Potential benefits of adaptive intensity-modulated proton therapy in nasopharyngeal carcinomas.

PURPOSE: To investigate potential advantages of adaptive intensity-modulated proton beam therapy (A-IMPT) by comparing it to adaptive intensity-modulated X-ray therapy (A-IMXT) for nasopharyngeal carcinomas (NPC). METHODS: Ten patients with NPC treated with A-IMXT (step and shoot approach) and concomitant chemotherapy between 2014 and 2016 were selected. In the actual treatment, 46 Gy in 23 fractions (46Gy/23Fx.) was prescribed using the initial plan and 24Gy/12Fx was prescribed using an adapted plan thereafter. New treatment planning of A-IMPT was made for the same patients using equivalent dose fractionation schedule and dose constraints. The dose volume statistics based on deformable images and dose accumulation was used in the comparison of A-IMXT with A-IMPT. RESULTS: The means of the Dmean of the right parotid gland (P < 0.001), right TM joint (P < 0.001), left TM joint (P < 0.001), oral cavity (P < 0.001), supraglottic larynx (P = 0.001), glottic larynx (P < 0.001), , middle PCM (P = 0.0371), interior PCM (P < 0.001), cricopharyngeal muscle (P = 0.03643), and thyroid gland (P = 0.00216), in A-IMPT are lower than those of A-IMXT, with statistical significance. The means of, D0.03cc , and Dmean of each sub portion of auditory apparatus and D30% for Eustachian tube and D0.5cc for mastoid volume in A-IMPT are significantly lower than those of A-IMXT. The mean doses to the oral cavity, supraglottic larynx, and glottic larynx were all reduced by more than 20 Gy (RBE = 1.1). CONCLUSIONS: An adaptive approach is suggested to enhance the potential benefit of IMPT compared to IMXT to reduce adverse effects for patients with NPC.

Difference in LET-based biological doses between IMPT optimization techniques: Robust and PTV-based optimizations.

PURPOSE: While a large amount of experimental data suggest that the proton relative biological effectiveness (RBE) varies with both physical and biological parameters, current commercial treatment planning systems (TPS) use the constant RBE instead of variable RBE models, neglecting the dependence of RBE on the linear energy transfer (LET). To conduct as accurate a clinical evaluation as possible in this circumstance, it is desirable that the dosimetric parameters derived by TPS ( D RBE = 1.1 ) are close to the "true" values derived with the variable RBE models ( D v RBE ). As such, in this study, the closeness of D RBE = 1.1 to D v RBE was compared between planning target volume (PTV)-based and robust plans. METHODS: Intensity-modulated proton therapy (IMPT) treatment plans for two Radiation Therapy Oncology Group (RTOG) phantom cases and four nasopharyngeal cases were created using the PTV-based and robust optimizations, under the assumption of a constant RBE of 1.1. First, the physical dose and dose-averaged LET (LETd ) distributions were obtained using the analytical calculation method, based on the pencil beam algorithm. Next, D v RBE was calculated using three different RBE models. The deviation of D v RBE from D RBE = 1.1 was evaluated with D99 and Dmax , which have been used as the evaluation indices for clinical target volume (CTV) and organs at risk (OARs), respectively. The influence of the distance between the OAR and CTV on the results was also investigated. As a measure of distance, the closest distance and the overlapped volume histogram were used for the RTOG phantom and nasopharyngeal cases, respectively. RESULTS: As for the OAR, the deviations of D max v RBE from D max RBE = 1.1 were always smaller in robust plans than in PTV-based plans in all RBE models. The deviation would tend to increase as the OAR was located closer to the CTV in both optimization techniques. As for the CTV, the deviations of D 99 v RBE from D 99 RBE = 1.1 were comparable between the two optimization techniques, regardless of the distance between the CTV and the OAR. CONCLUSION: Robust optimization was found to be more favorable than PTV-based optimization in that the results presented by TPS were closer to the "true" values and that the clinical evaluation based on TPS was more reliable.

Dynamic gating window technique for the reduction of dosimetric error in respiratory-gated spot-scanning particle therapy: An initial phantom study using patient tumor trajectory data.

