Takeji Sakae

Proton beam therapy for hepatocellular carcinoma: a comparison of three treatment protocols.

BACKGROUND Our previous results for treatment of hepatocellular carcinoma (HCC) with proton beam therapy revealed excellent local control with low toxicity. Three protocols were used to avoid late complications such as gastrointestinal ulceration and bile duct stenosis. In this study, we examined the efficacy of these protocols. METHODS AND MATERIALS The subjects were 266 patients (273 HCCs) treated by proton beam therapy at the University of Tsukuba between January 2001 and December 2007. Three treatment protocols (A, 66 GyE in 10 fractions; B, 72.6 GyE in 22 fractions; and C, 77 GyE in 35 fractions) were used, depending on the tumor location. RESULTS Of the 266 patients, 104, 95, and 60 patients were treated with protocols A, B, and C, respectively. Seven patients with double lesions underwent two different protocols. The overall survival rates after 1, 3 and 5 years were 87%, 61%, and 48%, respectively (median survival, 4.2 years). Multivariate analysis showed that better liver function, small clinical target volume, and no prior treatment (outside the irradiated field) were associated with good survival. The local control rates after 1, 3, and 5 years were 98%, 87%, and 81%, respectively. Multivariate analysis did not identify any factors associated with good local control. CONCLUSIONS This study showed that proton beam therapy achieved good local control for HCC using each of three treatment protocols. This suggests that selection of treatment schedules based on tumor location may be used to reduce the risk of late toxicity and maintain good treatment efficacy.

Measurement of neutron ambient dose equivalent in passive carbon-ion and proton radiotherapies.

Secondary neutron ambient dose equivalents per the treatment absorbed dose in passive carbon-ion and proton radiotherapies were measured using a rem meter, WENDI-II at two carbon-ion radiotherapy facilities and four proton radiotherapy facilities in Japan. Our measured results showed that (1) neutron ambient dose equivalent in carbon-ion radiotherapy is lower than that in proton radiotherapy, and (2) the difference to the measured neutron ambient dose equivalents among the facilities is within a factor of 3 depending on the operational beam setting used at the facility and the arrangement of the beam line, regardless of the method for making a laterally uniform irradiation field: the double scattering method or the single-ring wobbling method. The reoptimization of the beam line in passive particle radiotherapy is an effective way to reduce the risk of secondary cancer because installing an adjustable precollimator and designing the beam line devices with consideration of their material, thickness and location, etc., can significantly reduce the neutron exposure. It was also found that the neutron ambient dose equivalent in passive particle radiotherapy is equal to or less than that in the photon radiotherapy. This result means that not only scanning particle radiotherapy but also passive particle radiotherapy can provide reduced exposure to normal tissues around the target volume without an accompanied increase in total body dose.

Comparisons of Dose-Volume Histograms for Proton-Beam versus 3-D Conformal X-Ray Therapy in Patients with Stage I Non-Small Cell Lung Cancer

Purpose:Dose-volume histograms (DVHs) were reviewed to determine if there is an advantage of the two modalities when treating patients with non-small cell lung cancer (NSCLC).Patients and Methods:24 stage I NSCLC patients who underwent proton-beam therapy (PBT) from June 2003 to May 2007 were included in this study. Based on the same clinical target volumes (CTVs), treatment planning was made to cover CTV within 90% isodose lines. Each patient was evaluated by two sets of DVHs, one for PBT and the other for three-dimensional conformal X-ray therapy (3D-CRT).Results:For all patients, the 95% isodose line covered 86.4% of the CTV for PBT, and 43.2% for 3D-CRT. PBT was associated with significantly lower mean doses to the ipsilateral lung, total lung, heart, esophagus, and spinal cord than 3D-CRT. PBT offered reduced radiation doses to the lung when evaluated in terms of percentage lung volumes receiving ≥ 5 Gy (V5), ≥ 10 Gy (V10), and ≥ 20 Gy (V20) when compared to 3D-CRT.Conclusion:PBT is advantageous over 3D-CRT in reducing doses to the lung, heart, esophagus, and spinal cord in treating stage I NSCLC.Ziel:Dosis-Volumen-Histogramme (DVHs) wurden untersucht, um die Vorteile der beiden Modalitäten bei der Behandlung von Patienten mit nichtkleinzelligem Lungenkarzinom (NSCLC) im Stadium I zu ermitteln.Patienten und Methodik:Die Studie umfasste 24 Patienten mit NSCLC Stadium I, die im Zeitraum von Juni 2003 bis Mai 2007 mit Protonenstrahltherapie („proton beam therapy“ [PBT]) behandelt wurden. Auf der Basis gleicher klinischer Zielvolumina (CTVs) wurde jeder Patient mit zwei Gruppen von DVHs beurteilt: einer für die PBT und einer für dreidimensionale konforme Röntgenstrahltherapie (3D-CRT).Ergebnisse:Bei allen Patienten wurden die CTVs von 90% der Isodosislinien sowohl bei PBT als auch bei 3D-CRT abgedeckt, während 95% der Isodosislinien bei PBT 86,4% und bei 3D-CRT 43,2% der CTVs abdeckten. Die PBT war mit einer signifikant niedrigeren mittleren Strahlendosis für die ipsilaterale Lunge, die gesamte Lunge, das Herz, die Speiseröhre und das Rückenmark assoziiert als die 3D-CRT. Die PBT bot reduzierte Strahlenbelastungen der Lunge, wenn der Prozentsatz des Lungenvolumens bewertet wurde, welches im Vergleich zur 3D-CRT einer Strahlenbelastung von ≥ 5 Gy (V5), ≥ 10 Gy (V10) und ≥ 20 Gy (V20) ausgesetzt war.Schlussfolgerung:Die PBT bietet gegenüber der 3D-CRT Vorteile bei der Reduktion der Strahlendosis für die umliegenden Organe und ist die Behandlung der Wahl insbesondere bei in der Nähe des Mediastinums liegenden Tumoren.

