Haruko Hashii

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.

Phase I/II Trial of Hyperfractionated Concomitant Boost Proton Radiotherapy for Supratentorial Glioblastoma Multiforme

PURPOSE To evaluate the safety and efficacy of postoperative hyperfractionated concomitant boost proton radiotherapy with nimustine hydrochloride for supratentorial glioblastoma multiforme (GBM). METHODS AND MATERIALS Twenty patients with histologically confirmed supratentorial GBM met the following criteria: (1) a Karnofsky performance status of >or=60; (2) the diameter of the enhanced area before radiotherapy was <or=40 cm; and (3) the enhanced area did not extend to the brain stem, hypothalamus, or thalamus. Magnetic resonance imaging (MRI) T(2)-weighted high area (clinical tumor volume 3 [CTV3]) was treated by x-ray radiotherapy in the morning (50.4 Gy in 28 fractions). More than 6 hours later, 250 MeV proton beams were delivered to the enhanced area plus a 10-mm margin (CTV2) in the first half of the protocol (23.1 GyE in 14 fractions) and to the enhanced volume (CTV1) in the latter half (23.1 GyE in 14 fraction). The total dose to the CTV1 was 96.6 GyE. Nimustine hydrochloride (80 mg/m2) was administered during the first and fourth weeks. RESULTS Acute toxicity was mainly hematologic and was controllable. Late radiation necrosis and leukoencephalopathy were each seen in one patient. The overall survival rates after 1 and 2 years were 71.1% and 45.3%, respectively. The median survival period was 21.6 months. The 1- and 2-year progression-free survival rates were 45.0% and 15.5%, respectively. The median MRI change-free survival was 11.2 months. CONCLUSIONS Hyperfractionated concomitant boost proton radiotherapy (96.6 GyE in 56 fractions) for GBM was tolerable and beneficial if the target size was well considered. Further studies are warranted to pursue the possibility of controlling border region recurrences.

RADIOTHERAPY FOR PATIENTS WITH METASTASES TO THE SPINAL COLUMN: A REVIEW OF 603 PATIENTS AT SHIZUOKA CANCER CENTER HOSPITAL

PURPOSE Long- and short-course radiotherapy have similar outcomes in the treatment of spinal metastases. Long-course radiotherapy is recommended for patients with good predicted survival to reduce the risk of in-field recurrence, whereas short-course radiotherapy is used for those with poor predicted survival. Therefore, prediction of prognosis and local control is required for selecting the optimal course of radiotherapy. METHODS AND MATERIALS The subjects were 603 patients with spinal metastases who received radiotherapy at the Shizuoka Cancer Center Hospital between September 2002 and February 2007. Factors associated with survival and local control were retrospectively investigated by multivariate analyses. Local recurrence was defined as regrowth within the irradiated field or exacerbation of symptoms such as pain and motor deficits. RESULTS Of the 603 patients, 555 (92%) were followed for 12 months or until death. The survival rates after 6, 12, and 24 months were 50%, 32%, and 19%, respectively, with a median survival of 6.2 months. The median survival periods after long- and short-course radiotherapy were 7.9 and 1.8 months, respectively. In multivariate analysis, primary tumor site, good performance status, absence of previous chemotherapy, absence of visceral metastasis, single bone metastasis, younger age, and nonhypercalcemia were associated with good survival. The local control rates after 6, 12, and 24 months were 91%, 79%, and 69%, respectively, and non-mass-type tumor, breast cancer, and absence of previous chemotherapy were predictors of good local control. CONCLUSIONS Identification of factors associated with good local control and survival may allow selection of an optimal radiotherapy schedule for patients with spinal metastases.

Clinical Results of Proton-Beam Therapy for Locoregionally Advanced Esophageal Cancer