Spot-scanning particle therapy possesses advantages, such as high conformity to the target and efficient energy utilization compared with those of the passive scattering irradiation technique. However, this irradiation technique is sensitive to target motion. In the current clinical situation, some motion management techniques, such as respiratory-gated irradiation, which uses an external or internal surrogate, have been clinically applied. In surrogate-based gating, the size of the gating window is fixed during the treatment in the current treatment system. In this study, we propose a dynamic gating window technique, which optimizes the size of gating window for each spot by considering a possible dosimetric error. The effectiveness of the dynamic gating window technique was evaluated by simulating irradiation using a moving target in a water phantom. In dosimetric characteristics comparison, the dynamic gating window technique exhibited better performance in all evaluation volumes with different effective depths compared with that of the fixed gate approach. The variation of dosimetric characteristics according to the target depth was small in dynamic gate compared to fixed gate. These results suggest that the dynamic gating window technique can maintain an acceptable dose distribution regardless of the target depth. The overall gating efficiency of the dynamic gate was approximately equal or greater than that of the fixed gating window. In dynamic gate, as the target depth becomes shallower, the gating efficiency will be reduced, although dosimetric characteristics will be maintained regardless of the target depth. The results of this study suggest that the proposed gating technique may potentially improve the dose distribution. However, additional evaluations should be undertaken in the future to determine clinical applicability by assuming the specifications of the treatment system and clinical situation.

Quantitative analysis of treatments using real-time image gated spot-scanning with synchrotron-based proton beam therapy system log data.

A synchrotron-based real-time image gated spot-scanning proton beam therapy (RGPT) system with inserted fiducial markers can irradiate a moving tumor with high accuracy. As gated treatments increase the beam delivery time, this study aimed to investigate the frequency of intra-field adjustments corresponding to the baseline shift or drift and the beam delivery efficiency of a synchrotron-based RGPT system. Data from 118 patients corresponding to 127 treatment plans and 2810 sessions between October 2016 and March 2019 were collected. We quantitatively analyzed the proton beam delivery time, the difference between the ideal beam delivery time based on a simulated synchrotron magnetic excitation pattern and the actual treatment beam delivery time, frequency corresponding to the baseline shift or drift, and the gating efficiency of the synchrotron-based RGPT system according to the proton beam delivery machine log data. The mean actual beam delivery time was 7.1 min, and the simulated beam delivery time in an ideal environment with the same treatment plan was 2.9 min. The average difference between the actual and simulated beam delivery time per session was 4.3 min. The average frequency of intra-field adjustments corresponding to baseline shift or drift and beam delivery efficiency were 21.7% and 61.8%, respectively. Based on our clinical experience with a synchrotron-based RGPT system, we determined the frequency corresponding to baseline shift or drift and the beam delivery efficiency using the beam delivery machine log data. To maintain treatment accuracy within ± 2.0 mm, intra-field adjustments corresponding to baseline shift or drift were required in approximately 20% of cases. Further improvements in beam delivery efficiency may be realized by shortening the beam delivery time.

Analysis of treatment process time for real-time-image gated-spot-scanning proton-beam therapy (RGPT) system.

We developed a synchrotron-based real-time-image gated-spot-scanning proton-beam therapy (RGPT) system and utilized it to clinically operate on moving tumors in the liver, pancreas, lung, and prostate. When the spot-scanning technique is linked to gating, the beam delivery time with gating can increase, compared to that without gating. We aim to clarify whether the total treatment process can be performed within approximately 30 min (the general time per session in several proton therapy facilities), even for gated-spot-scanning proton-beam delivery with implanted fiducial markers. Data from 152 patients, corresponding to 201 treatment plans and 3577 sessions executed from October 2016 to June 2018, were included in this study. To estimate the treatment process time, we utilized data from proton beam delivery logs during the treatment for each patient. We retrieved data, such as the disease site, total target volume, field size at the isocenter, and the number of layers and spots for each field, from the treatment plans. We quantitatively analyzed the treatment process, which includes the patient load (or setup), bone matching, marker matching, beam delivery, patient unload, and equipment setup, using the data obtained from the log data. Among all the cases, 90 patients used the RGPT system (liver: n = 34; pancreas: n = 5; lung: n = 4; and prostate: n = 47). The mean and standard deviation (SD) of the total treatment process time for the RGPT system was 30.3 ± 7.4 min, while it was 25.9 ± 7.5 min for those without gating treatment, excluding craniospinal irradiation (CSI; head and neck: n = 16, pediatric: n = 31, others: n = 15); for CSI (n = 11) with two or three isocenters, the process time was 59.9 ± 13.9 min. Our results demonstrate that spot-scanning proton therapy with a gating function can be achieved in approximately 30-min time slots.

