Koichi Tokuuye

Proton Beam Therapy for Hepatocellular Carcinoma: A Retrospective Review of 162 Patients

Purpose: We present results of patients with hepatocellular carcinoma (HCC) treated with proton beam therapy. Experimental Design: We reviewed 162 patients having 192 HCCs treated from November 1985 to July 1998 by proton beam therapy with or without transarterial embolization and percutaneous ethanol injection. The patients in the present series were considered unsuitable for surgery for various reasons, including hepatic dysfunction, multiple tumors, recurrence after surgical resection, and concomitant illnesses. The median total dose of proton irradiation was 72 Gy in 16 fractions over 29 days. Results: The overall survival rate for all of the 162 patients was 23.5% at 5 years. The local control rate at 5 years was 86.9% for all 192 tumors among the 162 patients. The degree of impairment of hepatic functions attributable to coexisting liver cirrhosis and the number of tumors in the liver significantly affected patient survival. For 50 patients having least impaired hepatic functions and a solitary tumor, the survival rate at 5 years was 53.5%. The patients had very few acute reactions to treatments and a few late sequelae during and after the treatments. Conclusions: Proton beam therapy for patients with HCC is effective, safe, well tolerable, and repeatable. It is the useful treatment mode for either cure or palliation for patients with HCC irrespective of tumor size, tumor location in the liver, insufficient feeding of the tumor with arteries, presence of vascular invasion, impaired hepatic functions, and coexisting intercurrent diseases.

Clinical evaluation of proton radiotherapy for non-small-cell lung cancer.

PURPOSE To evaluate the clinical results of proton radiotherapy for patients with non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS Between 1983 and 2000, 51 NSCLC patients were treated with proton beams at the University of Tsukuba. There were 28 patients in Stage I, 9 in Stage II, 8 in Stage III, 1 in Stage IV, and 5 with recurrent disease. Thirty-three patients had squamous cell carcinoma, 17 had adenocarcinoma, and 1 had large-cell carcinoma. Median fraction and total doses given were 3.0 Gy (range 2.0-6.0 Gy), and 76.0 Gy (range 49.0-93.0 Gy), respectively. RESULTS The 5-year overall survival rate was 29% for all patients, 70% for 9 Stage IA patients, and 16% for 19 Stage IB patients, respectively (IA vs. IB: p < 0.05). The 5-year in-field local control rate was higher in patients with Stage IA (89%) when compared with those with Stage IB (39%). Forty-seven patients (92%) experienced acute lung toxicity of Grade 1 or less; 3 had Grade 2, 1 had Grade 3, and none experienced Grade 4 or higher. Patients in the present series showed very little late toxicity. CONCLUSIONS Proton therapy is a very safe and effective treatment for patients with NSCLC, especially for those with early stages. The relative merit of proton therapy in comparison with stereotactic photon radiotherapy or three-dimensional conformal photon radiotherapy remains to be defined through future clinical trials.

A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma.

PURPOSE To evaluate the efficacy and safety of hypofractionated proton beam therapy for patients with hepatocellular carcinoma (HCC). METHODS AND MATERIALS Between September 2001 and August 2004, 51 patients with HCC greater than 2 cm away from the porta hepatis or gastrointestinal tract were treated with proton beam therapy to 66 Gy-equivalents (GyE) in 10 fractions. RESULTS Overall survival rates were 49.2 and 38.7% at 3 and 5 years after treatment. Local control rates were 94.5 and 87.8% at 3 and 5 years after treatment. Posttreatment serum alpha-fetoprotein values were significantly reduced when compared with pretreatment values (p < 0.0001). Patients experienced only minor acute reactions of Grade 1 or less, and 3 patients experienced late sequelae of Grade 2 or higher. However, there were no treatment-related deaths. CONCLUSIONS Hypofractionated proton beam therapy is safe and well-tolerated by patients with HCC located greater than 2 cm away from the porta hepatis or gastrointestinal tract and may be effective alternative to other modalities.

Proton beam therapy for hepatocellular carcinoma: the University of Tsukuba experience.

The authors have published a series of studies evaluating the safety and efficacy of proton beam therapy for the treatment of hepatocellular carcinoma in a variety of clinical settings. In the current study, they retrospectively reviewed their entire experience treating hepatocellular carcinoma patients with proton beam therapy at their hospital‐based facility at the University of Tsukuba.

Proton-Beam Therapy for Hepatocellular Carcinoma Associated with Portal Vein Tumor Thrombosis*

