Teiji Nishio

Phase II Study of Radiotherapy Employing Proton Beam for Hepatocellular Carcinoma

4024 Background: Proton beam radiotherapy (PRT) has an excellent depth-dose profile that can deliver high dose to the liver tumor without debilitating liver function compared to photon beam radiotherapy. It is reasonable to evaluate the safety and efficacy of PRT prospectively for hepatocellular carcinoma (HCC). METHODS Eligibility criteria for this study were: solitary HCC; neither surgery nor local ablation therapy were indicated; no ascites; age ≥20 years; Zubord performance status is 0∼2; no serious co-morbidities other than liver cirrhosis; written informed consent. Tumor close to the stomach or intestinal loop was not considered as a subject for this study. Clinical target volume (CTV) was defined as gross tumor volume plus 5 mm of lateral and cranio-caudal margin. PRT administering 76 GyE/20 fractions/5 weeks to the CTV was done using respiration-gated irradiation system (ReGIS) with 150∼190 MeV proton beam. Relative biological effectiveness of our proton beam was defined as 1.1. No patients received transarterial chemoembolization or local ablation in combination with PRT. RESULTS Thirty patients were enrolled between May 1999 and Feb. 2003. There were 20 male and 10 female with a median age of 70 years (range: 48∼87 years). Maximum tumor diameter ranged from 25 ∼ 82 mm (median 45 mm). All patients had liver cirrhosis of which the degree was Child class A in 9, B in 19, and C in 2. Acute reactions of PRT were well tolerated, and PRT were completed as planned in all patients. After a median follow-up period of 31 months (14∼54 months), only 1 patient experienced tumor recurrence within the CTV and 2-year actuarial local control rate was as 96% (95% confidence interval: 88%∼100%). Actuarial overall survival rate at 2 years was 64% (46∼83%). Pretreatment liver function that was evaluated with indocyanin green clearance at 15 minutes (ICG 15), and liver volume that received 30 GyE or more (V30) significantly correlated with overall survival. CONCLUSIONS Since PRT showed minimal acute toxicity and excellent tumor control within CTV, it is expected as one of the convincing non-surgical treatment options for HCC. ICG 15 and V30 were considered as useful indicators of patient prognosis. No significant financial relationships to disclose.

The Development and Clinical Use of a Beam ON-LINE PET System Mounted on a Rotating Gantry Port in Proton Therapy

PURPOSE To verify the usefulness of our developed beam ON-LINE positron emission tomography (PET) system mounted on a rotating gantry port (BOLPs-RGp) for dose-volume delivery-guided proton therapy (DGPT). METHODS AND MATERIALS In the proton treatment room at our facility, a BOLPs-RGp was constructed so that a planar PET apparatus could be mounted with its field of view covering the iso-center of the beam irradiation system. Activity measurements were performed in 48 patients with tumors of the head and neck, liver, lungs, prostate, and brain. The position and intensity of the activity were measured using the BOLPs-RGp during the 200 s immediately after the proton irradiation. RESULTS The daily measured activity images acquired by the BOLPs-RGp showed the proton irradiation volume in each patient. Changes in the proton-irradiated volume were indicated by differences between a reference activity image (taken at the first treatment) and the daily activity-images. In the case of head-and-neck treatment, the activity distribution changed in the areas where partial tumor reduction was observed. In the case of liver treatment, it was observed that the washout effect in necrotic tumor cells was slower than in non-necrotic tumor cells. CONCLUSIONS The BOLPs-RGp was developed for the DGPT. The accuracy of proton treatment was evaluated by measuring changes of daily measured activity. Information about the positron-emitting nuclei generated during proton irradiation can be used as a basis for ensuring the high accuracy of irradiation in proton treatment.

Dose‐volume delivery guided proton therapy using beam on‐line PET system

Proton therapy is one form of radiotherapy in which the irradiation can be concentrated on a tumor using a scanned or modulated Bragg peak. Therefore, it is very important to evaluate the proton-irradiated volume accurately. The proton-irradiated volume can be confirmed by detection of pair annihilation gamma rays from positron emitter nuclei generated by the target nuclear fragment reaction of irradiated proton nuclei and nuclei in the irradiation target using a positron emission tomography (PET) apparatus, and dose-volume delivery guided proton therapy (DGPT) can thereby be achieved using PET images. In the proton treatment room, a beam ON-LINE PET system (BOLPs) was constructed so that a PET apparatus of the planar-type with a high spatial resolution of about 2 mm was mounted with the field of view covering the isocenter of the beam irradiation system. The position and intensity of activity were measured using the BOLPs immediately after the proton irradiation of a gelatinous water target containing 16O nuclei at different proton irradiation energy levels. The change of the activity-distribution range against the change of the physical range was observed within 2 mm. The experiments of proton irradiation to a rabbit and the imaging of the activity were performed. In addition, the proton beam energy used to irradiate the rabbit was changed. When the beam condition was changed, the difference between the two images acquired from the measurement of the BOLPs was confirmed to clearly identify the proton-irradiated volume.