Physical and biological impacts of collimator-scattered protons in spot-scanning proton therapy.

To improve the penumbra of low-energy beams used in spot-scanning proton therapy, various collimation systems have been proposed and used in clinics. In this paper, focused on patient-specific brass collimators, the collimator-scattered protons' physical and biological effects were investigated. The Geant4 Monte Carlo code was used to model the collimators mounted on the scanning nozzle of the Hokkaido University Hospital. A systematic survey was performed in water phantom with various-sized rectangular targets; range (5-20 cm), spread-out Bragg peak (SOBP) (5-10 cm), and field size (2 × 2-16 × 16 cm2 ). It revealed that both the range and SOBP dependences of the physical dose increase had similar trends to passive scattering methods, that is, it increased largely with the range and slightly with the SOBP. The physical impact was maximized at the surface (3%-22% for the tested geometries) and decreased with depth. In contrast, the field size (FS) dependence differed from that observed in passive scattering: the increase was high for both small and large FSs. This may be attributed to the different phase-space shapes at the target boundary between the two dose delivery methods. Next, the biological impact was estimated based on the increase in dose-averaged linear energy transfer (LETd ) and relative biological effectiveness (RBE). The LETd of the collimator-scattered protons were several keV/µm higher than that of unscattered ones; however, since this large increase was observed only at the positions receiving a small scattered dose, the overall LETd increase was negligible. As a consequence, the RBE increase did not exceed 0.05. Finally, the effects on patient geometries were estimated by testing two patient plans, and a negligible RBE increase (0.9% at most in the critical organs at surface) was observed in both cases. Therefore, the impact of collimator-scattered protons is almost entirely attributed to the physical dose increase, while the RBE increase is negligible.

[Advanced radiation therapy project for cancer treatment--from Hokkaido to the world, the world access to Hokkaido].

Cancer is the most major cause of death in Japan recently. In this symposium, we explained advanced treatment technology for cancer treatment, now used and that will be used in near future at the Hokkaido University Hospital. Intensity Moderated Radiation Therapy (IMRT) and Proton Beam Therapy (PBT) are considered to be the most promising and advanced technologies for cancer treatment. Various kinds of radiation treatment equipment and methods have been developed and constructed at the Hokkaido University. One of the most worlds wide famous one is the real time tumor tracking radiotherapy system. The FIRST (Funding for World-Leading Innovative R&D on Science and Technology) Program has been supporting us to produce cutting-edge technology. We hope that this symposium would help the audience to understand the latest technology for cancer treatment especially in the field of radiation therapy and also we wish the audience would recognize the importance of the research aspect that have been performed at Hokkaido University and its Hospital.

Application of motion prediction based on a long short-term memory network for imaging dose reduction in real-time tumor-tracking radiation therapy.

