Hidetsugu Nakayama

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.

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.

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.

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.

FRACTIONATED STEREOTACTIC RADIOTHERAPY OF SMALL INTRACRANIAL MALIGNANCIES

PURPOSE To retrospectively evaluate the effectiveness of fractionated stereotactic radiotherapy (FSRT) in patients with small intracranial malignancies. METHODS AND MATERIALS From July 1991 to March 1997, 80 patients with a total of 121 brain or skull-base tumors were treated with FSRT alone, and were followed for periods ranging from 3 to 62 months (median 9.8). The majority of patients received 42 Gy in 7 fractions over 2.3 weeks, but in July 1993, protocols using smaller fraction doses were introduced for patients whose radiation-field diameters were larger than 3 cm or whose tumors were close to critical normal tissues. RESULTS For 64 patients with metastatic brain tumors the overall median survival was 8.3 months and 1-year actuarial survival rate was 33%. Significant prognostic factors were: the presence of extracranial tumors, pre-treatment performance status, and the lung as a primary site. Patients without extracranial tumors prior to FSRT had a median survival of 21.2 months. For seven patients with high-grade glioma, 1-year actuarial local control rate was 75%, with a median survival of 10.3 months. For patients with skull-base tumors the local control was achieved in 6 of 6 patients (100%), with a median survival of 30.7 months. No one suffered from acute complications, but three patients, two of whom had undergone FSRT as the third course of radiotherapy, developed late radiation injuries. CONCLUSION Overall high local control and low morbidity rates suggest that FSRT is an effective and safe modality, even for those with a history of prior irradiation. However, patients with risk factors should be treated with smaller fraction doses.