Carbon-ion radiotherapy for urological cancers.

Carbon-ions are charged particles with a high linear energy transfer, and therefore, they make a better dose distribution with greater biological effects on the tumors compared with photons and protons. Since prostate cancer, renal cell carcinoma, and retroperitoneal sarcomas such as liposarcoma and leiomyosarcoma are known to be radioresistant tumors, carbon-ion radiotherapy, which provides the advantageous radiobiological properties such as an increasing relative biological effectiveness toward the Bragg peak, a reduced oxygen enhancement ratio, and a reduced dependence on fractionation and cell-cycle stage, has been tested for these urological tumors at the National Institute for Radiological Sciences since 1994. To promote carbon-ion radiotherapy as a standard cancer therapy, the Japan Carbon-ion Radiation Oncology Study Group was established in 2015 to create a registry of all treated patients and conduct multi-institutional prospective studies in cooperation with all the Japanese institutes. Based on accumulating evidence of the efficacy and feasibility of carbon-ion therapy for prostate cancer and retroperitoneal sarcoma, it is now covered by the Japanese health insurance system. On the other hand, carbon-ion radiotherapy for renal cell cancer is not still covered by the insurance system, although the two previous studies showed the efficacy. In this review, we introduce the characteristics, clinical outcomes, and perspectives of carbon-ion radiotherapy and our efforts to disseminate the use of this new technology worldwide.

External dosimetry audit for quality assurance of carbon-ion radiation therapy clinical trials.

PURPOSE: The QA team of the Japan carbon-ion radiation oncology study group (J-CROS) was organized in 2015 to enhance confidence in the accuracy of clinical dosimetry and ensure that the facility QA procedures are adequate. The team conducted onsite dosimetry audits in all the carbon-ion radiation therapy centers in Japan. MATERIALS AND METHODS: A special phantom was fabricated for the onsite dosimetry audit. Target volumes such as the GTV, CTV, and PTV were contoured to the obtained CT images, and two plans with different isocenter depths were created. The dose at the isocenter was measured by an ionization chamber, in the onsite audit and compared with the calculated dose. RESULTS: For all the centers, the average of the percentage ratio between the measured and calculated doses (measured/calculated) was 0.5% (-2.7% to +2.6%) and the standard deviation, 1.7%. In all the centers, the beams were within the set tolerance level of 3%. CONCLUSIONS: The audit demonstrated that the dose at a single point in the water phantom was within tolerance, but it is a big step to say that all doses are correct. In addition, this external dosimetry audit encouraged centers to improve the quality of their dosimetry systems.

Biological dose optimization incorporating intra-tumoural cellular radiosensitivity heterogeneity in ion-beam therapy treatment planning.

Objective.Treatment plans of ion-beam therapy have been made under an assumption that all cancer cells within a tumour equally respond to a given radiation dose. However, an intra-tumoural cellular radiosensitivity heterogeneity clearly exists, and it may lead to an overestimation of therapeutic effects of the radiation. The purpose of this study is to develop a biological model that can incorporate the radiosensitivity heterogeneity into biological optimization for ion-beam therapy treatment planning.Approach.The radiosensitivity heterogeneity was modeled as the variability of a cell-line specific parameter in the microdosimetric kinetic model following the gamma distribution. To validate the developed intra-tumoural-radiosensitivity-heterogeneity-incorporated microdosimetric kinetic (HMK) model, a treatment plan with H-ion beams was made for a chordoma case, assuming a radiosensitivity heterogeneous region within the tumour. To investigate the effects of the radiosensitivity heterogeneity on the biological effectiveness of H-, He-, C-, O-, and Ne-ion beams, the relative biological effectiveness (RBE)-weighted dose distributions were planned for a cuboid target with the stated ion beams without considering the heterogeneity. The planned dose distributions were then recalculated by taking the heterogeneity into account.Main results. The cell survival fraction and corresponding RBE-weighted dose were formulated based on the HMK model. The first derivative of the RBE-weighted dose distribution was also derived, which is needed for fast biological optimization. For the patient plan, the biological optimization increased the dose to the radiosensitivity heterogeneous region to compensate for the heterogeneity-induced reduction in biological effectiveness of the H-ion beams. The reduction in biological effectiveness due to the heterogeneity was pronounced for low linear energy transfer (LET) beams but moderate for high-LET beams. The RBE-weighted dose in the cuboid target decreased by 7.6% for the H-ion beam, while it decreased by just 1.4% for the Ne-ion beam.Significance.Optimal treatment plans that consider intra-tumoural cellular radiosensitivity heterogeneity can be devised using the HMK model.