PURPOSE: To demonstrate the possibility of using a lower imaging rate while maintaining acceptable accuracy by applying motion prediction to minimize the imaging dose in real-time image-guided radiation therapy. METHODS: Time-series of three-dimensional internal marker positions obtained from 98 patients in liver stereotactic body radiation therapy were used to train and test the long-short-term memory (LSTM) network. For real-time imaging, the root mean squared error (RMSE) of the prediction on three-dimensional marker position made by LSTM, the residual motion of the target under respiratory-gated irradiation, and irradiation efficiency were evaluated. In the evaluation of the residual motion, the system-specific latency was assumed to be 100 ms. RESULTS: Except for outliers in the superior-inferior (SI) direction, the median/maximum values of the RMSE for imaging rates of 7.5, 5.0, and 2.5 frames per second (fps) were 0.8/1.3, 0.9/1.6, and 1.2/2.4 mm, respectively. The median/maximum residual motion in the SI direction at an imaging rate of 15.0 fps without prediction of the marker position, which is a typical clinical setting, was 2.3/3.6 mm. For rates of 7.5, 5.0, and 2.5 fps with prediction, the corresponding values were 2.0/2.6, 2.2/3.3, and 2.4/3.9 mm, respectively. There was no significant difference between the irradiation efficiency with and that without prediction of the marker position. The geometrical accuracy at lower frame rates with prediction applied was superior or comparable to that at 15 fps without prediction. In comparison with the current clinical setting for real-time image-guided radiation therapy, which uses an imaging rate of 15.0 fps without prediction, it may be possible to reduce the imaging dose by half or more. CONCLUSIONS: Motion prediction can effectively lower the frame rate and minimize the imaging dose in real-time image-guided radiation therapy.

Geometric target margin strategy of proton craniospinal irradiation for pediatric medulloblastoma.

In proton craniospinal irradiation (CSI) for skeletally immature pediatric patients, a treatment plan should be developed to ensure that the dose is uniformly delivered to all vertebrae, considering the effects on bone growth balance. The technical (t) clinical target volume (CTV) is conventionally set by manually expanding the CTV from the entire intracranial space and thecal sac, based on the physician's experience. However, there are differences in contouring methods among physicians. Therefore, we aimed to propose a new geometric target margin strategy. Nine pediatric patients with medulloblastoma who underwent proton CSI were enrolled. We measured the following water equivalent lengths for each vertebra in each patient: body surface to the dorsal spinal canal, vertebral limbus, ventral spinal canal and spinous processes. A simulated tCTV (stCTV) was created by assigning geometric margins to the spinal canal using the measurement results such that the vertebral limb and dose distribution coincided with a margin assigned to account for the uncertainty of the proton beam range. The stCTV with a growth factor (correlation between body surface area and age) and tCTV were compared and evaluated. The median values of each index for cervical, thoracic and lumber spine were: the Hausdorff distance, 9.14, 9.84 and 9.77 mm; mean distance-to-agreement, 3.26, 2.65 and 2.64 mm; Dice coefficient, 0.84, 0.81 and 0.82 and Jaccard coefficient, 0.50, 0.60 and 0.62, respectively. The geometric target margin setting method used in this study was useful for creating an stCTV to ensure consistent and uniform planning.

Investigation of interfractional range variation owing to anatomical changes with beam directions based on water equivalent thickness in proton therapy for pancreatic cancer.

To assess the interfractional anatomical range variations (ARVs) with beam directions and their impact on dose distribution in intensity modulated proton therapy, we analyzed water equivalent thickness (WET) from 10 patients with pancreatic cancer. The distributions of the interfractional WET difference ($\Delta{\mathrm{WET}}^{\theta }$) across 360° were visualized using polar histograms. Interfractional ARVs were evaluated using the mean absolute error and ΔWET pass rate, indicating the percentage of $\Delta \mathrm{WE}{\mathrm{T}}^{\theta }$ < thresholds. The impact on dose distribution in proton therapy was evaluated based on two treatment plans for 40 Gy(RBE)/5 fractions: 'Plan A', using two beam angles, in which the target was closest to the body surface among four perpendicular directions; and 'Plan B', using two beam angles with small ARVs. Analysis revealed individual variations in angular trends of interfractional ARVs. Three distinct trends were identified: Group 1 exhibited small ARVs around posterior directions; Group 2 exhibited small ARVs except ~60°; Group 3 demonstrated minimal ARVs only ~90°. In dose evaluation, while 150° and 210° were selected in Plan B for 9 out of 10 patients, for the remaining patient, 60° and 90° were chosen. Comparing dose volume histogram parameters for all patients, Plan B significantly reduced target coverage loss while maintaining organ-at-risk sparing comparable to Plan A. These results demonstrated that selecting beam angles with small interfractional ARVs for each patient enhances the robustness of dose distribution, reducing target coverage loss.

Technical note: Application of an optical hydrophone to ionoacoustic range detection in a tissue-mimicking agar phantom.

