Kikuo Umegaki

Real-time 4-D radiotherapy for lung cancer.

Respiratory motion considerably influences dose distribution, and thus clinical outcomes in radiotherapy for lung cancer. Breath holding, breath coaching, respiratory gating with external surrogates, and mathematical predicting models all have inevitable uncertainty due to the unpredictable variations of internal tumor motion. The amplitude of the same tumor can vary with standard deviations >5 mm occurring in 23% of T1–2N0M0 non‐small cell lung cancers. Residual motion varied 1–6 mm (95th percentile) for the 40% duty cycle of respiratory gating with external surrogates. The 4‐D computed tomography is vulnerable to problems relating to the external surrogates. Real‐time 4‐D radiotherapy (4DRT), where the temporal changes in anatomy during the delivery of radiotherapy are explicitly considered in real time, is emerging as a new method to reduce these known sources of uncertainty. Fluoroscopic, real‐time tumor‐tracking technology using internal fiducial markers near the tumor has ±2 mm accuracy, and has achieved promising clinical results when used with X‐ray therapy. Instantaneous irradiation based on real‐time verification of internal fiducial markers is considered the minimal requisite for real‐time 4DRT of lung cancers at present. Real‐time tracking radiotherapy using gamma rays from positron emitters in tumors is in the preclinical research stage, but has been successful in experiments in small animals. Real‐time tumor tracking via spot‐scanning proton beam therapy has the capability to cure large lung cancers in motion, and is expected to be the next‐generation real‐time 4DRT. (Cancer Sci 2012; 103: 1–6)

A proton beam therapy system dedicated to spot-scanning increases accuracy with moving tumors by real-time imaging and gating and reduces equipment size.

Purpose A proton beam therapy (PBT) system has been designed which dedicates to spot-scanning and has a gating function employing the fluoroscopy-based real-time-imaging of internal fiducial markers near tumors. The dose distribution and treatment time of the newly designed real-time-image gated, spot-scanning proton beam therapy (RGPT) were compared with free-breathing spot-scanning proton beam therapy (FBPT) in a simulation. Materials and Methods In-house simulation tools and treatment planning system VQA (Hitachi, Ltd., Japan) were used for estimating the dose distribution and treatment time. Simulations were performed for 48 motion parameters (including 8 respiratory patterns and 6 initial breathing timings) on CT data from two patients, A and B, with hepatocellular carcinoma and with clinical target volumes 14.6 cc and 63.1 cc. The respiratory patterns were derived from the actual trajectory of internal fiducial markers taken in X-ray real-time tumor-tracking radiotherapy (RTRT). Results With FBPT, 9/48 motion parameters achieved the criteria of successful delivery for patient A and 0/48 for B. With RGPT 48/48 and 42/48 achieved the criteria. Compared with FBPT, the mean liver dose was smaller with RGPT with statistical significance (p<0.001); it decreased from 27% to 13% and 28% to 23% of the prescribed doses for patients A and B, respectively. The relative lengthening of treatment time to administer 3 Gy (RBE) was estimated to be 1.22 (RGPT/FBPT: 138 s/113 s) and 1.72 (207 s/120 s) for patients A and B, respectively. Conclusions This simulation study demonstrated that the RGPT was able to improve the dose distribution markedly for moving tumors without very large treatment time extension. The proton beam therapy system dedicated to spot-scanning with a gating function for real-time imaging increases accuracy with moving tumors and reduces the physical size, and subsequently the cost of the equipment as well as of the building housing the equipment.