Washout measurement of radioisotope implanted by radioactive beams in the rabbit.

Washout of 10C and 11C implanted by radioactive beams in brain and thigh muscle of rabbits was studied. The biological washout effect in a living body is important in the range verification system or three-dimensional volume imaging in heavy ion therapy. Positron emitter beams were implanted in the rabbit and the annihilation gamma-rays were measured by an in situ positron camera which consisted of a pair of scintillation cameras set on either side of the target. The ROI (region of interest) was set as a two-dimensional position distribution and the time-activity curve of the ROI was measured. Experiments were done under two conditions: live and dead. By comparing the two sets of measurement data, it was deduced that there are at least three components in the washout process. Time-activity curves of both brain and thigh muscle were clearly explained by the three-component model analysis. The three components ratios (and washout half-lives) were 35% (2.0 s), 30% (140 s) and 35% (10 191 s) for brain and 30% (10 s), 19% (195 s) and 52% (3175 s) for thigh muscle. The washout effect must be taken into account for the verification of treatment plans by means of positron camera measurements.

Proton Beam Therapy for Unresectable Malignancies of the Nasal Cavity and Paranasal Sinuses

PURPOSE The cure rate for unresectable malignancies of the nasal cavity and paranasal sinuses is low. Because irradiation with proton beams, which are characterized by their rapid fall-off at the distal end of the Bragg peak and sharp lateral penumbra, depending on energy, depth, and delivery, provide better dose distribution than X-ray irradiation, proton beam therapy (PBT) might improve treatment outcomes for conditions located in proximity to risk organs. We retrospectively analyzed the clinical profile of PBT for unresectable malignancies of the nasal cavity and paranasal sinuses. METHODS AND MATERIALS We reviewed 39 patients in our database fulfilling the following criteria: unresectable malignant tumors of the nasal cavity, paranasal sinuses or skull base; N0M0 disease; and treatment with PBT (>60 GyE) from January 1999 to December 2006. RESULTS Median patient age was 57 years (range, 22-84 years); 22 of the patients were men and 17 were women. The most frequent primary site was the nasal cavity (n=26, 67%). The local control rates at 6 months and 1 year were 84.6% and 77.0%, respectively. With a median active follow-up of 45.4 months, 3-year progression-free and overall survival were 49.1% and 59.3%, respectively. The most common acute toxicities were mild dermatitis (Grade 2, 33.3%), but no severe toxicity was observed (Grade 3 or greater, 0%). Five patients (12.8%) experienced Grade 3 to 5 late toxicities, and one treatment-related death was reported, caused by cerebrospinal fluid leakage Grade 5 (2.6%). CONCLUSION These findings suggest that the clinical profile of PBT for unresectable malignancies of the nasal cavity and paranasal sinuses make it is a promising treatment option.

Application of an RI-beam for cancer therapy: In-vivo verification of the ion-beam range by means of positron imaging

Abstract In cancer treatment with heavy ions, verification of the ion range in the patients body is important. For this purpose, a positron emitter beam provides the possibility of range verification. To use the positron emitter beam, we have constructed a secondary beam course and its irradiation system. In this paper the constructed system is presented together with some results of beam experiments.

Measurement of neutron ambient dose equivalent in passive carbon-ion and proton radiotherapies.

Secondary neutron ambient dose equivalents per the treatment absorbed dose in passive carbon-ion and proton radiotherapies were measured using a rem meter, WENDI-II at two carbon-ion radiotherapy facilities and four proton radiotherapy facilities in Japan. Our measured results showed that (1) neutron ambient dose equivalent in carbon-ion radiotherapy is lower than that in proton radiotherapy, and (2) the difference to the measured neutron ambient dose equivalents among the facilities is within a factor of 3 depending on the operational beam setting used at the facility and the arrangement of the beam line, regardless of the method for making a laterally uniform irradiation field: the double scattering method or the single-ring wobbling method. The reoptimization of the beam line in passive particle radiotherapy is an effective way to reduce the risk of secondary cancer because installing an adjustable precollimator and designing the beam line devices with consideration of their material, thickness and location, etc., can significantly reduce the neutron exposure. It was also found that the neutron ambient dose equivalent in passive particle radiotherapy is equal to or less than that in the photon radiotherapy. This result means that not only scanning particle radiotherapy but also passive particle radiotherapy can provide reduced exposure to normal tissues around the target volume without an accompanied increase in total body dose.