Modeling of the resensitization effect on carbon-ion radiotherapy for stage I non-small cell lung cancer.

Objective. To investigate the effect of redistribution and reoxygenation on the 3-year tumor control probability (TCP) of patients with stage I non-small cell lung cancer (NSCLC) treated with carbon-ion radiotherapy.Approach. A meta-analysis of published clinical data of 233 NSCLC patients treated by carbon-ion radiotherapy under 18-, 9-, 4-, and single-fraction schedules was conducted. The linear-quadratic (LQ)-based cell-survival model incorporating the radiobiological 5Rs, radiosensitivity, repopulation, repair, redistribution, and reoxygenation, was developed to reproduce the clinical TCP data. Redistribution and reoxygenation were regarded together as a single phenomenon and termed 'resensitization' in the model. The optimum interval time between fractions was investigated for each fraction schedule using the determined model parameters.Main results.The clinical TCP data for 18-, 9-, and 4-fraction schedules were reasonably reproduced by the model without the resensitization effect, whereas its incorporation was essential to reproduce the TCP data for all fraction schedules including the single fraction. The curative dose for the single-fraction schedule was estimated to be 49.0 Gy (RBE), which corresponds to the clinically adopted dose prescription of 50.0 Gy (RBE). For 18-, 9-, and 4-fraction schedules, a 2-to-3-day interval is required to maximize the resensitization effect during the time interval. In contrast, the single-fraction schedule cannot benefit from the resensitization effect, and the shorter treatment time is preferable to reduce the effect of sub-lethal damage repair during the treatment.Significance.The LQ-based cell-survival model incorporating the radiobiological 5Rs was developed and used to evaluate the effect of the resensitization on clinical results of NSCLC patients treated with hypo-fractionated carbon-ion radiotherapy. The incorporation of the resensitization into the cell-survival model improves the reproducibility to the clinical TCP data. A shorter treatment time is preferable in the single-fraction schedule, while a 2-to-3-day interval between fractions is preferable in the multi-fraction schedules for effective treatments.

Inter-fractional error and intra-fractional motion of prostate and dosimetry comparisons of patient position registrations with versus without fiducial markers during treatment with carbon-ion radiotherapy.

A few reports have discussed the influence of inter-fractional position error and intra-fractional motion on dose distribution, particularly regarding a spread-out Bragg peak. We investigated inter-fractional and intra-fractional prostate position error by monitoring fiducial marker positions. In 2020, data from 15 patients with prostate cancer who received carbon-ion beam radiotherapy (CIRT) with gold markers were investigated. We checked marker positions before and during irradiation to calculate the inter-fractional positioning and intra-fractional movement and evaluated the CIRT dose distribution by adjusting the planning beam isocenter and clinical target volume (CTV) position. We compared the CTV dose coverages (CTV receiving 95% [V95%] or 98% [V98%] of the prescribed dose) between skeletal and fiducial matching irradiation on the treatment planning system. For inter-fractional error, the mean distance between the marker position in the planning images and that in a patient starting irradiation with skeletal matching was 1.49 ± 1.11 mm (95th percentile = 1.85 mm). The 95th percentile (maximum) values of the intra-fractional movement were 0.79 mm (2.31 mm), 1.17 mm (2.48 mm), 1.88 mm (4.01 mm), 1.23 mm (3.00 mm), and 2.09 mm (8.46 mm) along the lateral, inferior, superior, dorsal, and ventral axes, respectively. The mean V95% and V98% were 98.2% and 96.2% for the skeletal matching plan and 99.5% and 96.8% for the fiducial matching plan, respectively. Fiducial matching irradiation improved the CTV dose coverage compared with skeletal matching irradiation for CIRT for prostate cancer.