What is the appropriate size criterion for proton radiotherapy for hepatocellular carcinoma? A dosimetric comparison of spot-scanning proton therapy versus intensity-modulated radiation therapy

BackgroundWe performed a dosimetric comparison of spot-scanning proton therapy (SSPT) and intensity-modulated radiation therapy (IMRT) for hepatocellular carcinoma (HCC) to investigate the impact of tumor size on the risk of radiation induced liver disease (RILD).MethodsA number of alternative plans were generated for 10 patients with HCC. The gross tumor volumes (GTV) varied from 20.1 to 2194.5 cm3. Assuming all GTVs were spherical, the nominal diameter was calculated and ranged from 3.4 to 16.1 cm. The prescription dose was 60 Gy for IMRT or 60 cobalt Gy-equivalents for SSPT with 95% planning target volume (PTV) coverage. Using IMRT and SSPT techniques, extensive comparative planning was conducted. All plans were evaluated by the risk of RILD estimated using the Lyman-normal-tissue complication probability model.ResultsFor IMRT the risk of RILD increased drastically between 6.3–7.8 cm nominal diameter of GTV. When the nominal diameter of GTV was more than 6.3 cm, the average risk of RILD was 94.5% for IMRT and 6.2% for SSPT.ConclusionsRegarding the risk of RILD, HCC can be more safely treated with SSPT, especially if its nominal diameter is more than 6.3 cm.

Development of a 3D Brain PET Scanner Using CdTe Semiconductor Detectors and Its First Clinical Application

Targeting improved spatial resolution, a three-dimensional positron-emission-tomography (PET) scanner employing CdTe semiconductor detectors and using depth-of-interaction (DOI) information was developed, and its physical performance was evaluated. This PET scanner is the first to use semiconductor detectors dedicated to the human brain and head-and-neck region. Imaging performance of the scanner used for 18F -fluorodeoxy glucose (FDG) scans of phantoms and human brains was evaluated. The gantry of the scanner has a 35.0-cm-diameter patient port, the trans-axial field of view (FOV) is 31.0 cm, and the axial FOV is 24.6 cm. The energy resolution averaged over all detector channels and timing resolution were 4.1% and 6.8 ns (each in FWHM), respectively. Spatial resolution measured at the center of FOV was 2.3-mm FWHM-which is one of the best resolutions achieved by human PET scanners. Noise-equivalent count ratio (NEC2R) has a maximum in the energy window of 390 to 540 keV and is 36 kcps/Bq/cm3 at 3.7 kBq/cm3 . The sensitivity of the system according to NEMA 1994 was 25.9 cps/Bq/cm3. Scatter fraction of the scanner is 37% for the energy window of 390 to 540 keV and 23% for 450 to 540 keV. Images of a hot-rod phantom and images of brain glucose metabolism show that the structural accuracy of the images obtained with the semiconductor PET scanner is higher than that possible with a conventional Bismuth Germanium Oxide (BGO) PET scanner. In addition, the developed scanner permits better delineation of the head-and-neck cancer. These results show that the semiconductor PET scanner will play a major role in the upcoming era of personalized medicine.

Preliminary analysis for integration of spot-scanning proton beam therapy and real-time imaging and gating

PURPOSE Spot-scanning proton beam therapy (PBT) can create good dose distribution for static targets. However, there exists larger uncertainty for tumors that move due to respiration, bowel gas or other internal circumstances within the patients. We have developed a real-time tumor-tracking radiation therapy (RTRT) system that uses an X-ray linear accelerator gated to the motion of internal fiducial markers introduced in the late 1990s. Relying on more than 10 years of clinical experience and big log data, we established a real-time image gated proton beam therapy system dedicated to spot scanning. MATERIALS AND METHODS Using log data and clinical outcomes derived from the clinical usage of the RTRT system since 1999, we have established a library to be used for in-house simulation for tumor targeting and evaluation. Factors considered to be the dominant causes of the interplay effects related to the spot scanning dedicated proton therapy system are listed and discussed. RESULTS/CONCLUSIONS Total facility design, synchrotron operation cycle, and gating windows were listed as the important factors causing the interplay effects contributing to the irradiation time and motion-induced dose error. Fiducial markers that we have developed and used for the RTRT in X-ray therapy were suggested to have the capacity to improve dose distribution. Accumulated internal motion data in the RTRT system enable us to improve the operation and function of a Spot-scanning proton beam therapy (SSPT) system. A real-time-image gated SSPT system can increase accuracy for treating moving tumors. The system will start clinical service in early 2014.

