D. Miyawaki

Clinical results and risk factors of proton and carbon ion therapy for hepatocellular carcinoma

The objective of this study was to evaluate the clinical outcome of proton and carbon ion therapy for hepatocellular carcinoma (HCC).

High‐dose proton therapy and carbon‐ion therapy for stage I nonsmall cell lung cancer

A study was undertaken to evaluate the clinical outcome of particle therapy for stage I nonsmall cell lung cancer (NSCLC).

Analysis of Vision loss caused by radiation-induced optic neuropathy after particle therapy for head-and-neck and skull-base tumors adjacent to optic nerves.

PURPOSE To assess the incident rates of vision loss (VL; based on counting fingers or more severe) caused by radiation-induced optic neuropathy (RION) after particle therapy for tumors adjacent to optic nerves (ONs), and to evaluate factors that may contribute to VL. METHODS AND MATERIALS From August 2001 to August 2006, 104 patients with head-and-neck or skull-base tumors adjacent to ONs were treated with carbon ion or proton radiotherapy. Among them, 145 ONs of 75 patients were irradiated and followed for greater than 12 months. The incident rate of VL and the prognostic factors for occurrence of VL were evaluated. The late effects of carbon ion and proton beams were compared on the basis of a biologically effective dose at alpha/beta = 3 gray equivalent (GyE(3)). RESULTS Eight patients (11%) experienced VL resulting from RION. The onset of VL ranged from 17 to 58 months. The median follow-up was 25 months. No significant difference was observed between the carbon ion and proton beam treatment groups. On univariate analysis, age (>60 years), diabetes mellitus, and maximum dose to the ON (>110 GyE(3)) were significant, whereas on multivariate analysis only diabetes mellitus was found to be significant for VL. CONCLUSIONS The time to the onset of VL was highly variable. There was no statistically significant difference between carbon ion and proton beam treatments over the follow-up period. Based on multivariate analysis, diabetes mellitus correlated with the occurrence of VL. A larger study with longer follow-up is warranted.

Brain Injury After Proton Therapy or Carbon Ion Therapy for Head-and-Neck Cancer and Skull Base Tumors

PURPOSE To assess the incidence of early delayed or late morbidity of the brain after particle therapy for skull base tumors and head-and-neck cancers. METHODS AND MATERIALS Between May 2001 and December 2005, 59 patients with cancerous invasion of the skull base were treated with proton or carbon ion therapy at the Hyogo Ion Beam Medical Center. Adverse events were assessed according to the magnetic resonance imaging findings (late effects of normal tissue-subjective, objective, management, analytic [LENT-SOMA]) and symptoms (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0). Dose-volume histograms were used to analyze the relationship between the dose and volume of the irradiated brain and the occurrence of brain injury. The median follow-up time was 33 months. RESULTS Of the 48 patients treated with proton therapy and 11 patients treated with carbon ion radiotherapy, 8 (17%) and 7 (64%), respectively, developed radiation-induced brain changes (RIBCs) on magnetic resonance imaging (LENT-SOMA Grade 1-3). Four patients (7%) had some clinical symptoms, such as vertigo and headache (CTCAE Grade 2) or epilepsy (CTCAE Grade 3). The actuarial occurrence rate of RIBCs at 2 and 3 years was 20% and 39%, respectively, with a significant difference in the incidence between the proton and carbon ion radiotherapy groups. The dose-volume histogram analyses revealed significant differences between the brain lobes with and without RIBCs in the actuarial volume of brain lobes receiving high doses. CONCLUSION Particle therapies produced minimal symptomatic brain toxicities, but sequential evaluation with magnetic resonance imaging detected a greater incidence of RIBCs. Significant differences were observed in the irradiated brain volume between the brain lobes with and without RIBCs.

Prognostic Value of FDG PET Imaging in Patients with Laryngeal Cancer

Background and Purpose To investigate the prognostic value of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with laryngeal cancer. Materials and Methods The study included 51 patients of whom 30 underwent definitive radiotherapy with or without chemotherapy and 21 underwent radical surgery with or without adjuvant chemoradiation therapy. FDG uptake by both the primary lesion and the neck node was measured using the maximum standardized uptake value (SUVmax). The effects of clinicopathological factors including primary tumor SUVmax and nodal SUVmax on progression-free survival, local control, nodal progression-free survival, and distant metastasis-free survival were evaluated using the log-rank test and Cox method. Results The median duration of follow-up was 48.6 months (range 8 to 82.1 months). Univariate analysis showed that nodal SUVmax, N status, and tumor TNM stage were significantly associated with recurrence, whereas primary tumor SUVmax, age, treatment strategy and T status were not. Multivariate analysis demonstrated that only the nodal SUVmax was a significantly unfavorable factor for progression-free survival (p = 0.029, hazard ratio 0.54, 95% CI 0.38-0.87) and nodal progression-free survival (p = 0.023, hazard ratio 0.51, 95% CI 0.34-0.81). ROC curve analysis and log-rank test showed that patients with a high nodal SUVmax (≧4) had a significantly lower progression-free survival rate than those with a low SUVmax (<4; p<0.0001). Conclusions The pretreatment SUVmax of nodal disease in patients with laryngeal cancer is prognostic for recurrence.