Event-by-event approach to the oxygen-effect-incorporated stochastic microdosimetric kinetic model for hypofractionated multi-ion therapy.

An oxygen-effect-incorporated stochastic microdosimetric kinetic (OSMK) model was previously developed to estimate the survival fraction of cells exposed to charged-particle beams with wide dose and linear energy transfer (LET) ranges under various oxygen conditions. In the model, hypoxia-induced radioresistance was formulated based on the dose-averaged radiation quality. This approximation may cause inaccuracy in the estimation of the biological effectiveness of the radiation with wide variation in energy deposited to a sensitive volume per event, such as spread-out Bragg peak (SOBP) beams. The purpose of this study was to apply an alternative approach so as to consider the energy depositions on an event-by-event basis. The production probability of radiation-induced lesions per energy was formulated with oxygen partial pressure to account for the hypoxia-induced radioresistance. The reduction in the oxygen enhancement ratio for high-LET radiations was modeled by reducing the sensitive-volume size and increasing the saturation energy in microdosimetry. The modified OSMK model was tested against the reported survival data of three cell lines exposed to six species of ions with wide dose and LET ranges under aerobic and hypoxic conditions. The model reasonably reproduced the reported cell survival data. To evaluate the event-by-event approach, survival distributions of Chinese hamster ovary cells exposed to SOBP beams were estimated using the original and modified OSMK models. The differences in the estimated survival distributions between the models were marginal even under extreme hypoxia. The event-by-event approach improved the theoretical validity of the OSMK model. However, the original OSMK model can still provide an accurate estimation of the biological effectiveness of therapeutic radiations.

Stopping-power ratio of body tissues with updated effective energies and elemental I values for treatment planning of proton therapy and ion beam therapy with helium, carbon, oxygen, and neon ions.

The stopping-power ratio (SPR) of body tissues relative to water depends on the particle energy and mean excitation energy (I value) of the tissues. Effective energies to minimize the range error in proton therapy and ion beam therapy with helium, carbon, oxygen, and neon ions and elemental I values have been updated in recent studies. We investigated the effects of these updates on SPR estimation for computed tomography-based treatment planning. The updates led to an increase of up to 0.5% in the SPRs of soft tissues, whereas they led to a decrease of up to 1.9% in the SPRs of bone tissues compared with the current clinical settings. For 44 proton beams planned for 15 randomly sampled patients, the mean water-equivalent target depth change was - 0.2 mm with a standard deviation of 0.2 mm. The maximum change was - 0.6 mm, which we consider to be insignificant in clinical practice.

Improved Algorithm for Estimation of Linear Energy Transfer in Carbon Ion Radiotherapy Plans.

BACKGROUND/AIM: This study aimed to develop an improved algorithm for linear energy transfer (LET) estimation in carbon ion radiotherapy (CIRT) using relative biological effectiveness (RBE) and to establish a clinical pipeline for LET assessment. MATERIALS AND METHODS: New approximation functions for LET versus RBE were developed for the overkill region. LET estimation performance was examined at two facilities (A and B) using archival- and Monte Carlo simulation-derived LET data, respectively, as a reference. A clinical pipeline for LET assessment was developed using Python and treatment planning systems (TPS). RESULTS: In dataset A, LET estimation accuracy in the overkill region was improved by 80.0%. In dataset B, estimation accuracy was 2.3%±0.67% across 5 data points examined. LET distribution and LET-volume histograms were visualized for multiple CIRT plans. CONCLUSION: The new algorithm showed a greater LET estimation performance at multiple facilities using the same TPS. A clinical pipeline for LET assessment was established.