BACKGROUND: Ionoacoustics is a promising approach to reduce the range uncertainty in proton therapy. A miniature-sized optical hydrophone (OH) was used as a measuring device to detect weak ionoacoustic signals with a high signal-to-noise ratio in water. However, further development is necessary to prevent wave distortion because of nearby acoustic impedance discontinuities while detection is conducted on the patient's skin. PURPOSE: A prototype of the probe head attached to an OH was fabricated and the required dimensions were experimentally investigated using a 100-MeV proton beam from a fixed-field alternating gradient accelerator and k-Wave simulations. The beam range of the proton in a tissue-mimicking phantom was estimated by measuring γ-waves and spherical ionoacoustic waves with resonant frequency (SPIRE). METHODS: Four sizes of probe heads were fabricated from agar blocks for the OH. Using the prototype, the Î³-wave was detected at distal and lateral positions to the Bragg peak on the phantom surface for proton beams delivered at seven positions. For SPIRE, independent measurements were performed at distal on- and off-axis positions. The range positions were estimated by solving the linear equation using the sensitive matrix for the γ-wave and linear fitting of the correlation curve for SPIRE; they were compared with those measured using a film. RESULTS: The first peak of the γ-wave was undistorted with the 3 × 3 × 3-cm3 probe head used at the on-axis and 3-cm off-axis positions. The range positions estimated by the γ-wave agreed with the film-based range in the depth direction (the maximum deviation was 0.7 mm), although a 0.6-2.1 mm deviation was observed in the lateral direction. For SPIRE, the deviation was <1 mm for the two measurement positions. CONCLUSIONS: The attachment of a relatively small-sized probe head allowed the OH to measure the beam range on the phantom surface.

A Single-Institution Prospective Study To Evaluate the Safety and Efficacy of Real- Time Image-Gated Spot-Scanning Proton Therapy (RGPT) for Prostate Cancer.

Purpose: In real-time image-gated spot-scanning proton therapy (RGPT), the dose distribution is distorted by gold fiducial markers placed in the prostate. Distortion can be suppressed by using small markers and more than 2 fields, but additional fields may increase the dose to organs at risk. Therefore, we conducted a prospective study to evaluate the safety and short-term clinical outcome of RGPT for prostate cancer. Methods and Materials: Based on the previously reported frequency of early adverse events (AE) and the noninferiority margin of 10%, the required number of cases was calculated to be 43 using the one-sample binomial test by the Southwest Oncology Group statistical tools with the one-sided significance level of 2.5% and the power 80%. Patients with localized prostate cancer were enrolled and 3 to 4 pure gold fiducial markers of 1.5-mm diameter were inserted in the prostate. The prescribed dose was 70 Gy(relative biologic effectiveness) in 30 fractions, and treatment was performed with 3 fields from the left, right, and the back, or 4 fields from either side of slightly anterior and posterior oblique fields. The primary endpoint was the frequency of early AE (≥grade 2) and the secondary endpoint was the biochemical relapse-free survival rate and the frequency of late AE. Results: Forty-five cases were enrolled between 2015 and 2017, and all patients completed the treatment protocol. The median follow-up period was 63.0 months. The frequency of early AE (≥grade 2) was observed in 4 cases (8.9%), therefore the noninferiority was verified. The overall 5-year biochemical relapse-free survival rate was 88.9%. As late AE, grade 2 rectal bleeding was observed in 8 cases (17.8%). Conclusions: The RGPT for prostate cancer with 1.5-mm markers and 3- or 4- fields was as safe as conventional proton therapy in early AE, and its efficacy was comparable with previous studies.

Technical note: Performance evaluation of volumetric imaging based on motion modeling by principal component analysis.

