results and calculations from ionization chamber measurements were performed at 3%/2 mm criteria with a threshold of 10% in clinical QA plans. Using a virtual model consisting of a center slab density of 4.2 g/cm3 and both side slabs density of 1.9 g/cm3 , we demonstrated close agreement between measured dose and the TPS calculated dose. Agreement was within 1% for all gantry angles at the isocenter and within 2% in off-axis plans. In validation of the couch modeling in a clinical QA plan, the average gamma passing rate improved approximately 0.6%-5.1%. It was statistically significant (P < 0.05) for all treatment sites. We successfully generated an accurate couch model for a TomoTherapy TPS by interactively optimizing the physical density of the couch using a planning support system. This modeling proved to be an efficient way of correcting the dosimetric effects of the treatment couch in tomotherapy planning and delivery.

Concurrent Chemoradiotherapy with Docetaxel, Cisplatin, and 5-fluorouracil Improves Survival of Patients with Advanced Esophageal Cancer Compared with Conventional Concurrent Chemoradiotherapy with Cisplatin and 5-fluorouracil.

Purpose: To compare treatment outcomes and adverse events between concurrent chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-RT) and conventional concurrent chemoradiotherapy with cisplatin and 5-fluorouracil (CF-RT). Methods and Materials: We retrospectively investigated treatment outcomes and adverse events in 121 patients with advanced esophageal cancer who underwent concurrent chemoradiotherapy with CF-RT (n = 83) or DCF-RT (n = 38). In the CF-RT group, patients were administered cisplatin (70 mg/m2) and 5-fluorouracil (700 mg/m2) for 5 days; in the DCF-RT group, patients were administered docetaxel (50 mg/m2), cisplatin (50 mg/m2), and 5-fluorouracil (500 mg/m2) for 5 days. The radiotherapy dose was 1.8-2 Gy per session, up to a total of 50-60 Gy. Results: The complete response (CR) rate was 37.8% in the CF-RT group and 52.6% in the DCF-RT group. Overall survival (OS) rates at 2 and 3 years were 45.0% and 37.5%, respectively, in the CF-RT group and 62.9% and 56.7%, respectively, in the DCF-RT group, with a significant intergroup difference (p = 0.032). Progression-free survival rates at 2 and 3 years were 44.1% and 36.9%, respectively, in the CF-RT group and 45.0% and 45.0%, respectively, in the DCF-RT group (p = 0.10). Local control rates at 2 and 3 years were 59.1% and 54.6%, respectively, in the CF-RT group and 71.8% and 71.8%, respectively, in the DCF-RT group (p = 0.12). The incidence of Grade 3/4 leukopenia was 55.4% (n = 46) in the CF-RT group and 78.9% (n = 30) in the DCF-RT group, with a significant intergroup difference (p = 0.022). The incidence of Grade 3/4 neutropenia was 47.0% (n = 39) in the CF-RT group and 65.8% (n = 25) in the DCF-RT group, with a notable albeit not statistically significant difference between the groups (p = 0.054). There were no significant intergroup differences in anemia, thrombocytopenia, radiation-induced dermatitis, radiation esophagitis, or late adverse events. Conclusions: Rates of OS and CR were improved after treatment with DCF-RT compared with CF-RT. Although DCF-RT-treated patients had higher rates of leukopenia, treatment safety was ensured through proper management of myelotoxicity. DCF-RT is a promising treatment regimen for advanced esophageal cancer.

Performance evaluation of a direct-conversion flat-panel detector system in imaging and quality assurance for a high-dose-rate 192Ir source.

