Masashi Mizumoto

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

PURPOSEnTo evaluate the efficacy and safety of hypofractionated proton beam therapy for patients with hepatocellular carcinoma (HCC).nnnMETHODS AND MATERIALSnBetween 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.nnnRESULTSnOverall 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.nnnCONCLUSIONSnHypofractionated 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

PURPOSEnTo investigate the safety and efficacy of proton beam therapy (PBT) in patients with large hepatocellular carcinoma (HCC).nnnMETHODS AND MATERIALSnTwenty-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).nnnRESULTSnThe 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.nnnCONCLUSIONSnThe 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.

BACKGROUNDnOur 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.nnnMETHODS AND MATERIALSnThe 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.nnnRESULTSnOf 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.nnnCONCLUSIONSnThis 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

PURPOSEnTo evaluate the safety and efficacy of postoperative hyperfractionated concomitant boost proton radiotherapy with nimustine hydrochloride for supratentorial glioblastoma multiforme (GBM).nnnMETHODS AND MATERIALSnTwenty 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.nnnRESULTSnAcute 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.nnnCONCLUSIONSnHyperfractionated 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

PURPOSEnLong- 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.nnnMETHODS AND MATERIALSnThe 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.nnnRESULTSnOf 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.nnnCONCLUSIONSnIdentification 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.

Palliative radiotherapy for bleeding from advanced gastric cancer: is a schedule of 30 Gy in 10 fractions adequate?

PurposeTo evaluate the effectiveness of short-course radiotherapy (RT) with 30xa0Gy in 10 fractions for bleeding from advanced gastric cancer.MethodsWe reviewed the data for all patients with gastric cancer requiring blood transfusions due to gastric bleeding who were treated with RT at the Shizuoka Cancer Center Hospital between September 2002 and March 2007. Patients with curative-intent chemoradiotherapy or previous irradiation were excluded. RT was planned to deliver a total of 30xa0Gy at 3xa0Gy per fraction. We defined RT as effective if the patients did not require blood transfusions for 1 or more months after RT.ResultsTwenty-two out of 30 patients (73%) responded to RT, and rebleeding occurred in 11 (50%) of 22 patients responding to RT. The median actuarial time to rebleeding was 3.3xa0months. Twelve patients received concurrent chemoradiotherapy and had a significantly lower rebleeding rate than patients undergoing RT alone (Pxa0=xa00.001). Among patients receiving CRT, 1 with grade 3 non-hematological toxicity and 5 with grade 3–4 hematological toxicity were observed. No Grade 3 or higher adverse events were observed in patients treated with RT alone.ConclusionsRT with 30xa0Gy in 10 fractions is an adequate treatment for bleeding from advanced gastric cancer, especially in patients with poor prognosis.

Analysis of dose-volume histogram parameters for radiation pneumonitis after definitive concurrent chemoradiotherapy for esophageal cancer

PURPOSEnTo evaluate dose-volume histogram (DVH) parameters as predictors of radiation pneumonitis (RP) in esophageal cancer patients treated with definitive concurrent chemoradiotherapy.nnnPATIENTS AND METHODSnThirty-seven esophageal cancer patients treated with radiotherapy with concomitant chemotherapy consisting of 5-fluorouracil and cisplatin were reviewed. Radiotherapy was delivered at 2 Gy per fraction to a total of 60 Gy. For most of the patients, two weeks of interruption was scheduled after 30 Gy. The percentage of lung volume receiving more than 5-50 Gy in increments of 5 Gy (V5-V50, respectively), and the mean lung dose (MLD) were analyzed.nnnRESULTSnTen (27%) patients developed RP of grade 2; 2 (5%), grade 3; 0 (0%), grade 4; and 1 (3%), grade 5. By univariate analysis, all DVH parameters (i.e., V5-V50 and MLD) were significantly associated with grade 2 RP (p < 0.01). The incidences of grade 2 RP were 13%, 33%, and 78% in patients with V20s of 24%, 25-36%, and 37%, respectively. The optimal V20 threshold to predict symptomatic RP was 30.5% according to the receiver operating characteristics curve analysis.nnnCONCLUSIONnDVH parameters were predictors of symptomatic RP and should be considered in the evaluation of treatment planning for esophageal cancer.