Results of Proton Beam Therapy without Concurrent Chemotherapy for Patients with Unresectable Stage III Non-small Cell Lung Cancer

Introduction: This study was performed retrospectively to evaluate the outcome of patients with stage III non-small cell lung cancer (NSCLC) after proton beam therapy (PBT) alone. Methods: The subjects were 57 patients with histologically confirmed NSCLC (stage IIIA/IIIB: 24/33) who received PBT without concurrent chemotherapy. The cohort included 32 cases of squamous cell carcinoma, 18 adenocarcinoma, and 7 non-small cell carcinoma. Lymph node metastases were N0 7, N1 5, N2 30, and N3 15. Planned total doses ranged from 50 to 84.5 GyE (median, 74 GyE). Results: Planned treatment was completed in 51 patients (89%). At the time of analysis, 20 patients were alive, and the median follow-up periods were 16.2 months for all patients and 22.2 months for survivors. The median overall survival period was 21.3 months (95% confidence interval: 14.2–28.4 months), and the 1- and 2-year overall survival rates were 65.5% (52.9–78.0%) and 39.4% (25.3–53.5%), respectively. Disease progression occurred in 38 patients, and the 1- and 2-year progression-free survival rates were 36.2% (23.1–49.4%) and 24.9% (12.7–37.2%), respectively. Local recurrence was observed in 13 patients, and the 1- and 2-year local control rates were 79.1% (66.8–91.3%) and 64.1% (47.5–80.7%), respectively. Grade ≥3 lung toxicity was seen in six patients, esophageal toxicity occurred at grade ⩽2, and there was no cardiac toxicity. Conclusion: The prognosis of patients with unresectable stage III NSCLC is poor without chemotherapy. Our data suggest that high-dose PBT is beneficial and tolerable for these patients.

Experimental evaluation of validity of simplified Monte Carlo method in proton dose calculations

It is important for proton therapy to calculate dose distributions accurately in treatment planning. Dose calculations in the body for treatment planning are converted to dose distributions in water, and the converted calculations are then generally evaluated by the dose measurements in water. In this paper, proton dose calculations were realized for a phantom simulating a clinical heterogeneity. Both dose calculations in the phantom calculated by two dose calculation methods, the range-modulated pencil beam algorithm (RMPBA) and the simplified Monte Carlo (SMC) method, and dose calculations converted to dose distributions in water by the same two methods were verified experimentally through comparison with measured distributions, respectively. For the RMPBA, though the converted calculations in water agreed moderately well with the measured ones, the calculated results in the actual phantom produced large errors. This meant that dose calculations in treatment planning should be evaluated by the dose measurements not in water but in the body with heterogeneity. On the other hand, the results calculated in the phantom, even by the less rigorous SMC method, reproduced the experimental ones well. This finding showed that actual dose distributions in the body should be predicted by the SMC method.

Evaluation of liver function after proton beam therapy for hepatocellular carcinoma.

PURPOSE Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. METHODS AND MATERIALS The subjects were 259 patients treated with PBT at the University of Tsukuba between January 2001 and December 2007. We evaluated the Child-Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the Child-Pugh score of 1 or more was defined as an adverse event. RESULTS Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child-Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child-Pugh score, 15 had a 1-point increase, and 10 had an increase of ≥2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. CONCLUSION Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.

Proton beam therapy interference with implanted cardiac pacemakers.