Relationship between electron density and effective densities of body tissues for stopping, scattering, and nuclear interactions of proton and ion beams.

PURPOSE: In treatment planning of charged-particle radiotherapy, patient heterogeneity is conventionally modeled as variable-density water converted from CT images to best reproduce the stopping power, which may lead to inaccuracies in the handling of multiple scattering and nuclear interactions. Although similar conversions can be defined for these individual interactions, they would be valid only for specific CT systems and would require additional tasks for clinical application. This study aims to improve the practicality of the interaction-specific heterogeneity correction. METHODS: The authors calculated the electron densities and effective densities for stopping power, multiple scattering, and nuclear interactions of protons and ions, using the standard elemental-composition data for body tissues to construct the invariant conversion functions. The authors also simulated a proton beam in a lung-like geometry and a carbon-ion beam in a prostate-like geometry to demonstrate the procedure and the effects of the interaction-specific heterogeneity correction. RESULTS: Strong correlations were observed between the electron density and the respective effective densities, with which the authors formulated polyline conversion functions. Their effects amounted to 10% differences in multiple-scattering angle and nuclear interaction mean free path for bones compared to those in the conventional heterogeneity correction. Although their realistic effect on patient dose distributions would be generally small, it could be at the level of a few percent when a carbon-ion beam traverses a large bone. CONCLUSIONS: The present conversion functions are invariant and may be incorporated in treatment planning systems with a common function relating CT number to electron density. This will enable improved beam dose calculation while minimizing initial setup and quality management of the user's specific system.

Evaluation of hybrid depth scanning for carbon-ion radiotherapy.

PURPOSE: In radiotherapy with a scanned carbon-ion beam, its Bragg peak is shifted along the depth direction either by inserting the range shifter plates or by changing the beam-extraction energy of a synchrotron. In the former technique (range shifter scanning: RS), the range shifter plates broaden the beam size and produce secondary fragments through nuclear reactions. In the latter technique (active-energy scanning: ES), it may take several seconds to change the beam energy depending on the synchrotron operation cycle, leading to a long treatment time. The authors propose a hybrid depth scan technique (hybrid scanning: HS), where several beam energies are used in conjunction with the range shifter plates for finer range shift. In this study, HS is evaluated from the viewpoints of dose distribution and treatment time. METHODS: Assuming realistic accelerator and beam-delivery systems, the authors performed computer simulations using GEANT4 Monte Carlo code for beam modeling and a treatment planning system to evaluate HS. Three target volumes with the same dimensions of 60 × 60 × 60 mm(3) were generated at depths of 45, 85, and 125 mm in water phantom, and uniform clinical dose was planned for these targets. The sizes of lateral dose falloff and the peak to plateau ratio defined as the ratio of the clinical dose averaged over the target to the clinical dose at the entrance as well as the treatment time were compared among the three depth scan techniques. RESULTS: The sizes of lateral dose falloffs at the center of SOBP are 11.4, 8.5, and 5.9 mm for the three targets in RS, while they are 5.7, 4.8, and 4.6 mm in ES and 6.6, 5.7, and 5.0 mm in HS, respectively. The peak to plateau ratios are 1.39, 1.96, and 2.15 in RS, while they are 1.48, 2.04, and 2.19 in ES and 1.47, 2.03, and 2.18 in HS, respectively. The treatment times are 128.7, 128.6, and 128.6 s in ES, while they are 61.2, 54.6, and 47.8 s in RS and 43.2, 44.1, and 44.7 s in HS, respectively. The multiple scattering and the nuclear reaction by range shifter degraded the beam qualities such as lateral dose falloff and peak to plateau ratio, which was especially pronounced for the shallow target in RS. The depth scan timing was limited by accelerator cycle in ES. That increased the treatment time by a few times. CONCLUSIONS: This study revealed that HS can provide dose distributions with steeper lateral dose falloffs and higher peak to plateau ratio comparing to RS and comparable to ES. In addition, the treatment time can be considerably reduced in HS compared to ES.