In high-dose-rate (HDR) brachytherapy, a direct-conversion flat-panel detector (d-FPD) clearly depicts a 192Ir source without image halation, even under the emission of high-energy gamma rays. However, it was unknown why iridium is visible when using a d-FPD. The purpose of this study was to clarify the reasons for visibility of the source core based on physical imaging characteristics, including the modulation transfer functions (MTF), noise power spectral (NPS), contrast transfer functions, and linearity of d-FPD to high-energy gamma rays. The acquired data included: x-rays, [X]; gamma rays, [γ]; dual rays (X + γ), [D], and subtracted data for depicting the source ([D] - [γ]). In the quality assurance (QA) test for the positional accuracy of a source core, the coordinates of each dwelling point were compared between the planned and actual source core positions using a CT/MR-compatible ovoid applicator and a Fletcher-Williamson applicator. The profile curves of [X] and ([D] - [γ]) matched well on MTF and NPS. The contrast resolutions of [D] and [X] were equivalent. A strongly positive linear correlation was found between the output data of [γ] and source strength (r 2 > 0.99). With regard to the accuracy of the source core position, the largest coordinate difference (3D distance) was noted at the maximum curvature of the CT/MR-compatible ovoid and Fletcher-Williamson applicators, showing 1.74 ± 0.02 mm and 1.01 ± 0.01 mm, respectively. A d-FPD system provides high-quality images of a source, even when high-energy gamma rays are emitted to the detector, and positional accuracy tests with clinical applicators are useful in identifying source positions (source movements) within the applicator for QA.

Short treatment time and excellent treatment outcome in accelerated hyperfractionated radiotherapy for T1 glottic cancer.

Accelerated hyperfractionated radiotherapy was performed as treatment for patients with T1 glottic cancer, and its utility was evaluated based on treatment outcomes and adverse effects. Fifty-eight men who had undergone radiotherapy were retrospectively reviewed. Tumor classification was Tis in 4 patients, T1a in 38, and T1b in 16. Histological examination revealed squamous cell carcinoma in 55 patients. Travel time from home to hospital was 0-1 hour for 24 patients, 1-2 hours for 9, and >2 hours for 25. Laser vaporization was performed prior to radiotherapy in 38 patients, and 19 patients received concurrent chemotherapy with an agent such as S-1. Patients were irradiated twice daily using an irradiation container. Most patients received a dose of 1.5 Gy/fraction up to a total of 60 Gy. The median overall treatment time was 30 days, with a median observation period of 59.6 months. A complete response was observed in all patients. The 5-year overall survival, disease-free survival, and local control rates were 97.2%, 93.2%, and 97.8%, respectively. Although grade 3 pharyngeal mucositis was observed in 2 patients, there were no other grade 3 or higher acute adverse events. As late toxicity, grade 2 laryngeal edema and grade 1 laryngeal hemorrhage were observed in 1 patient each, but no serious events such as laryngeal necrosis or laryngeal stenosis were observed. In conclusion, this treatment method brings excellent outcome and will substantially reduce the treatment duration among patients who need to stay at nearby hotels while undergoing treatment at hospitals in rural areas.

Usefulness of direct-conversion flat-panel detector system as a quality assurance tool for high-dose-rate 192Ir source.

The routine quality assurance (QA) procedure for a high-dose-rate (HDR) 192Ir radioactive source is an important task to provide appropriate brachytherapy. Traditionally, it has been difficult to obtain good quality images using the 192Ir source due to irradiation from the high-energy gamma rays. However, a direct-conversion flat-panel detector (d-FPD) has made it possible to confirm the localization and configuration of the 192Ir source. The purpose of the present study was to evaluate positional and temporal accuracy of the 192Ir source using a d-FPD system, and the usefulness of d-FPD as a QA tool. As a weekly verification of source positional accuracy test, we obtained 192Ir core imaging by single-shot radiography for three different positions (1300/1400/1500 mm) of a check ruler. To acquire images for measurement of the 192Ir source movement distance with varying interval steps (2.5/5.0/10.0 mm) and temporal accuracy, we used the high-speed image acquisition technique and digital subtraction. For accuracy of the 192Ir source dwell time, sequential images were obtained using various dwell times ranging from 0.5 to 30.0 sec, and the acquired number of image frames was assessed. Analysis of the data was performed using the measurement analysis function of the d-FPD system. Although there were slight weekly variations in source positional accuracy, the measured positional errors were less than 1.0 mm. For source temporal accuracy, the temporal errors were less than 1.0%, and the correlation between acquired frames and programmed time showed excellent linearity (R2 = 1). All 192Ir core images were acquired clearly without image halation, and the data were obtained quantitatively. All data were successfully stored in the picture archiving and communication system (PACS) for time-series analysis. The d-FPD is considered useful as the QA tool for the 192Ir source.

