Yoshiko Oshiro

Proton Beam Therapy for Large Hepatocellular Carcinoma

PURPOSE To investigate the safety and efficacy of proton beam therapy (PBT) in patients with large hepatocellular carcinoma (HCC). METHODS AND MATERIALS Twenty-two patients with HCC larger than 10 cm were treated with proton beam therapy at our institution between 1985 and 2006. Twenty-one of the 22 patients were not surgical candidates because of advanced HCC, intercurrent disease, or old age. Median tumor size was 11 cm (range, 10-14 cm), and median clinical target volume was 567 cm(3) (range, 335-1,398 cm(3)). Hepatocellular carcinoma was solitary in 18 patients and multifocal in 4 patients. Tumor types were nodular and diffuse in 18 and 4 patients, respectively. Portal vein tumor thrombosis was present in 11 patients. Median total dose delivered was 72.6 GyE in 22 fractions (range, 47.3-89.1 GyE in 10-35 fractions). RESULTS The median follow-up period was 13.4 months (range, 1.5-85 months). Tumor control rate at 2 years was 87%. One-year overall and progression-free survival rates were 64% and 62%, respectively. Two-year overall and progression-free survival rates were 36% and 24%, respectively. The predominant tumor progression pattern was new hepatic tumor development outside the irradiated field. No late treatment-related toxicity of Grade 3 or higher was observed. CONCLUSIONS The Bragg peak properties of PBT allow for improved conformality of the treatment field. As such, large tumor volumes can be irradiated to high doses without significant dose exposure to surrounding normal tissue. Proton beam therapy therefore represents a promising modality for the treatment of large-volume HCC. Our study shows that PBT is an effective and safe method for the treatment of patients with large HCC.

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.

Role of radiotherapy for local control of asymptomatic adrenal metastasis from lung cancer.

Introduction: Several studies have reported improved survival after adrenalectomy in patients with adrenal metastases from lung cancer. In this study, we evaluated the clinical results of radiotherapy performed for local control in patients with this disease. Materials and Methods: We retrospectively reviewed 19 patients with adrenal metastasis from lung cancer, who were treated by radiation therapy between 1999 and 2008. The patients included 18 men and 1 woman, and had a mean age of 63 years. Adrenal metastasis was defined as synchronous and metachronous in 11 and 8 patients, respectively. All tumors were asymptomatic with a median size of 30 mm, and were treated with doses of 30 to 60 Gy (median, 45 Gy) in 1 to 27 fractions (median, 10 fractions). Results: The estimated overall 1-, 2- and 5-year survival rates for all patients were 56%, 33%, and 22%, respectively. More favorable prognosis was observed for patients with a metachronous metastasis, with overall 1-, 2-, and 5- year survival rates following adrenal irradiation of 83%, 56%, and 56%, respectively. Conclusion: Our results indicate that radiotherapy may contribute to survival of patients with adrenal metastasis from lung cancer. We suggest that radiotherapy is a treatment option that can be used in addition to surgical resection.

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.

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.

High-dose concurrent chemo–proton therapy for Stage III NSCLC: preliminary results of a Phase II study

The aim of this report is to present the preliminary results of a Phase II study of high-dose (74 Gy RBE) proton beam therapy (PBT) with concurrent chemotherapy for unresectable locally advanced non-small-cell lung cancer (NSCLC). Patients were treated with PBT and chemotherapy with monthly cisplatin (on Day 1) and vinorelbine (on Days 1 and 8). The treatment doses were 74 Gy RBE for the primary site and 66 Gy RBE for the lymph nodes without elective lymph nodes. Adapted planning was made during the treatment. A total of 15 patients with Stage III NSCLC (IIIA: 4, IIIB: 11) were evaluated in this study. The median follow-up period was 21.7 months. None of the patients experienced Grade 4 or 5 non-hematologic toxicities. Acute pneumonitis was observed in three patients (Grade 1 in one, and Grade 3 in two), but Grade 3 pneumonitis was considered to be non-proton-related. Grade 3 acute esophagitis and dermatitis were observed in one and two patients, respectively. Severe ( ≥ Grade 3) leukocytopenia, neutropenia and thrombocytopenia were observed in 10 patients, seven patients and one patient, respectively. Late radiation Grades 2 and 3 pneumonitis was observed in one patient each. Six patients (40%) experienced local recurrence at the primary site and were treated with 74 Gy RBE. Disease progression was observed in 11 patients. The mean survival time was 26.7 months. We concluded that high-dose PBT with concurrent chemotherapy is safe to use in the treatment of unresectable Stage III NSCLC.

Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer

INTRODUCTION This study was conducted to determine disease control rates and prognostic factors associated with recurrence of centrally and peripherally located stage I NSCLC treated using high-dose PBT. PATIENTS AND METHODS Seventy-four patients with 80 centrally or peripherally located stage I NSCLCs were treated with PBT. A protocol using 72.6 Gy (RBE) in 22 fractions was used for centrally located tumors, and 66 Gy (RBE) in 10 or 12 fractions was used for peripherally located tumors. Data were collected and control rates and prognostic factors for recurrence were evaluated retrospectively. RESULTS The median follow-up period was 31.0 months. The overall survival, disease-specific survival, and progression-free survival rates were 76.7%, 83.0%, and 58.6% at 3 years, respectively. Disease recurrence was noted in 30 patients and local recurrence of 11 tumors occurred. The 3-year local control rate was 86.2% for stage IA tumors and 67.0% for stage IB tumors. Radiation dose was identified as a significant prognostic factor for disease recurrence and local recurrence. Tumor diameter and age were only significantly associated with disease recurrence. The 3-year local control rate was 63.9% for centrally located tumors irradiated with 72.6 Gy (RBE) and 88.4% for peripherally located tumors irradiated with 66 Gy (RBE). CONCLUSION Radiation dose was shown to be the most significant prognostic factor for tumor control in stage I NSCLC treated using high-dose PBT. Tumor diameter was not significant for local control. Further evaluation of PBT for centrally located tumors is warranted.

Dose-volume histogram analysis for risk factors of radiation-induced rib fracture after hypofractionated proton beam therapy for hepatocellular carcinoma.

Abstract Background. Radiation-induced rib fracture has been reported as a late complication after external radiotherapy to the chest. The purpose of this study was to clarify the characteristics and risk factors of rib fracture after hypofractionated proton beam therapy (PBT). Material and methods. The retrospective study comprised 67 patients with hepatocellular carcinoma who were treated using PBT of 66 Cobalt-Gray-equivalents [Gy (RBE)] in 10 fractions. We analyzed the patients’ characteristics and determined dose-volume histograms (DVHs) for the irradiated ribs, and then estimated relationships between risk of fracture and several dose-volume parameters. An irradiated rib was defined to be any rib included in the area irradiated by PBT as determined by treatment-planning computed tomography. Results. Among the 67 patients, a total of 310 ribs were identified as irradiated ribs. Twenty-seven (8.7%) of the irradiated ribs developed fractures in 11 patients (16.4%). No significant relationships were seen between incidence of fracture and characteristics of patients, including sex, age, tumor size, tumor site, and follow-up period (p ≥ 0.05). The results of receiver operating characteristic curve analysis using DVH parameters demonstrated that the largest area under the curve (AUC) was observed for the volume of rib receiving a biologically effective dose of more than 60 Gy3 (RBE) (V60) [The equivalent dose in 2 Gy fractions (EQD2); 36 Gy3] and the AUCs of V30 to V120 (EQD2; 18–72 Gy3) and Dmax to D10cm3 were similar to that of V60. No significant relationships were seen for DVH parameters and intervals from PBT to incidence of fracture. Conclusion. DVH parameters are useful in predicting late adverse events of rib irradiation. This study identified that V60 was a most statistically significant parameter, and V30 to V120 and Dmax to D10cm3 were also significant and clinically useful for estimating the risk of rib fracture after hypofractionated PBT.