Carbon-ion beam irradiation in combination with cisplatin effectively suppresses xenografted malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer. This study investigated the growth-inhibitory effects of the combination of carbon ion beam irradiation (IR) and cisplatin (CDDP) on MPM xenografts. Carbon-ion beam IR at 15 Gy effectively inhibited tumor growth and decreased the tumor volume more than 90% after 9 weeks. However, tumor regrowth was observed after 17 weeks. The combination of carbon-ion beam IR (15 Gy) and CDDP significantly suppressed tumor growth after 9 weeks, with tumor regression being observed for more than 18 weeks. In contrast, X-ray IR (30 Gy) alone or in combination with CDDP effectively suppressed tumor growth and decreased the tumor volume after 11 weeks, but tumor growth was observed after 15 weeks. Carbon-ion beam IR at 25 Gy resulted in complete tumor regression without tumor regrowth in the 20-week follow-up period. Histopathological analysis revealed that combination of carbon-ion beam IR and CDDP exerted effective cytotoxic effects on MPM xenograft tumor cells and significantly promoted tumor cell necrosis, cavitation, and fibrosis when compared with individual treatment with carbon-ion beam, X-ray IR, or CDDP. Immunohistochemical analysis revealed that the expression levels of tumor cell migration and invasion-related proteins such as CXCL12, MMP2 and MMP9 were not significantly affected upon low dose (15 Gy) carbon-ion beam IR alone or in combination with CDDP but were markedly upregulated upon treatment with CDDP alone relative to control. However, IR with a high dose (25 Gy) carbon-ion beam inhibited tumor growth without upregulating these proteins. In conclusion, the combination of IR with a low dose (15 Gy) carbon ion beam and CDDP effectively suppressed MPM tumor in vivo without significantly upregulating CXCL12, MMP2 and MMP9, suggesting that combination therapy of carbon ion beam IR and chemotherapy is a promising therapeutic strategy for MPM.

Effects of dose and dose-averaged linear energy transfer on pelvic insufficiency fractures after carbon-ion radiotherapy for uterine carcinoma.

BACKGROUND AND PURPOSE: The correlation between dose-averaged linear energy transfer (LETd) and its therapeutic or adverse effects, especially in carbon-ion radiotherapy (CIRT), remains controversial. This study aimed to investigate the effects of LETd and dose on pelvic insufficiency fractures after CIRT. MATERIAL AND METHODS: Among patients who underwent CIRT for uterine carcinoma, 101 who were followed up for > 6 months without any other therapy were retrospectively analyzed. The sacrum insufficiency fractures (SIFs) were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity criteria. The correlations between the relative biological effectiveness (RBE)-weighted dose, LETd, physical dose, clinical factors, and SIFs were evaluated. In addition, we analyzed the association of SIF with LETd, physical dose, and clinical factors in cases where the sacrum D50% RBE-weighted dose was above the median dose. RESULTS: At the last follow-up, 19 patients developed SIFs. Receiver operating characteristic curve analysis revealed that the sacrum D50% RBE-weighted dose was a valuable predictor of SIF. Univariate analyses suggested that LETd V10 keV/µm, physical dose V5 Gy, and smoking status were associated with SIF. Cox regression analysis in patients over 50 years of age validated that current smoking habit was the sole risk factor for SIF. Therefore, LETd or physical dose parameters were not associated with SIF prediction. CONCLUSION: The sacrum D50% RBE-weighted dose was identified as a risk factor for SIF. Additionally, neither LETd nor physical dose parameters were associated with SIF prediction.

[Report of the 121st Scientific Meeting of the Japan Society of Medical Physics].