Reduction of fibroproliferative changes in irradiated rat lung with soluble transforming growth factor-ß receptor.

The present study investigated whether established fibroproliferative changes in the irradiated rat lung are histopathologically reduced by an adenovirus­mediated soluble transforming growth factor (TGF)­ß type II receptor. Replication­defective adenoviral vectors expressing a type II human TGF­ß receptor (AdTß­ExR) were prepared. Male Fisher­344 rats were divided into the C, R and R + T groups. The rats in the C group did not receive irradiation or treatment. The rats in the R and R + T group each received 30 Gy irradiation to the right lung. Eight weeks following irradiation, the rats in the R and R + T group were treated with saline or AdTß­ExR, respectively. To analyze the TGF­ß expression, myofibroblast proliferation and macrophage/monocyte infiltration, sections of the lung were immunohistochemically stained at 16 weeks following irradiation. Silver staining was performed for semi­quantitative evaluation of the fibroproliferative changes. Definitive TGF­ß expression, myofibroblast proliferation and macrophage/monocyte infiltration were observed in the lungs of the R group, but were significantly lower in the lungs of the R + T group. With respect to the fibroproliferative changes, the proportion of red­stained areas in the R + T group was markedly lower than that in the R group. These data indicate that fibroproliferative changes induced by radiation are reversible and that TGF­ß has a critical role in fibroproliferative changes in the irradiated lung. The present results suggest that gene therapy with an adenoviral vector expressing a soluble TGF­ß receptor may be effective in reducing the established pulmonary fibrosis caused by radiation.

Appropriate evaluation of and risk factors for radiation dermatitis in breast cancer patients receiving hypofractionated whole-breast irradiation after breast-conserving surgery.

BACKGROUND: In grading radiation-induced dermatitis (RID), there are not only inter-evaluator differences but also intra-evaluator variations. We retrospectively analyzed the advantages of establishing a more precise evaluation method using photographs to minimize intra-evaluator variations and RID risk factors. METHODS: We analyzed 301 breasts, including those of 3 patients with bilateral breast cancer who underwent hypofractionated whole-breast irradiation (WBI) after breast-conserving surgery. Four radiation oncologists (A, B, C and D) evaluated photographs taken before, during and after radiation therapy and graded RID using two methods. RESULTS: The percentages of maximum grades between the two methods varied widely. Kappa statistics revealed that the inter- and intra-evaluator agreements were mostly fair. In multivariate analysis, age (≤60 years old), boost irradiation, concurrent hormonal therapy and chemotherapy prior to WBI are statistically significant risk factors for ≥ grade 2 RID according to two evaluators (B and D), two evaluators (A and B), one evaluator (B) and one evaluator (D), respectively. CONCLUSIONS: The assessment of serial skin change in photographs is useful for judging RID. No risk factor was statistically significant for all evaluators because of wide intra-evaluator variations and large inter-evaluator differences. More objective criteria are needed for appropriate evaluation of RID.

Pifithrin-µ, an inhibitor of heat-shock protein 70, can increase the antitumor effects of hyperthermia against human prostate cancer cells.