Distributions of β+ decayed nuclei generated in the CH2 and H2O targets by the target nuclear fragment reaction-using therapeutic MONO and SOBP proton beam

In proton radiotherapy, the irradiation dose can be concentrated on a tumor. To use this radiotherapy efficiently in the clinical field, it is necessary to evaluate the proton-irradiated area and condition. The proton-irradiated area can be confirmed by coincidence detection of pair annihilation gamma rays from beta+ decayed nuclei generated by target nuclear fragment reaction of irradiated proton nuclei and nuclei in the irradiation target. In this study, we performed experiments of proton irradiation to a polyethylene (PE:CH2) target containing 12C nuclei, which is a major component of the human body, and a gelatinous water (H2O) target containing 16O nuclei at different proton irradiation energy levels under different beam conditions of mono-energetic Bragg peak and spread-out Bragg peak. The distribution of the activity in the target after proton irradiation was measured by a positron emission tomography (PET) apparatus, and compared with the calculated distribution. The temporal dependence of the activity distribution during the period between the completion of proton irradiation and the start of measurement by the PET apparatus was examined. The activity by clinical proton irradiation was 3 kB/cc in the PE target and 13 kB/cc in the water target, indicating that the intensity was sufficient for the evaluation of the distribution. The range of the activity distribution against the physical range was short (several millimeter water equivalent length), indicating the presence of target dependence. The range difference in the water target was slightly large with time dependence until the start of measurement. The difference of the lateral widths with full width half at maximum in the distributions of the measured irradiated dose and activity was within 1 mm.

Proton Beam Therapy as a Nonsurgical Approach to Mucosal Melanoma of the Head and Neck: A Pilot Study

PURPOSE The aim of this pilot study was to assess the clinical benefit of proton beam therapy for mucosal melanoma of the head and neck. METHODS AND MATERIALS Patients with mucosal melanoma of the head and neck with histologically confirmed malignant melanoma and N0 and M0 disease were enrolled. Proton therapy was delivered three times per week with a planned total dose of 60 Gy equivalents (GyE) in 15 fractions. RESULTS Fourteen consecutive patients were enrolled from January 2004 through February 2008. Patient characteristics were as follows: median age 73 years old (range, 56 to 79 years); male/female ratio, 7/7; and T stage 1/2/3/4, 3/2/0/9. All patients were able to receive the full dose of proton therapy. The most common acute toxicities were mucositis (grade 3, 21%) and mild dermatitis (grade 3, 0%). As for late toxicity, 2 patients had a unilateral decrease in visual acuity, although blindness did not occur. No treatment-related deaths occurred throughout the study. Initial local control rate was 85.7%, and, with a median follow-up period of 36.7 months, median progression-free survival was 25.1 months, and 3-year overall survival rates were 58.0%. The most frequent site of first failure was cervical lymph nodes (6 patients), followed by local failure in 1 patient and lung metastases in 1 patient. On follow-up, 5 patients died of disease, 4 died due to cachexia caused by distant metastases, and 1 patient by carotid artery perforation cause by lymph nodes metastases. CONCLUSIONS Proton beam radiotherapy showed promising local control benefits and would benefit from ongoing clinical study.

Experimental verification of proton beam monitoring in a human body by use of activity image of positron-emitting nuclei generated by nuclear fragmentation reaction.

Proton therapy is a form of radiotherapy that enables concentration of dose on a tumor by use of a scanned or modulated Bragg peak. Therefore, it is very important to evaluate the proton-irradiated volume accurately. The proton-irradiated volume can be confirmed by detection of pair-annihilation gamma rays from positron-emitting nuclei generated by the nuclear fragmentation reaction of the incident protons on target nuclei using a PET apparatus. The activity of the positron-emitting nuclei generated in a patient was measured with a PET-CT apparatus after proton beam irradiation of the patient. Activity measurement was performed in patients with tumors of the brain, head and neck, liver, lungs, and sacrum. The 3-D PET image obtained on the CT image showed the visual correspondence with the irradiation area of the proton beam. Moreover, it was confirmed that there were differences in the strength of activity from the PET-CT images obtained at each irradiation site. The values of activity obtained from both measurement and calculation based on the reaction cross section were compared, and it was confirmed that the intensity and the distribution of the activity changed with the start time of the PET imaging after proton beam irradiation. The clinical use of this information about the positron-emitting nuclei will be important for promoting proton treatment with higher accuracy in the future.