Background and Purpose:The prognosis of patients with advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is extremely poor, as effective treatment options are limited. The authors performed a retrospective review to evaluate the efficacy of proton-beam therapy (PBT) for patients presenting with PVTT in the setting of HCC.Patients and Methods:Between February 1991 and September 2005, 35 patients with HCC and tumor thrombi in the main trunk or major branches of the portal vein presented for consideration of PBT. Their tumor sizes ranged from 25 mm to 130 mm (median, 60 mm). A median total dose of 72.6 GyE in 22 fractions was delivered over 31 days to a target volume that encompassed both the primary hepatic lesion and the PVTT.Results:32 patients were progression-free during a median follow-up period of 21 months (range, 2–88 months) and three patients experienced disease progression. Local progression-free survival rates were 46% at 2 years and 20% at 5 years, and the median local progression-free survival was 21 months. Acute toxicity ≥ grade 3 was observed in three patients, and no patient experienced late toxicity ≥ grade 3. None of the patients had to discontinue treatment as a result of toxicity.Conclusion:PBT improved local control and significantly prolonged survival in HCC patients with PVTT.Hintergrund und Ziel:Die Prognose von Patienten mit fortgeschrittenem hepatozellulären Karzinom (HCC) mit Tumorthrombose der Pfortader ist in Ermangelung effektiver Behandlungsmöglichkeiten äußerst schlecht. In einer retrospektiven Studie untersuchten die Autoren die Wirksamkeit einer Protonenbestrahlung bei Patienten, die an einer durch das HCC verursachten Tumorthrombose der Pfortader litten.Patienten und Methodik:Zwischen Februar 1991 und September 2005 stellten sich 35 Patienten mit HCC und Tumorthromben in der Pfortader selbst oder in deren großen Ästen zur Erwägung einer Protonenbestrahlung vor. Die Tumorgröße betrug zwischen 25 mm und 130 mm (median 60 mm). Eine mediane Gesamtdosis von 72,6 GyE wurde in 22 Fraktionen über einen Zeitraum von 31 Tagen im Zielvolumen, das sowohl den Primärtumor als auch die Tumorthrombose in der Pfortader beinhaltete, appliziert.Ergebnisse:32 Patienten blieben über einen medianen Nachbeobachtungszeitraum von 21 Monaten progressionsfrei (Spanne 2–88 Monate), drei Patienten erlitten einen Krankheitsprogress. Das lokale progressionsfreie Überleben betrug 46% nach 2 Jahren und 20% nach 5 Jahren, das mediane lokale progressionsfreie Überleben lag bei 21 Monaten. Akuttoxizitäten ≥ Grad 3 wurden bei drei Patienten beobachtet, kein Patient erlitt Spättoxizitäten ≥ Grad 3. Bei keinem Patienten musste die Behandlung infolge von Toxizitäten abgebrochen werden.Schlussfolgerung:Die Protonenbestrahlung verbesserte die lokale Kontrolle und führte zu einer signifikanten Verlängerung des Überlebens von Patienten mit HCC und einer Tumorthrombose der Pfortader.

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 Adjacent to the Porta Hepatis

PURPOSE To evaluate the efficacy and safety of proton beam therapy (PBT) for patients with hepatocellular carcinoma (HCC) located adjacent to the porta hepatis. METHODS AND MATERIALS Subjects of the study were 53 patients with HCC located within 2 cm of the main portal vein. All patients had tumor confined to the radiation field with no evidence of metastatic disease. All patients had hepatic function levels of a Child-Pugh score of 10 or less, Eastern Cooperative Oncology Group performance status of 2 or less, and no uncontrolled ascites. Patients underwent PBT of 72.6 GyE in 22 fractions from Sept 2001 to Dec 2004. RESULTS After 3 years, the actuarial survival rate was 45.1% and local control rate was 86.0%. Prognostic factors for survival included Child-Pugh score, number of tumors, and alpha-fetoprotein levels. No late treatment-related toxicity of Grade 2 or higher was observed. CONCLUSIONS The PBT delivering 72.6 GyE in 22 fractions appears to be effective and safe for HCC adjacent to the porta hepatis.

Fractionated stereotactic radiotherapy of brain metastases from renal cell carcinoma

PURPOSE To retrospectively evaluate the effectiveness of fractionated stereotactic radiotherapy (FSRT) for brain metastases from renal cell carcinoma (RCC). METHODS AND MATERIALS From May 1983 to September 1998, 35 patients with brain metastases from RCC underwent radiotherapy at the National Cancer Center Hospital, Tokyo; 10 patients treated initially with FSRT (FSRT group); 11 with surgery followed by conventional radiotherapy (S/CR group); and 14 with conventional radiotherapy (CR group). Survival and local control rates were determined for patients who had an ECOG performance status of 0-2. RESULTS Overall median survival rate was 18 months, and actuarial 1- and 2-year survival rates were 57.6% and 31.0%, respectively. Median survival rates were 25.6 months for the FSRT group, 18.7 months for the S/CR group, and 4.3 months for the CR group. Significant prognostic factors associated with survival were age less than 60 years and good performance status. In patients treated with FSRT, imaging studies revealed that 21 of 24 tumors (88%) were locally controlled during a median follow-up time of 5.2 months (range 0.5-68). Actuarial 1- and 2-year local control rates were 89.6% and 55.2%, respectively. No patient suffered from acute or late complications during and following FSRT. CONCLUSIONS FSRT offers better tumor control and prolonged survival over the S/CR or CR groups, and should be considered as primary treatment for brain metastases from RCC. Patients under 60-years-old and those with a good performance status at the beginning of radiotherapy had a better prognosis.

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.

PROTON BEAM THERAPY FOR PATIENTS WITH MEDICALLY INOPERABLE STAGE I NON―SMALL-CELL LUNG CANCER AT THE UNIVERSITY OF TSUKUBA

PURPOSE To evaluate in a retrospective review the role of proton beam therapy for patients with medically inoperable Stage I non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS From November 2001 to July 2008, 55 medically inoperable patients with Stage I NSCLC were treated with proton beam therapy. A total of 58 (T1/T2, 30/28) tumors were treated. The median age of study participants was 77 years (range, 52-86 years). A total dose of 66 GyE in 10 fractions was given to peripherally located tumors and 72.6 GyE in 22 fractions to centrally located tumors. RESULTS The rates (95% confidence interval) of overall and progression-free survival of all patients and of local control of all tumors at 2 years were 97.8% (93.6-102.0%), 88.7% (77.9-99.5%), and 97.0% (91.1-102.8%), respectively. There was no statistically significant difference in progression-free rate between T1 and T2 tumors (p = 0.87). Two patients (3.6%) had deterioration in pulmonary function, and 2 patients (3.6%) had Grade 3 pneumonitis. CONCLUSION Proton beam therapy was effective and well tolerated in medically inoperable patients with Stage I NSCLC.