Hyperthermia (HT) improves the efficacy of anti-cancer radiotherapy and chemotherapy. However, HT also inevitably evokes stress responses and increases the expression of heat-shock proteins (HSPs) in cancer cells. Among the HSPs, HSP70 is known as a pro-survival protein. In this study, we investigated the sensitizing effect of pifithrin (PFT)-µ, a small molecule inhibitor of HSP70, when three human prostate cancer cell lines (LNCaP, PC-3, and DU-145) were treated with HT (43°C for 2 h). All cell lines constitutively expressed HSP70, and HT further increased its expression in LNCaP and DU-145. Knockdown of HSP70 with RNA interference decreased the viability and colony-forming ability of cancer cells. PFT-µ decreased the viabilities of all cell lines at one-tenth the dose of Quercetin, a well-known HSP inhibitor. The combination therapy with suboptimal doses of PFT-µ and HT decreased the viability of cancer cells most effectively when PFT-µ was added immediately before HT, and this combination effect was abolished by pre-knockdown of HSP70, suggesting that the effect was mediated via HSP70 inhibition. The combination therapy induced cell death, partially caspase-dependent, and decreased proliferating cancer cells, with decreased expression of c-Myc and cyclin D1 and increased expression of p21(WAF1/Cip), indicating arrest of cell growth. Additionally, the combination therapy significantly decreased the colony-forming ability of cancer cells compared to therapy with either alone. Furthermore, in a xenograft mouse model, the combination therapy significantly inhibited PC-3 tumor growth. These findings suggest that PFT-µ can effectively enhance HT-induced antitumor effects via HSP70 inhibition by inducing cell death and arrest of cell growth, and that PFT-µ is a promising agent for use in combination with HT to treat prostate cancer.

Long-term results of radiation oncology seminar for medical students and residents held between 1995 and 2011: career paths of the participants.

PURPOSE: The radiation oncology seminar for medical students and residents was initiated by the Japanese Society for Therapeutic Radiology and Oncology (JASTRO) with the aim of increasing the numbers of radiation oncologists. We investigated the long-term results related to the career paths of the program participants. METHODS: This study enrolled 531 individuals who were medical students and residents at the time of program participation, between 1995 and 2011. We surveyed participants with regard to their affiliation status with the Japan Radiological Society (JRS) and JASTRO and whether they were board-certified radiation oncologists. RESULTS: Forty-two percent of the participants were members of JRS and 26.4 % were members of JASTRO. The membership status with JASTRO was investigated in program participants from 2004 to 2009, and comparison by status revealed that 30.1 % of medical students and 47.2 % of residents were members, with a significant difference (p = 0.013). As high as 92.3 % of the participants in the 1995-2001 cohort who had joined JRS and JASTRO were board-certified radiation oncologists. CONCLUSION: This program has greatly contributed to increasing the numbers of radiation oncologists. Because residents had a higher rate of affiliation than medical students, it is necessary to share information with not only medical universities, but also teaching hospitals.

Sivelestat sodium hydrate reduces radiation-induced lung injury in mice by inhibiting neutrophil elastase.

The aim of this study was to investigate whether sivelestat, a neutrophil elastase (NE) inhibitor, mitigates radiation-induced lung injury in mice. C57BL/6J mice were administered a dose of 20 Gy to the bilateral whole lungs. Sivelestat was administered immediately before and 1 h after irradiation in group RE2, and immediately before and 1, 3 and 6 h after irradiation in group RE4. Group R received irradiation without sivelestat injection. Mice that did not receive sivelestat injection or irradiation were used as controls. NE activity was measured 24 and 48 h after irradiation, and the mice were sacrificed 24 h, 48 h and 15 weeks after irradiation for histopathological examination. In groups RE2 and RE4, NE activity was significantly suppressed until 48 h after irradiation compared to group R. The degree of lung damage in each group was scored during histopathological examination. Results showed that the scores of groups RE2 and RE4 were significantly lower compared to those of group R 15 weeks after irradiation. In conclusion, sivelestat reduced radiation­induced lung injury in the mice by suppressing NE activity and excessive inflammatory reactions.

Bevacizumab treatment for symptomatic radiation necrosis diagnosed by amino acid PET.