PURPOSE To investigate the effect of proton beam therapy (PBT) on implanted cardiac pacemaker function. METHODS AND MATERIALS After a phantom study confirmed the safety of PBT in patients with cardiac pacemakers, we treated 8 patients with implanted pacemakers using PBT to a total tumor dose of 33-77 gray equivalents (GyE) in dose fractions of 2.2-6.6 GyE. The combined total number of PBT sessions was 127. Although all pulse generators remained outside the treatment field, 4 patients had pacing leads in the radiation field. All patients were monitored by means of electrocardiogram during treatment, and pacemakers were routinely examined before and after PBT. RESULTS The phantom study showed no effect of neutron scatter on pacemaker generators. In the study, changes in heart rate occurred three times (2.4%) in 2 patients. However, these patients remained completely asymptomatic throughout the PBT course. CONCLUSIONS PBT can result in pacemaker malfunctions that manifest as changes in pulse rate and pulse patterns. Therefore, patients with cardiac pacemakers should be monitored by means of electrocardiogram during PBT.

Indoor concentrations of 220Rn and its decay products.

The distribution of 220Rn atoms in a room was derived from the diffusion equation. The activity concentrations of 212Pb and 212Bi were obtained in relation to 220Rn exhalation rate from a concrete wall. Near the surface of the concrete wall, the radiation exposure due to inhalation of 220Rn decay products may be significant in some cases.

The Major DNA Repair Pathway after Both Proton and Carbon-Ion Radiation is NHEJ, but the HR Pathway is More Relevant in Carbon Ions

The purpose of this study was to identify the roles of non-homologous end-joining (NHEJ) or homologous recombination (HR) pathways in repairing DNA double-strand breaks (DSBs) induced by exposure to high-energy protons and carbon ions (C ions) versus gamma rays in Chinese hamster cells. Two Chinese hamster cell lines, ovary AA8 and lung fibroblast V79, as well as various mutant sublines lacking DNA-PKcs (V3), X-ray repair cross-complementing protein-4 [XRCC4 (XR1), XRCC3 (irs1SF) and XRCC2 (irs1)] were exposed to gamma rays (137Cs), protons (200 MeV; 2.2 keV/μm) and C ions (290 MeV; 50 keV/μm). V3 and XR1 cells lack the NHEJ pathway, whereas irs1 and irs1SF cells lack the HR pathway. After each exposure, survival was measured using a clonogenic survival assay, in situ DSB induction was evaluated by immunocytochemical analysis of histone H2AX phosphorylation at serine 139 (γ-H2AX foci) and chromosome aberrations were examined using solid staining. The findings from this study showed that clonogenic survival clearly depended on the NHEJ and HR pathway statuses, and that the DNA-PKcs–/– cells (V3) were the most sensitive to all radiation types. While protons and γ rays yielded almost the same biological effects, C-ion exposure greatly enhanced the sensitivity of wild-type and HR-deficient cells. However, no significant enhancement of sensitivity in cell killing was seen after C-ion irradiation of NHEJ deficient cells. Decreases in the number of γ-H2AX foci after irradiation occurred more slowly in the NHEJ deficient cells. In particular, V3 cells had the highest number of residual γ-H2AX foci at 24 h after C-ion irradiation. Chromosomal aberrations were significantly higher in both the NHEJ- and HR-deficient cell lines than in wild-type cell lines in response to all radiation types. Protons and gamma rays induced the same aberration levels in each cell line, whereas C ions introduced higher but not significantly different aberration levels. Our results suggest that the NHEJ pathway plays an important role in repairing DSBs induced by both clinical proton and C-ion beams. Furthermore, in C ions the HR pathway appears to be involved in the repair of DSBs to a greater extent compared to gamma rays and protons.

Induction of in situ DNA double-strand breaks and apoptosis by 200 MeV protons and 10 MV X-rays in human tumour cell lines

Purpose: To clarify the properties of clinical high-energy protons by comparing with clinical high-energy X-rays. Materials and methods: Human tumor cell lines, ONS76 and MOLT4, were irradiated with 200 MeV protons or 10 MV X-rays. In situ DNA double-strand breaks (DDSB) induction was evaluated by immunocytochemical staining of phosphorylated histone H2AX (γ-H2AX). Apoptosis was measured by flow-cytometry after staining with Annexin V. The relative biological effectiveness (RBE) was obtained by clonogenic survival assay. Results: DDSB induction was significantly higher for protons than X-rays with average ratios of 1.28 (ONS76) and 1.59 (MOLT4) at 30 min after irradiation. However the differences became insignificant at 6 h. Also, apoptosis induction in MOLT4 cells was significantly higher for protons than X-rays with an average ratio of 2.13 at 12 h. However, the difference became insignificant at 20 h. RBE values of protons to X-rays at 10% survival were 1.06 ± 0.04 and 1.02 ± 0.15 for ONS76 and MOLT4, respectively. Conclusions: Cell inactivation may differ according to different timings and/or endpoints. Proton beams demonstrated higher cell inactivation than X-rays in the early phases. These data may facilitate the understanding of the biological properties of clinical proton beams.