Purpose:To evaluate the efficacy and safety of proton-beam therapy for locoregionally advanced esophageal cancer.Patients and Methods:The subjects were 51 patients with esophageal cancer who were treated between 1985 and 2005 using proton beams with or without X-rays. All but one had squamous cell carcinoma. Of the 51 patients, 33 received combinations of X-rays (median 46 Gy) and protons (median 36 GyE) as a boost. The median total dose of combined X-rays and proton radiation for these 33 patients was 80 GyE (range 70–90 GyE). The other 18 patients received proton-beam therapy alone (median 79 GyE, range 62–98 GyE).Results:Treatment interruption due to radiation-induced esophagitis or hematologic toxicity was not required for any patient. The overall 5-year actuarial survival rate for the 51 patients was 21.1% and the median survival time was 20.5 months (95% confidence interval 10.9–30.2). Of the 51 patients, 40 (78%) showed a complete response within 4 months after completing treatment and seven (14%) showed a partial response, giving a response rate of 92% (47/51). The 5-year local control rate for all 51 patients was 38.0% and the median local control time was 25.5 months (95% confidence interval 14.6–36.3).Conclusion:The results suggest that proton-beam therapy is an effective treatment for patients with locally advanced esophageal cancer. Further studies are required to determine the optimal total dose, fractionation schedules, and best combination of proton therapy with chemotherapy.ZusammenfassungZiel:Evaluierung der Wirksamkeit und Sicherheit der Protonenstrahlentherapie bei lokoregionar fortgeschrittenem Speiserohrenkrebs.Patienten und Methodik:Es handelte sich um 51 Patienten mit Speiserohrenkrebs, die zwischen 1985 und 2005 mit Protonenstrahlen allein oder kombiniert mit Linac-Photonen behandelt wurden. Bis auf eine Ausnahme hatten alle Patienten ein Plattenepithelkarzinom. Von den 51 Patienten erhielten 33 eine Kombination von Photonen (median 46 Gy) und Protonen (median 36 GyE) als Boost. Die mediane Gesamtdosis der kombinierten Rontgen- und Protonenstrahlung betrug 80 GyE (Spanne 70–90 GyE). Die anderen 18 Patienten wurden ausschlieslich mit Protonenstrahlentherapie behandelt (median 79 GyE, Spanne 62–98 GyE).Ergebnisse:Bei keinem Patienten war eine Behandlungsunterbrechung aufgrund strahleninduzierter Osophagitis oder hamatologischer Toxizitat erforderlich. Die aktuarische Gesamtuberlebensrate der 51 Patienten lag bei 21,1% in 5 Jahren und die mediane Uberlebenszeit 20,5 Monate (95%-Konfidenzintervall 10,9–30,2). Von den 51 Patienten erreichten 40 (78%) innerhalb von 4 Monaten nach Behandlungsende eine komplette Remission und sieben (14%) eine partielle Remission, was eine Ansprechrate von 92% (47/51) ergibt. Die lokale Kontrollrate nach 5 Jahren betrug bei allen 51 Patienten 38,0% und das mediane lokalrezidivfreie Intervall 25,5 Monate (95%-Konfidenzintervall 14,6–36,3).Schlussfolgerung:Die Protonenstrahlentherapie ist eine wirksame Behandlung fur Patienten mit lokal fortgeschrittenem Speiserohrenkrebs. Weitere Studien sind notwendig, um optimale Gesamtdosis, Fraktionierung und die beste Kombination von Protonenstrahlen- mit Chemotherapie zu ermitteln.

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.

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.

Prognostic Factors and a Scoring System for Survival After Radiotherapy for Metastases to the Spinal Column A Review of 544 Patients at Shizuoka Cancer Center Hospital

To optimize selection of a radiotherapy schedule for patients with spinal metastases, the authors analyzed prognostic factors and developed a scoring system to predict survival in such patients.

Comparison of the Effects of High-Energy Photon Beam Irradiation (10 and 18 MV) on 2 Types of Implantable Cardioverter-Defibrillators

PURPOSE Radiation therapy for cancer may be required for patients with implantable cardiac devices. However, the influence of secondary neutrons or scattered irradiation from high-energy photons (≥10 MV) on implantable cardioverter-defibrillators (ICDs) is unclear. This study was performed to examine this issue in 2 ICD models. METHODS AND MATERIALS ICDs were positioned around a water phantom under conditions simulating clinical radiation therapy. The ICDs were not irradiated directly. A control ICD was positioned 140 cm from the irradiation isocenter. Fractional irradiation was performed with 18-MV and 10-MV photon beams to give cumulative in-field doses of 600 Gy and 1600 Gy, respectively. Errors were checked after each fraction. Soft errors were defined as severe (change to safety back-up mode), moderate (memory interference, no changes in device parameters), and minor (slight memory change, undetectable by computer). RESULTS Hard errors were not observed. For the older ICD model, the incidences of severe, moderate, and minor soft errors at 18 MV were 0.75, 0.5, and 0.83/50 Gy at the isocenter. The corresponding data for 10 MV were 0.094, 0.063, and 0 /50 Gy. For the newer ICD model at 18 MV, these data were 0.083, 2.3, and 5.8 /50 Gy. Moderate and minor errors occurred at 18 MV in control ICDs placed 140 cm from the isocenter. The error incidences were 0, 1, and 0 /600 Gy at the isocenter for the newer model, and 0, 1, and 6 /600Gy for the older model. At 10 MV, no errors occurred in control ICDs. CONCLUSIONS ICD errors occurred more frequently at 18 MV irradiation, which suggests that the errors were mainly caused by secondary neutrons. Soft errors of ICDs were observed with high energy photon beams, but most were not critical in the newer model. These errors may occur even when the device is far from the irradiation field.