Consensus Guidelines for Implementing Pencil-Beam Scanning Proton Therapy for Thoracic Malignancies on Behalf of the PTCOG Thoracic and Lymphoma Subcommittee

Pencil-beam scanning (PBS) proton therapy (PT), particularly intensity modulated PT, represents the latest advanced PT technology for treating cancers, including thoracic malignancies. On the basis of virtual clinical studies, PBS-PT appears to have great potential in its ability to tightly tailor the dose to the target while sparing critical structures, thereby reducing treatment-related toxicities, particularly for tumors in areas with complicated anatomy. However, implementing PBS-PT for moving targets has several additional technical challenges compared with intensity modulated photon radiation therapy or passive scattering PT. Four-dimensional computed tomography-based motion management and robust optimization and evaluation are crucial for minimizing uncertainties associated with beam range and organ motion. Rigorous quality assurance is required to validate dose delivery both before and during the course of treatment. Active motion management (eg, breath hold), beam gating, rescanning, tracking, or adaptive planning may be needed for cases involving significant motion or changes in motion or anatomy over the course of treatment.

Biological effect of dose distortion by fiducial markers in spot-scanning proton therapy with a limited number of fields: A simulation study

PURPOSE In accurate proton spot-scanning therapy, continuous target tracking by fluoroscopic x ray during irradiation is beneficial not only for respiratory moving tumors of lung and liver but also for relatively stationary tumors of prostate. Implanted gold markers have been used with great effect for positioning the target volume by a fluoroscopy, especially for the cases of liver and prostate with the targets surrounded by water-equivalent tissues. However, recent studies have revealed that gold markers can cause a significant underdose in proton therapy. This paper focuses on prostate cancer and explores the possibility that multiple-field irradiation improves the underdose effect by markers on tumor-control probability (TCP). METHODS A Monte Carlo simulation was performed to evaluate the dose distortion effect. A spherical gold marker was placed at several characteristic points in a water phantom. The markers were with two different diameters of 2 and 1.5 mm, both visible on fluoroscopy. Three beam arrangements of single-field uniform dose (SFUD) were examined: one lateral field, two opposite lateral fields, and three fields (two opposite lateral fields + anterior field). The relative biological effectiveness (RBE) was set to 1.1 and a dose of 74 Gy (RBE) was delivered to the target of a typical prostate size in 37 fractions. The ratios of TCP to that without the marker (TCP(r)) were compared with the parameters of the marker sizes, number of fields, and marker positions. To take into account the dependence of biological parameters in TCP model, α∕β values of 1.5, 3, and 10 Gy (RBE) were considered. RESULTS It was found that the marker of 1.5 mm diameter does not affect the TCPs with all α∕β values when two or more fields are used. On the other hand, if the marker diameter is 2 mm, more than two irradiation fields are required to suppress the decrease in TCP from TCP(r) by less than 3%. This is especially true when multiple (two or three) markers are used for alignment of a patient. CONCLUSIONS It is recommended that 1.5-mm markers be used to avoid the reduction of TCP as well as to spare the surrounding critical organs, as long as the markers are visible on x-ray fluoroscopy. When 2-mm markers are implanted, more than two fields should be used and the markers should not be placed close to the distal edge of any of the beams.