Bevacizumab is effective in treating radiation necrosis; however, radiation necrosis was not definitively diagnosed in most previous reports. Here we used amino acid positron emission tomography to diagnose radiation necrosis for the application of bevacizumab in treating progressive radiation necrosis. Lesion/normal tissue ratios of <2.5 on (18)fluoride-labeled boronophenylalanine-positron emission tomography were defined as an indication of effective bevacizumab treatment. Thirteen patients were treated with bevacizumab at a dose of 5 mg/kg every 2 weeks. Two patients were excluded because of adverse events. The median reduction rate in perilesional edema was 65.5%. Karnofsky performance status improved in six patients after bevacizumab treatment. Lesion/normal tissue ratios on (18)fluoride-labeled boronophenylalanine-positron emission tomography (P = 0.0084) and improvement in Karnofsky performance status after bevacizumab treatment (P = 0.0228) were significantly associated with reduced rates of perilesional edema. Thus, (18)fluoride-labeled boronophenylalanine-positron emission tomography could be useful for diagnosing radiation necrosis and predicting the efficacy of bevacizumab in progressive radiation necrosis.

Extra-nodal natural killer/T cell lymphoma, nasal-type, treated by concurrent chemoradiotherapy.

The present study reports on a case of extra-nodal natural killer/T cell lymphoma, nasal-type (ENKL), stage IIEA, in a 50-year-old woman who presented with a white tumor on a refractory ulcer on the gum. Concurrent chemoradiotherapy was administered, and effected a partial response. However, tumor recurrence was observed 5 months after the final diagnosis, and the patient succumbed 1 month after recurrence. Although a definitive treatment for ENKL has yet to be established due to its rarity, radiation therapy (RT) is crucial to therapy, as ENKL is very sensitive to RT. However, treatment with radiation levels above 50 Gy with an extended RT field are required for a favorable outcome. The development of novel chemotherapy regimens may therefore be useful. Additionally, autologous or allogenic hematopoietic stem-cell transplantation may prove to be a promising approach.

Phase I study of a new radiosensitizer containing hydrogen peroxide and sodium hyaluronate for topical tumor injection: a new enzyme-targeting radiosensitization treatment, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II).

Using a currently employed linear accelerator, our intent was to inactivate peroxidase/catalase in tumor tissue by the application of hydrogen peroxide, which is degraded to produce oxygen, thus re-oxygenizing the tumor tissue. In this way, we can convert radioresistant tumors into radiosensitive ones. On the basis of this strategy, we previously developed a new enzyme-targeting radiosensitization treatment named KORTUC I, which remarkably enhances the radiotherapeutic effect on various types of superficially exposed and locally advanced malignant neoplasms. Based on our clinical experience using KORTUC I, we also developed a new radiosensitizer containing hydrogen peroxide and sodium hyaluronate for injection into various types of tumors that are not superficially exposed (KORTUC II; described herein). KORTUC II was approved by our local ethics committee for advanced skin cancer, including malignant melanoma, bone/soft tissue malignant neoplasms, breast cancer, and metastatic lymph nodes. A maximum of 6 ml of the agent was injected into tumor tissue one to two times per week under ultrasonographic guidance, just prior to each administration of radiation therapy. Eleven patients, including seven with breast cancer, were enrolled in the KORTUC II trial upon fully informed consent. KORTUC II was well tolerated, with a minimum of adverse effects. Nine of the 11 patients showed a complete response (CR), and no severe complications occurred in any of the 11 patients. This new enzyme-targeting radiosensitization treatment may be indicated for various types of locally advanced neoplasms, including soft tissue neoplasms and breast cancers.

Boron neutron capture therapy for newly diagnosed glioblastoma.