The Japan Society of Medical Physics (JSMP) held its 121st semiannual scientific meeting from April 15 to April 18, 2021 in Yokohama, jointly with two other radiological academic societies and radiological industry to constitute Japan Radiology Congress. The congress also included a web-based virtual venue from April 28 to June 3 to provide on-demand services of the same contents. Individual participants, once registered online, were given daily options to participate in either venue. The main theme of the congress was "Milestones and Beyond", which was accidentally ideal for JSMP to commemorate 60th anniversary since its establishment in 1961. Of 121 research presentations collected, 8 were proffered by 7 guest speakers from allied medical physics organizations of India, Bangladesh, Hong Kong, Nepal, and Philippines. The meeting also featured many symposia and lectures on medical physics and interdisciplinary topics. Among them were a special lecture on the history of JSMP with current and past JSMP presidents and an international symposium with distinguished panelists invited from Bangladesh, China, Thailand, Vietnam, and Japan. Of total 919 registrants, 297 participated in the real meeting in Yokohama under the COVID-19 pandemic. Nevertheless, the meeting was perfectly implemented as planned because unvisited speakers had submitted their self-recorded video presentations in advance for onsite viewing in their sessions and many of them remotely participated in real-time discussion over the network. The individual presentations from the speakers, the recorded onsite sessions, and their associated bulletin boards for discussion constituted main contents of the virtual meeting. I would like to express my sincere appreciation to all participants and organizers of this successful meeting. This report supplements the official meeting record including extended abstracts of all presentations, which has been published as the Proceedings of the 121st Scientific Meeting of JSMP (Japanese Journal of Medical Physics Volume 41 Supplement 1, JSMP, Tokyo, April 1, 2021).

Adaptation of stochastic microdosimetric kinetic model to hypoxia for hypo-fractionated multi-ion therapy treatment planning.

For hypo-fractionated multi-ion therapy (HFMIT), the stochastic microdosimetric kinetic (SMK) model had been developed to estimate the biological effectiveness of radiation beams with wide linear energy transfer (LET) and dose ranges. The HFMIT will be applied to radioresistant tumors with oxygen-deficient regions. The response of cells to radiation is strongly dependent on the oxygen condition in addition to radiation type, LET and absorbed dose. This study presents an adaptation of the SMK model to account for oxygen-pressure dependent cell responses, and develops the oxygen-effect-incorporated stochastic microdosimetric kinetic (OSMK) model. In the model, following assumptions were made: the numbers of radiation-induced sublethal lesions (double-strand breaks) are reduced due to lack of oxygen, and the numbers of oxygen-mediated lesions are reduced for radiation with high LET. The model parameters were determined by fitting survival data under aerobic and anoxic conditions for human salivary gland tumor cells and V79 cells exposed to helium-, carbon-, and neon-ion beams over the LET range of 18.5-654.0 keVµm-1. The OSMK model provided good agreement with the experimental survival data of the cells with determination coefficients >0.9. In terms of oxygen enhancement ratio, the OSMK model reproduced the experimental data behavior, including slight dependence on particle type at the same LET. The OSMK model was then implemented into the in-house treatment planning software for the HFMIT to validate its applicability in clinical practice. A treatment plan with helium- and neon-ion beams was made for a pancreatic cancer case assuming an oxygen-deficient region within the tumor. The biological optimization based on the OSMK model preferentially placed the neon-ion beam to the hypoxic region, while it placed both helium- and neon-ion beams to the surrounding normoxic region. The OSMK model offered the accuracy and usability required for hypoxia-based biological optimization in HFMIT treatment planning.

Application of lung substitute material as ripple filter for multi-ion therapy with helium-, carbon-, oxygen-, and neon-ion beams.