PURPOSE: To quantitatively evaluate the achievable performance of volumetric imaging based on lung motion modeling by principal component analysis (PCA). METHODS: In volumetric imaging based on PCA, internal deformation was represented as a linear combination of the eigenvectors derived by PCA of the deformation vector fields evaluated from patient-specific four-dimensional-computed tomography (4DCT) datasets. The volumetric image was synthesized by warping the reference CT image with a deformation vector field which was evaluated using optimal principal component coefficients (PCs). Larger PCs were hypothesized to reproduce deformations larger than those included in the original 4DCT dataset. To evaluate the reproducibility of PCA-reconstructed volumetric images synthesized to be close to the ground truth as possible, mean absolute error (MAE), structure similarity index measure (SSIM) and discrepancy of diaphragm position were evaluated using 22 4DCT datasets of nine patients. RESULTS: Mean MAE and SSIM values for the PCA-reconstructed volumetric images were approximately 80 HU and 0.88, respectively, regardless of the respiratory phase. In most test cases including the data of which motion range was exceeding that of the modeling data, the positional error of diaphragm was less than 5 mm. The results suggested that large deformations not included in the modeling 4DCT dataset could be reproduced. Furthermore, since the first PC correlated with the displacement of the diaphragm position, the first eigenvector became the dominant factor representing the respiration-associated deformations. However, other PCs did not necessarily change with the same trend as the first PC, and no correlation was observed between the coefficients. Hence, randomly allocating or sampling these PCs in expanded ranges may be applicable to reasonably generate an augmented dataset with various deformations. CONCLUSIONS: Reasonable accuracy of image synthesis comparable to those in the previous research were shown by using clinical data. These results indicate the potential of PCA-based volumetric imaging for clinical applications.

Deformed dose restoration to account for tumor deformation and position changes for adaptive proton therapy.

BACKGROUND: Online adaptation during intensity-modulated proton therapy (IMPT) can minimize the effect of inter-fractional anatomical changes, but remains challenging because of the complex workflow. One approach for fast and automated online IMPT adaptation is dose restoration, which restores the initial dose distribution on the updated anatomy. However, this method may fail in cases where tumor deformation or position changes occur. PURPOSE: To develop a fast and robust IMPT online adaptation method named "deformed dose restoration (DDR)" that can adjust for inter-fractional tumor deformation and position changes. METHODS: The DDR method comprises two steps: (1) calculation of the deformed dose distribution, and (2) restoration of the deformed dose distribution. First, the deformable image registration (DIR) between the initial clinical target volume (CTV) and the new CTV were performed to calculate the vector field. To ensure robustness for setup and range uncertainty and the ability to restore the deformed dose distribution, an expanded CTV-based registration to maintain the dose gradient outside the CTV was developed. The deformed dose distribution was obtained by applying the vector field to the initial dose distribution. Then, the voxel-by-voxel dose difference optimization was performed to calculate beam parameters that restore the deformed dose distribution on the updated anatomy. The optimization function was the sum of total dose differences and dose differences of each field to restore the initial dose overlap of each field. This method only requires target contouring, which eliminates the need for organs at risk (OARs) contouring. Six clinical cases wherein the tumor deformation and/or position changed on repeated CTs were selected. DDR feasibility was evaluated by comparing the results with those from three other strategies, namely, not adapted (continuing the initial plan), adapted by previous dose restoration, and fully optimized. RESULTS: In all cases, continuing the initial plan was largely distorted on the repeated CTs and the dose-volume histogram (DVH) metrics for the target were reduced due to the tumor deformation or position changes. On the other hand, DDR improved DVH metrics for the target to the same level as the initial dose distribution. Dose increase was seen for some OARs because tumor growth had reduced the relative distance between CTVs and OARs. Robustness evaluation for setup and range uncertainty (3 mm/3.5%) showed that deviation in DVH-bandwidth for CTV D95% from the initial plan was 0.4% ± 0.5% (Mean ± S.D.) for DDR. The calculation time was 8.1 ± 6.4 min. CONCLUSIONS: An online adaptation algorithm was developed that improved the treatment quality for inter-fractional anatomical changes and retained robustness for intra-fractional setup and range uncertainty. The main advantage of this method is that it only requires target contouring alone and saves the time for OARs contouring. The fast and robust adaptation method for tumor deformation and position changes described here can reduce the need for offline adaptation and improve treatment efficiency.

Study of hepatic toxicity in small liver tumors after photon or proton therapy based on factors predicting the benefits of proton.