Efficacy of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein tumor thrombosis/inferior vena cava tumor thrombosis: evaluation by comparison with conventional three-dimensional conformal radiotherapy

This study aimed to evaluate the efficacy of stereotactic body radiotherapy (SBRT) compared with three-dimensional conformal radiotherapy (3DCRT). Forty-three patients with portal vein tumor thrombosis (PVTT)/inferior vena cava tumor thrombosis (IVCTT) treated with SBRT (27 with CyberKnife (CK) and 16 with TrueBeam (TB)) from April 2013 to December 2014, and 54 treated with 3DCRT from June 2008 to March 2013 were evaluated. Dosimetric parameters, response to radiotherapy (RT) and survival outcomes were compared in total SBRT vs. 3DCRT, CK vs. 3DCRT and TB vs. 3DCRT, respectively. The median biologically effective dose 10 (BED10) values in total SBRT, CK, TB and 3DCRT were 73.4 Gy10, 75.0 Gy10, 60.5 Gy10 and 58.5 Gy10, respectively (P < 0.001 in total SBRT vs. 3DCRT, P < 0.001 in CK vs. 3DCRT, P = 0.004 in TB vs. 3DCRT). The tumor response rates were 67%, 70%, 62% and 46%, respectively (P = 0.04, P = 0.04, P = 0.25). The 1-year overall survival rates were 49.3%, 56.7%, 38.1% and 29.3%, respectively (P = 0.02, P = 0.02, P = 0.30), and the 1-year local progression rates were 20.4%, 21.9%, 18.8% and 43.6%, respectively (P = 0.01, P = 0.04, P = 0.10). The use of SBRT made it possible to achieve a higher BED10 compared with the use of 3DCRT. Improvements in local control and survival were achieved in the CK group and the total SBRT group. Our results suggest that SBRT may have the potential to be the standard RT technique for the treatment of PVTT/IVCTT.

Patterns of failure after multimodal treatments for high-grade glioma: effectiveness of MIB-1 labeling index.

BackgroundThe purpose of the present study was to analyze the recurrence pattern of high-grade glioma treated with a multimodal treatment approach and to evaluate whether the MIB-1 labeling index (LI) could be a useful marker for predicting the pattern of failure in glioblastoma (GB).Methods and materialsWe evaluated histologically confirmed 131 patients with either anaplastic astrocytoma (AA) or GB. A median dose was 60 Gy. Concomitant and adjuvant chemotherapy were administered to 111 patients. MIB-1 LI was assessed by immunohistochemistry. Recurrence patterns were categorized according to the areas of recurrence as follows: central failure (recurrence in the 95% of 60 Gy); in-field (recurrence in the high-dose volume of 50 Gy; marginal (recurrence outside the high-dose volume) and distant (recurrence outside the RT field).ResultsThe median follow-up durations were 13 months for all patients and 19 months for those remaining alive. Among AA patients, the 2-year progression-free and overall survival rates were 23.1% and 39.2%, respectively, while in GB patients, the rates were 13.3% and 27.6%, respectively. The median survival time was 20 months for AA patients and 15 months for GB patients. Among AA patients, recurrences were central in 68.7% of patients; in-field, 18.8%; and distant, 12.5%, while among GB patients, 69.0% of recurrences were central, 15.5% were in-field, 12.1% were marginal, and 3.4% were distant. The MIB-1 LI medians were 18.2% in AA and 29.8% in GB. Interestingly, in patients with GB, the MIB-1 LI had a strong effect on the pattern of failure (P = 0.014), while the extent of surgical removal (P = 0.47) and regimens of chemotherapy (P = 0.57) did not.ConclusionsMIB-1 LI predominantly affected the pattern of failure in GB patients treated with a multimodal approach, and it might be a useful tool for the management of the disease.

Treatment outcomes of the patients with early glottic cancer treated with initial radiotherapy and salvaged by conservative surgery.