A development project for hypo-fractionated multi-ion therapy has been initiated at the National Institute of Radiological Sciences in Japan. In the treatment, helium, carbon, oxygen, and neon ions will be used as primary beams with pencil beam scanning. A ripple filter (RiFi), consisting of a thin plastic or aluminum plate with a fine periodic ridge and groove structure, has been used to broaden the Bragg peak of heavy-ion beams in the beam direction. To sufficiently broaden the Bragg peak of helium-, carbon-, oxygen-, and neon-ion beams with suppressed lateral scattering and surface dose inhomogeneity, in this study, we tested a plate made of a lung substitute material, Gammex LN300, as the RiFi. The planar integrated dose distribution of a 183.5 MeV u-1neon-ion beam was measured behind a 3 cm thick LN300 plate in water. The Bragg peak of the pristine beam was broadened following the normal distribution with the standard deviationσvalue of 1.29 mm, while the range of the beam was reduced by 8.8 mm by the plate. To verify the LN300 performance as the RiFi in multi-ion therapy, we measured the pencil beam data of helium-, carbon-, oxygen- and neon-ion beams penetrating the 3 cm thick LN300 plate. The data were then modeled and used in a treatment planning system to achieve a uniform 10% survival of human undifferentiated carcinoma cells within a cuboid target by the beam for each of the different ion species. The measured survival fractions were reasonably reproduced by the planned ones for all the ion species. No surface dose inhomogeneity was observed for any ion species even when the plate was placed close to the phantom surface. The plate made of lung substitute material, Gammex LN300, is applicable as the RiFi in multi-ion therapy with helium-, carbon-, oxygen- and neon-ion beams.

Dose-averaged linear energy transfer per se does not correlate with late rectal complications in carbon-ion radiotherapy.

BACKGROUND AND PURPOSE: Several studies have focused on increasing the linear energy transfer (LET) within tumours to achieve higher biological effects in carbon-ion radiotherapy (C-ion RT). However, it remains unclear whether LET affects late complications. We assessed whether physical dose and LET distribution can be specific factors for late rectal complications in C-ion RT. MATERIALS AND METHODS: Overall, 134 patients with uterine carcinomas were registered and retrospectively analysed. Of 134 patients, 132 who were followed up for >6 months were enrolled. The correlations between the relative biological effectiveness (RBE)-weighted dose based on the Kanai model (the ostensible "clinical dose"), dose-averaged LET (LETd), or physical dose and rectal complications were evaluated. Rectal complications were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS: Nine patients developed grade 3 or 4 late rectal complications. Linear regression analysis found that D2cc in clinical dose was the sole risk factor for ≥grade 3 late rectal complications (p = 0.012). The receiver operating characteristic analysis found that D2cc of 60.2 Gy (RBE) was a suitable cut-off value for predicting ≥grade 3 late rectal complications. Among 35 patients whose rectal D2cc was ≥60.2 Gy (RBE), no correlations were found between severe rectal toxicities and LETd alone or physical dose per se. CONCLUSION: We demonstrated that severe rectal toxicities were related to the rectal D2cc of the clinical dose in C-ion RT. However, no correlations were found between severe rectal toxicities and LETd alone or physical dose per se.

Experimental validation of stochastic microdosimetric kinetic model for multi-ion therapy treatment planning with helium-, carbon-, oxygen-, and neon-ion beams.

The National Institute of Radiological Sciences (NIRS) has initiated a development project for hypo-fractionated multi-ion therapy. In the treatment, heavy ions up to neon ions will be used as a primary beam, which is a high linear energy transfer (LET) radiation. The fractionated dose of the treatment will be 10 Gy or more. The microdosimetric kinetic (MK) model overestimates the biological effectiveness of high-LET and high-dose radiations. To address this issue, the stochastic microdosimetric kinetic (SMK) model has been developed as an extension of the MK model. By taking the stochastic nature of domain-specific and cell nucleus-specific energies into account, the SMK model could estimate the biological effectiveness of radiations with wide LET and dose ranges. Previously, the accuracy of the SMK model was examined by comparison of estimated and reported survival fractions of human cells exposed to pristine helium-, carbon-, and neon-ion beams. In this study, we verified the SMK model in treatment planning of scanned helium-, carbon-, oxygen-, and neon-ion beams as well as their combinations through the irradiations of human undifferentiated carcinoma and human pancreatic cancer cells. Treatment plans were made with the ion-species beams to achieve a uniform 10% survival of the cells within a cuboid target. The planned survival fractions were reasonably reproduced by the measured survival fractions in the whole region from the plateau to the fragment tail for all planned irradiations. The SMK model offers the accuracy and simplicity required in hypo-fractionated multi-ion therapy treatment planning.