OBJECTIVES: In a previous study of hepatic toxicity, the following three factors were identified to predict the benefits of proton beam therapy (PBT) for hepatocellular carcinomas (HCCs) with a maximum diameter of ≤5 cm and Child-pugh grade A (CP-A): number of tumors (1 vs ≥2), the location of tumors (hepatic hilum or others), and the sum of the diameters of lesions. The aim of this study is to analyze the association between these three factors and hepatic toxicity. METHODS: We retrospectively reviewed patients of CP-A treated with PBT or photon stereotactic body radiotherapy (X-ray radiotherapy, XRT) for HCC ≤5 cm. For normal liver dose, the V5, V10, V20 (volumes receiving 5, 10, and 20 Gy at least), and the mean dose was evaluated. The albumin-bilirubin (ALBI) and CP score changes from the baseline were evaluated at 3 and 6 months after treatment. RESULTS: In 89 patients (XRT: 48, PBT: 41), those with two or three (2-3) predictive factors were higher normal liver doses than with zero or one (0-1) factor. In the PBT group, the ALBI score worsened more in patients with 2-3 factors than those with 0-1 factor, at 3 months (median: 0.26 vs 0.02, p = 0.032) and at 6 months (median: 0.35 vs 0.10, p = 0.009). The ALBI score change in the XRT group and CP score change in either modality were not significantly different in the number of predictive factors. CONCLUSION: The predictive factor numbers predicted the ALBI score change in PBT but not in XRT. ADVANCES IN KNOWLEDGE: This study suggest that the number of predictive factors previously identified (0-1 vs 2-3) were significantly associated with dosimetric parameters of the normal liver in both modalities. In the proton group, the number of predictive factors was associated with a worsening ALBI score at 3 and 6 months, but these associations were not found in the photon SBRT group.

Graphical representation of the effects on tumor and OAR for determining the appropriate fractionation regimen in radiation therapy planning.

PURPOSE: The authors propose a graphical representation of the relation between the effect on the tumor and the damage effect on an organ at risk (OAR) against the irradiation dose, as an aid for choosing an appropriate fractionation regimen. METHODS: The graphical relation is depicted by the radiation effect on the tumor E(1) versus that on an OAR E(0). By observing the features of the E(1) vs E(0) relation curve, i.e., convex or concave shape, one can judge whether multifractionation is better or not. This method is applied to the linear-quadratic model (with α and ß parameters) as an example. Further, the method is extended to the general case for nonuniform dose distribution to the OAR, which is frequently seen in clinical situations. RESULTS: The criterion for selecting multi- or hypofractionation is based on the relation between the dose for the OAR and the α∕ß ratio of the OAR to the tumor. It is also shown that the graphical relation enables us to estimate the final effect after multifractionated treatment by plotting a tangent line on the curve. CONCLUSIONS: The graphical representation method is of use for improving planning in radiotherapy by determining the effective fractionation scheme.

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∕ß 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∕ß 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.

Hyperfractionated intensity-modulated proton therapy for pharyngeal cancer with variable relative biological effectiveness: A simulation study.

BACKGROUND: The relative biological effectiveness (RBE) of proton is considered to be dependent on biological parameters and fractional dose. While hyperfractionated photon therapy was effective in the treatment of patients with head and neck cancers, its effect in intensity-modulated proton therapy (IMPT) under the variable RBE has not been investigated in detail. PURPOSE: To study the effect of variable RBE on hyperfractionated IMPT for the treatment of pharyngeal cancer. We investigated the biologically effective dose (BED) to determine the theoretical effective hyperfractionated schedule. METHODS: The treatment plans of three pharyngeal cancer patients were used to define the ΔBED for the clinical target volume (CTV) and soft tissue (acute and late reaction) as the difference between the BED for the altered schedule with variable RBE and conventional schedule with constant RBE. The ΔBED with several combinations of parameters (treatment days, number of fractions, and prescribed dose) was comprehensively calculated. Of the candidate schedules, the one that commonly gave a higher ΔBED for CTV was selected as the resultant schedule. The BED volume histogram was used to compare the influence of variable RBE and fractionation. RESULTS: In the conventional schedule, compared with the constant RBE, the variable RBE resulted in a mean 2.6 and 2.7 Gy reduction of BEDmean for the CTV and soft tissue (acute reaction) of the three plans, respectively. Moreover, the BEDmean for soft tissue (late reaction) increased by 7.4 Gy, indicating a potential risk of increased RBE. Comprehensive calculation of the ΔBED resulted in the hyperfractionated schedule of 80.52 Gy (RBE = 1.1)/66 fractions in 6.5 weeks. When variable RBE was used, compared with the conventional schedule, the hyperfractionated schedule increased the BEDmean for CTV by 7.6 Gy; however, this was associated with a 7.8 Gy increase for soft tissue (acute reaction). The BEDmean for soft tissue (late reaction) decreased by 2.4 Gy. CONCLUSION: The results indicated a potential effect of the variable RBE on IMPT for pharyngeal cancer but with the possibility that hyperfractionation could outweigh this effect. Although biological uncertainties require conservative use of the resultant schedule, hyperfractionation is expected to be an effective strategy in IMPT for pharyngeal cancer.