OBJECTIVE This retrospective study analyzed the oncological and treatment outcomes of the patients with T1-T2N0 glottic cancer, who were treated with radiotherapy as initial treatment and salvaged by conservative surgery for radiation failure. METHODS Between May 1999 and December 2010, 115 patients with glottic laryngeal cancer were treated at Kobe University Hospital. At presentation, 54 patients had stage T1a disease, 26 had stage T1b disease and 35 had stage T2 disease. Seventy-nine patients were treated with conventional radiotherapy and 36 patients were treated with hyperfractionated radiotherapy as initial treatment. RESULTS Median duration of follow-up was 61 months. Five-year local control rates of radiotherapy were 92% in T1a, 83% in T1b and 86% in T2. Of 12 patients who developed local recurrence, larynx was successfully preserved in 3 patients by laryngomicrosurgery, 7 patients by vertical partial laryngectomy and one patient by subtotal laryngectomy. Ultimate 5-year laryngeal preservation rate and local control rate of all cases were 99 and 100%, respectively. CONCLUSIONS Present results suggest that initial treatment with radiotherapy salvaged by organ preservation surgery is an effective strategy for laryngeal preservation in the treatment of T1-T2N0 glottic laryngeal cancer.

Sparing of tissue by using micro-slit-beam radiation therapy reduces neurotoxicity compared with broad-beam radiation therapy

Micro-slit-beam radiation therapy (MRT) using synchrotron-generated X-ray beams allows for extremely high-dose irradiation. However, the toxicity of MRT in central nervous system (CNS) use is still unknown. To gather baseline toxicological data, we evaluated mortality in normal mice following CNS-targeted MRT. Male C57BL/6 J mice were head-fixed in a stereotaxic frame. Synchrotron X-ray-beam radiation was provided by the SPring-8 BL28B2 beam-line. For MRT, radiation was delivered to groups of mice in a 10 × 12 mm unidirectional array consisting of 25-μm-wide beams spaced 100, 200 or 300 μm apart; another group of mice received the equivalent broad-beam radiation therapy (BRT) for comparison. Peak and valley dose rates of the MRT were 120 and 0.7 Gy/s, respectively. Delivered doses were 96–960 Gy for MRT, and 24–120 Gy for BRT. Mortality was monitored for 90 days post-irradiation. Brain tissue was stained using hematoxylin and eosin to evaluate neural structure. Demyelination was evaluated by Klüver–Barrera staining. The LD50 and LD100 when using MRT were 600 Gy and 720 Gy, respectively, and when using BRT they were 80 Gy and 96 Gy, respectively. In MRT, mortality decreased as the center-to-center beam spacing increased from 100 μm to 300 μm. Cortical architecture was well preserved in MRT, whereas BRT induced various degrees of cerebral hemorrhage and demyelination. MRT was able to deliver extremely high doses of radiation, while still minimizing neuronal death. The valley doses, influenced by beam spacing and irradiated dose, could represent important survival factors for MRT.

Physiologic Reactions After Proton Beam Therapy in Patients With Prostate Cancer: Significance of Urinary Autoactivation

PURPOSE Proton therapy is a sophisticated treatment modality for prostate cancer. We investigated how physiologic factors affected the distribution of autoactivation as detected by positron emission tomography (PET) after proton beam therapy. METHODS AND MATERIALS Autoactivation was evaluated in 59 patients treated with a 210-MeV proton beam. Data acquisition for autoactivation by PET started 5 minutes after proton irradiation to assess activation. In the first 29 patients, five regions of interest were evaluated: planning target volume (PTV) center, urinary bladder inside the PTV, urinary bladder outside the PTV, rectum (outside the PTV), and contralateral femoral bone head (outside the PTV). In the remaining 30 patients, urine activity was measured directly. In a phantom study autoactivation and its diffusion after proton beam irradiation were evaluated with water or an ice block. RESULTS Mean activities calculated by use of PET were 629.3 Bq in the PTV center, 555.6 Bq in the urinary bladder inside the PTV, 332.5 Bq in the urinary bladder outside the PTV, 88.4 Bq in the rectum, and 23.7 Bq in the femoral bone head (p < 0.001). Mean urine activity was 679.4 Bq, recorded 10 minutes after therapy completion, and the half-life for urine autoactivation was 4.5 minutes. CONCLUSIONS Urine is a major diffusion mediator of autoactivation after proton beam therapy. Our results indicate that physiologic factors can influence PET images of autoactivation in the context of proton beam therapy verification.