We evaluate the clinical results of a form of tumor selective particle radiation known as boron neutron capture therapy (BNCT) for newly-diagnosed glioblastoma (NDGB) patients, especially in combination with X-ray treatment (XRT). Between 2002 and 2006, we treated 21 patients of NDGB with BNCT utilizing sodium borocaptate and boronophenylalanine simultaneously. The first 10 were treated with only BNCT (protocol 1), and the last 11 were treated with BNCT followed by XRT of 20 to 30 Gy (protocol 2) to reduce the possibility of local tumor recurrence. No chemotherapy was applied until tumor progression was observed. The patients treated with BNCT (protocol 1 plus 2) showed a significant survival prolongation compared with the institutional historical controls. BNCT also showed favorable results in correspondence with the RTOG- and EORTC-RPA subclasses. The median survival time (MST) was 15.6 months for protocols 1 and 2 together. For protocol 2, the MST was 23.5 months. The main causes of death were cerebrospinal fluid dissemination as well as local recurrence. Our modified BNCT protocol showed favorable results of patients with NDGB not only for those with good prognoses but also for those with poor prognoses.

New radiosensitization treatment (KORTUC I) using hydrogen peroxide solution-soaked gauze bolus for unresectable and superficially exposed neoplasms.

We developed a new radiosensitization treatment using a hydrogen peroxide solution (Oxydol)-soaked gauze named KORTUC I (Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas) for superficially exposed and unresectable neoplasms, such as malignant melanoma and malignant fibrous histiocytoma (MFH), based on our experimental results which demonstrated hydrogen peroxide as a strong radiosensitizer for the highly radioresistant osteosarcoma cell line, HS-Os-1. Five patients entered our clinical trial, one of whom had unresectable malignant melanoma; one, unresectable MFH; one, unresectable extramammary Paget's disease; one, locally advanced breast cancer and one with locally recurrent skin cancer. These patients were treated with radiation therapy using a high-energy electron beam from a linear accelerator. The total dose was 48 Gy, and each fraction size was 4 Gy. Radiation therapy for these patients was performed three times per week. Each time the radiation therapy was carried out, the superficially exposed tumors of these patients were covered with hydrogen peroxide solution (Oxydol)-soaked gauze, and the lesion was gently massaged for several minutes so as to allow the hydrogen peroxide solution to soak deeply into the tumor. In the treatment results, two of these five patients showed a clinically complete response (cCR) two to three months following the end of the KORTUC I radiosensitization treatment. The other three patients showed a clinically partial response (cCR) showing a decrement of more than half of the pretreatment volume. KORTUC I was completed without any severe complications, excluding mild radiation-induced dermatitis/mucositis (Grade I). In conclusion, this newly developed radiosensitization treatment using hydrogen peroxide solution (Oxydol)-soaked gauze for superficially exposed unresectable/radioresistant neoplasms appears to be an effective and valuable method of radiosensitization in terms of the blockade of anti-oxidative enzymes such as peroxidases, resulting in local oxygen production. Moreover, the KORTUC I radiosensitization treatment is relatively inexpensive and the method can therefore be utilized worldwide for many patients suffering from superficially exposed and locally advanced radioresistant neoplasms such as malignant melanoma, malignant fibrous histiocytoma (MFH) and various types of sarcomas.

Patients' subjective evaluation of early and late sequelae in patients with breast cancer irradiated with short fractionation for breast conservation therapy: comparison with conventional fractionation.

BACKGROUND: To compare the frequency of "subjective" complications and their severity between conventional and short fractionation and to analyze the differences between the two groups. METHODS: Data from 350 patients with breast cancer who received breast conservation therapy between 1992 and 2003 were retrospectively analyzed. One hundred and ninety-six patients and 154 patients received 50 Gy in 25 fractions over 35 days (group C) and 44 Gy in 16 fractions over 22 days (group S), respectively. Early sequelae were evaluated at the end of radiation therapy (point A) and 7-10 days after the treatment (point B). Late sequelae were assessed at least 6 months after the end of radiation therapy (point C). RESULTS: The most commonly observed toxicity at point A was erythema, followed by heat sensation, sense of discomfort, and pain. There were no significant differences in these symptoms between the two groups. The frequency of these symptoms hardly changed between points A and B. At point C a sense of hardness more frequently appeared in group S than in group C with a significant difference. Other commonly noted symptoms had no significant difference between the two groups. CONCLUSIONS: Short fractionation results in acceptable patient "subjective" sequelae comparable to the sequelae experienced following conventional fractionation.