Impact of a spatially dependent dose delivery time structure on the biological effectiveness of scanning proton therapy.

PURPOSE: In the scanning beam delivery of protons, different portions of the target are irradiated with different linear energy transfer protons with various time intervals and irradiation times. This research aimed to evaluate the spatially dependent biological effectiveness of protracted irradiation in scanning proton therapy. METHODS: One and two parallel opposed fields plans were created in water phantom with the prescribed dose of 2 Gy. Three scenarios (instantaneous, continuous, and layered scans) were used with the corresponding beam delivery models. The biological dose (physical dose × relative biological effectiveness) was calculated using the linear quadratic model and the theory of dual radiation action to quantitatively evaluate the dose delivery time effect. In addition, simulations using clinical plans (postoperative seminoma and prostate tumor cases) were conducted to assess the impact of the effects on the dose volume histogram parameters and homogeneity coefficient (HC) in targets. RESULTS: In a single-field plan of water phantom, when the treatment time was 19 min, the layered-scan scenario showed a decrease of <0.2% (almost 3.3%) in the biological dose from the plan on the distal (proximal) side because of the high (low) dose rate. This is in contrast to the continuous scenario, where the biological dose was almost uniformly decreased over the target by approximately 3.3%. The simulation with clinical geometry showed that the decrease rates in D99% were 0.9% and 1.5% for every 10 min of treatment time prolongation for postoperative seminoma and prostate tumor cases, respectively, whereas the increase rates in HC were 0.7% and 0.2%. CONCLUSIONS: In protracted irradiation in scanning proton therapy, the spatially dependent dose delivery time structure in scanning beam delivery can be an important factor for accurate evaluation of biological effectiveness.

A study on predicting cases that would benefit from proton beam therapy in primary liver tumors of less than or equal to 5 cm based on the estimated incidence of hepatic toxicity.

Background: For small primary liver tumors, favorable outcomes have been reported with both of proton beam therapy (PBT) and X-ray therapy (XRT). However, no clear criteria have been proposed in the cases for which and when of PBT or XRT has to be used. The aim of this study is to investigate cases that would benefit from PBT based on the predicted rate of hepatic toxicity. Materials and methods: Eligible patients were those who underwent PBT for primary liver tumors with a maximum diameter of ≤ 5 cm and Child-Pugh grade A (n = 40). To compare the PBT-plan, the treatment plan using volumetric modulated arc therapy was generated as the XRT-plan. The rate of predicted hepatic toxicity was estimated using five normal tissue complication probability (NTCP) models with three different endpoints. The differences in NTCP values (ΔNTCP) were calculated to determine the relative advantage of PBT. Factors predicting benefits of PBT were analyzed by logistic regression analysis. Results: From the dose-volume histogram comparisons, an advantage of PBT was found in sparing of the normal liver receiving low doses. The factors predicting the benefit of PBT differed depending on the selected NTCP model. From the five models, the total tumor diameter (sum of the target tumors), location (hepatic hilum vs other), and number of tumors (1 vs 2) were significant factors. Conclusions: From the radiation-related hepatic toxicity, factors were identified to predict benefits of PBT in primary liver tumors with Child-Pugh grade A, with the maximum tumor diameter of ≤ 5 cm.