Influence of secondary neutrons induced by proton radiotherapy for cancer patients with implantable cardioverter defibrillators

BackgroundAlthough proton radiotherapy is a promising new approach for cancer patients, functional interference is a concern for patients with implantable cardioverter defibrillators (ICDs). The purpose of this study was to clarify the influence of secondary neutrons induced by proton radiotherapy on ICDs.MethodsThe experimental set-up simulated proton radiotherapy for a patient with an ICD. Four new ICDs were placed 0.3 cm laterally and 3 cm distally outside the radiation field in order to evaluate the influence of secondary neutrons. The cumulative in-field radiation dose was 107 Gy over 10 sessions of irradiation with a dose rate of 2 Gy/min and a field size of 10 × 10 cm2. After each radiation fraction, interference with the ICD by the therapy was analyzed by an ICD programmer. The dose distributions of secondary neutrons were estimated by Monte-Carlo simulation.ResultsThe frequency of the power-on reset, the most serious soft error where the programmed pacing mode changes temporarily to a safety back-up mode, was 1 per approximately 50 Gy. The total number of soft errors logged in all devices was 29, which was a rate of 1 soft error per approximately 15 Gy. No permanent device malfunctions were detected. The calculated dose of secondary neutrons per 1 Gy proton dose in the phantom was approximately 1.3-8.9 mSv/Gy.ConclusionsWith the present experimental settings, the probability was approximately 1 power-on reset per 50 Gy, which was below the dose level (60-80 Gy) generally used in proton radiotherapy. Further quantitative analysis in various settings is needed to establish guidelines regarding proton radiotherapy for cancer patients with ICDs.

Technical Considerations for Noncoplanar Proton-Beam Therapy of Patients with Tumors Proximal to the Optic Nerve

Purpose:To investigate technical feasibilities of noncoplanar proton-beam therapy (PBT) on dose reduction to critical organs.Material and Methods:The degree of mechanical precision, rotational limitations of the gantry and the treatment couch were evaluated, and dose-volume histograms were compared for noncoplanar and coplanar PBT. Following these studies, three patients with tumors proximal to the optic nerve underwent noncoplanar PBT.Results:Noncoplanar PBT offered advantage in dose reduction to the optic nerve when compared to coplanar therapy. This advantage was more significant if the tumor reduced in size during treatment. None experienced radiation injury to the optic nerve during a short follow-up time of 7–12 months.Conclusion:Noncoplanar PBT appears to reduce doses to organs at risk.Ziel:Untersuchung der technischen Möglichkeiten der nichtkoplanaren Protonenstrahlentherapie (PST) im Hinblick auf die Reduktion der Dosisbelastung von kritischen Organen.Material und Methodik:Evaluiert wurden der Grad der mechanischen Präzision, die Rotationsbeschränkungen der Gantry und des Behandlungstischs, und es wurden Dosis-Volumen-Histogramme für die nichtkoplanare und koplanare PST verglichen. Im Anschluss daran wurden drei Patienten mit proximal des Sehnervs gelegenen Tumoren einer nichtkoplanaren PST unterzogen.Ergebnisse:Die nichtkoplanare PST war im Hinblick auf die Reduktion der Dosisbelastung des Sehnervs im Vergleich zur koplanaren Therapie von Vorteil. Dieser Vorteil war in den Fällen, in denen die Tumorgröße während der Behandlung abnahm, signifikanter. Bei keinem der Patienten traten während eines kurzen Nachuntersuchungszeitraums von 7–12 Monaten Strahlenschäden am Sehnerv auf.Schlussfolgerung:Die nichtkoplanare PST scheint die Dosisbelastung für Risikoorgane zu reduzieren.