Proton-induced x-ray fluorescence CT imaging

PURPOSE To demonstrate the feasibility of proton-induced x-ray fluorescence CT (pXFCT) imaging of gold in a small animal sized object by means of experiments and Monte Carlo (MC) simulations. METHODS First, proton-induced gold x-ray fluorescence (pXRF) was measured as a function of gold concentration. Vials of 2.2 cm in diameter filled with 0%-5% Au solutions were irradiated with a 220 MeV proton beam and x-ray fluorescence induced by the interaction of protons, and Au was detected with a 3 × 3 mm(2) CdTe detector placed at 90° with respect to the incident proton beam at a distance of 45 cm from the vials. Second, a 7-cm diameter water phantom containing three 2.2-diameter vials with 3%-5% Au solutions was imaged with a 7-mm FWHM 220 MeV proton beam in a first generation CT scanning geometry. X-rays scattered perpendicular to the incident proton beam were acquired with the CdTe detector placed at 45 cm from the phantom positioned on a translation/rotation stage. Twenty one translational steps spaced by 3 mm at each of 36 projection angles spaced by 10° were acquired, and pXFCT images of the phantom were reconstructed with filtered back projection. A simplified geometry of the experimental data acquisition setup was modeled with the MC TOPAS code, and simulation results were compared to the experimental data. RESULTS A linear relationship between gold pXRF and gold concentration was observed in both experimental and MC simulation data (R(2) > 0.99). All Au vials were apparent in the experimental and simulated pXFCT images. Specifically, the 3% Au vial was detectable in the experimental [contrast-to-noise ratio (CNR) = 5.8] and simulated (CNR = 11.5) pXFCT image. Due to fluorescence x-ray attenuation in the higher concentration vials, the 4% and 5% Au contrast were underestimated by 10% and 15%, respectively, in both the experimental and simulated pXFCT images. CONCLUSIONS Proton-induced x-ray fluorescence CT imaging of 3%-5% gold solutions in a small animal sized water phantom has been demonstrated for the first time by means of experiments and MC simulations.

NTCP modeling analysis of acute hematologic toxicity in whole pelvic radiation therapy for gynecologic malignancies : A dosimetric comparison of IMRT and spot-scanning proton therapy (SSPT)

PURPOSE This treatment planning study was conducted to determine whether spot scanning proton beam therapy (SSPT) reduces the risk of grade ⩾3 hematologic toxicity (HT3+) compared with intensity modulated radiation therapy (IMRT) for postoperative whole pelvic radiation therapy (WPRT). METHODS AND MATERIALS The normal tissue complication probability (NTCP) of the risk of HT3+ was used as an in silico surrogate marker in this analysis. IMRT and SSPT plans were created for 13 gynecologic malignancy patients who had received hysterectomies. The IMRT plans were generated using the 7-fields step and shoot technique. The SSPT plans were generated using anterior-posterior field with single field optimization. Using the relative biological effectives (RBE) value of 1.0 for IMRT and 1.1 for SSPT, the prescribed dose was 45Gy(RBE) in 1.8Gy(RBE) per fractions for 95% of the planning target volume (PTV). The homogeneity index (HI) and the conformity index (CI) of the PTV were also compared. RESULTS The bone marrow (BM) and femoral head doses using SSPT were significantly lower than with IMRT. The NTCP modeling analysis showed that the risk of HT3+ using SSPT was significantly lower than with IMRT (NTCP=0.04±0.01 and 0.19±0.03, p=0.0002, respectively). There were no significant differences in the CI and HI of the PTV between IMRT and SSPT (CI=0.97±0.01 and 0.96±0.02, p=0.3177, and HI=1.24±0.11 and 1.27±0.05, p=0.8473, respectively). CONCLUSION The SSPT achieves significant reductions in the dose to BM without compromising target coverage, compared with IMRT. The NTCP value for HT3+ in SSPT was significantly lower than in IMRT.

Pulse radiolysis study of polystyrene-based polymers with added photoacid generators: Reaction mechanism of extreme-ultraviolet and electron-beam chemically amplified resist

The reaction mechanism of chemically amplified resist (CAR) after irradiation with ionizing radiation is important for developing extreme-ultraviolet and electron-beam lithography. The acid generation after the ionization is an essential reaction in CAR. In this study, the intermediate of the proton source of acid (a radical cation of the base polymer) in the presence of a photoacid generator (PAG) was investigated by the pulse radiolysis method. The deprotonation kinetics of the radical cation of poly(4-hydroxystyrene) (PHS) in solutions with and without PAG shows only a small difference. However, the yield of radical cations of poly(4-methoxystyrene) (PMOS) as a model of the resist with a protecting (releasing) group increases upon adding PAG. The formation of the ion pair between the PMOS radical cation and the dissociated anion with a lifetime of approximately 30 to 40 µs is suggested. The lower acid yield in PMOS than in PHS film is also discussed in terms of the stability of the radical cation.