Effects of sivelestat sodium hydrate on the reduction of radiation pneumonitis.

In this study, we irradiated the murine lung and analyzed the inhibitory effects of sivelestat sodium hydrate, a neutrophil elastase (NE) inhibitor, on lung injury in mice. Sivelestat sodium hydrate (3 mg/kg) was administered by intraperitoneal injection immediately, 3, 6, and 12 h after irradiation in groups RE-0, RE-3, RE-6, and RE-12, respectively. A control group and a group receiving radiation without sivelestat (group R) were also used. NE activity was measured 24 and 48 h after irradiation. The lungs were simultaneously extirpated and stained with hematoxylin and eosin and a naphthol AS-D chloroacetate esterase stain (N-ASDCLA). NE activity increased in the groups in which the murine lungs were irradiated. There was no increase in NE activity in the control group. Among the sivelestat-administered groups, NE activity was slightly elevated in group RE-0 and was suppressed, compared to group R, in groups RE-3, RE-6, and RE-12 at 24 h after irradiation. In the irradiated groups, intra-alveolar neutrophil infiltration, perivascular edema, and alveolar wall thickness were observed, but these changes were mild in the sivelestat-administered groups. The number of N-ASDCLA-positive cells increased in the sivelestat-administered groups, while group R had low values. This indicated that sivelestat sodium hydrate blocked the release of NE from the neutrophils in the irradiated lungs. NE plays an important role in the development of radiation-induced lung injury. Sivelestat is thus expected to decrease radiation-induced lung toxicity by suppressing NE release from neutrophils.

Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone.

PURPOSE: To determine how the omission of whole brain radiotherapy (WBRT) affects the neurocognitive function of patients with one to four brain metastases who have been treated with stereotactic radiosurgery (SRS). METHODS AND MATERIALS: In a prospective randomized trial between WBRT+SRS and SRS alone for patients with one to four brain metastases, we assessed the neurocognitive function using the Mini-Mental State Examination (MMSE). Of the 132 enrolled patients, MMSE scores were available for 110. RESULTS: In the baseline MMSE analyses, statistically significant differences were observed for total tumor volume, extent of tumor edema, age, and Karnofsky performance status. Of the 92 patients who underwent the follow-up MMSE, 39 had a baseline MMSE score of < or =27 (17 in the WBRT+SRS group and 22 in the SRS-alone group). Improvements of > or =3 points in the MMSEs of 9 WBRT+SRS patients and 11 SRS-alone patients (p = 0.85) were observed. Of the 82 patients with a baseline MMSE score of > or =27 or whose baseline MMSE score was < or =26 but had improved to > or =27 after the initial brain treatment, the 12-, 24-, and 36-month actuarial free rate of the 3-point drop in the MMSE was 76.1%, 68.5%, and 14.7% in the WBRT+SRS group and 59.3%, 51.9%, and 51.9% in the SRS-alone group, respectively. The average duration until deterioration was 16.5 months in the WBRT+SRS group and 7.6 months in the SRS-alone group (p = 0.05). CONCLUSION: The results of the present study have revealed that, for most brain metastatic patients, control of the brain tumor is the most important factor for stabilizing neurocognitive function. However, the long-term adverse effects of WBRT on neurocognitive function might not be negligible.

Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.

CONTEXT: In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. OBJECTIVE: To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. INTERVENTIONS: Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). MAIN OUTCOME MEASURES: The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. RESULTS: The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. CONCLUSIONS: Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: C000000412.