Nuclear-interaction correction for patient dose calculations in treatment planning of helium-, carbon-, oxygen-, and neon-ion beams.

In charged-particle therapy treatment planning, the patient is conventionally modeled as variable-density water, i.e. stopping effective density ρ S, and the planar integrated dose distribution measured in water (PID) is applied for patient dose calculation based on path length scaling with the ρ S. This approximation assures the range accuracy of charged-particle beams. However, it causes dose calculation errors due to water nonequivalence of body tissues in nuclear interactions originating from compositional differences. We had previously proposed and validated a PID correction method for the errors in carbon-ion radiotherapy. In the present study, we verify the PID correction method for helium-, oxygen-, and neon-ion beams. The one-to-one relationships between ρ S and the nuclear effective density ρ N of body tissues were constructed for helium-, carbon-, oxygen-, and neon-ion beams, and were used to correct the PIDs to account for the dose calculation errors in patient. The correction method was tested for non-water materials with un-scanned and scanned ion beams. In un-scanned beams penetrating the materials, the dose calculation errors of up to 5.9% were observed at the Bragg peak region, while they were reduced to ⩽0.9% by the PID correction method. In scanned beams penetrating olive oil, the dose calculation errors of up to 2.7% averaged over the spread-out Bragg peak were observed, while they were reduced to ⩽0.4% by the correction method. To investigate the influence of water nonequivalence of body tissues on tumor dose, we carried out a treatment planning study for prostate and uterine cases. The tumor over-doses of 0.9%, 1.8%, 2.0%, and 2.2% were observed in the uterine case for the helium-, carbon-, oxygen-, and neon-ion beams, respectively. These dose errors could be diminished by the PID correction method. The present results verify that the PID correction method is simple, practical, and accurate for treatment planning of these four ion species.

Effect of External Magnetic Fields on Biological Effectiveness of Proton Beams.

PURPOSE: The purpose is to verify experimentally whether application of magnetic fields longitudinal and perpendicular to a proton beam alters the biological effectiveness of the radiation. METHODS AND MATERIALS: Proton beams with linear energy transfer of 1.1 and 3.3 keV/µm irradiated human cancer and normal cells under a longitudinal (perpendicular) magnetic field of BL (BP) = 0, 0.3, or 0.6 T. Cell survival curves were constructed to evaluate the effects of the magnetic fields on the biological effectiveness. The ratio of dose that would result in a survival fraction of 10% without the magnetic field Dwo to the dose with the magnetic field Dw, R10 = Dwo/Dw, was determined for each cell line and magnetic field. RESULTS: For cancer cells exposed to the 1.1- (3.3-) keV/µm proton beams, R10s were increased to 1.10 ± 0.07 (1.11 ± 0.07) and 1.11 ± 0.07 (1.12 ± 0.07) by the longitudinal magnetic fields of BL = 0.3 and 0.6 T, respectively. For normal cells, R10s were increased to 1.13 ± 0.06 (1.17 ± 0.06) and 1.17 ± 0.06 (1.30 ± 0.06) by the BLs. In contrast, R10s were not changed significantly from 1 by the perpendicular magnetic fields of BP = 0.3 and 0.6 T for both cancer and normal cells exposed to 1.1- and 3.3-keV/µm proton beams. CONCLUSIONS: The biological effectiveness of proton beams was significantly enhanced by longitudinal magnetic fields of BL = 0.3 and 0.6 T, whereas the biological effectiveness was not altered by perpendicular magnetic fields of the same strengths. This enhancement effect should be taken into account in magnetic resonance imaging guided proton therapy with a longitudinal magnetic field.