Technical challenges for FLASH proton therapy

There is growing interest in the radiotherapy community in the application of FLASH radiotherapy, wherein the dose is delivered to the entire treatment volume in less than a second. Early pre-clinical evidence suggests that these extremely high dose rates provide significant sparing of healthy tissue compared to conventional radiotherapy without reducing the damage to cancerous cells. This interest has been reflected in the proton therapy community, with early tests indicating that the FLASH effect is also present with high dose rate proton irradiation.In order to deliver clinically relevant doses at FLASH dose rates significant technical hurdles must be overcome in the accelerator technology before FLASH proton therapy can be realised. Of these challenges, increasing the average current from the present clinical range of 1–10 nA to in excess of 100 nA is at least feasible with existing technology, while the necessity for rapid energy adjustment on the order of a few milliseconds is much more challenging, particularly for synchrotron-based systems. However, the greatest challenge is to implement full pencil beam scanning, where scanning speeds 2 orders of magnitude faster than the existing state-of-the-art will be necessary, along with similar improvements in the speed and accuracy of associated dosimetry. Hybrid systems utilising 3D-printed patient specific range modulators present the most likely route to clinical delivery. However, to correctly adapt and develop existing technology to meet the challenges of FLASH, more pre-clinical studies are needed to properly establish the beam parameters that are necessary to produce the FLASH effect.     

Establishing the impact of temporary tissue expanders on electron and photon beam dose distributions

PurposeThis study investigates the effects of temporary tissue expanders (TTEs) on the dose distributions in breast cancer radiotherapy treatments under a variety of conditions.MethodsUsing EBT2 radiochromic film, both electron and photon beam dose distribution measurements were made for different phantoms, and beam geometries. This was done to establish a more comprehensive understanding of the implant's perturbation effects under a wider variety of conditions.ResultsThe magnetic disk present in a tissue expander causes a dose reduction of approximately 20% in a photon tangent treatment and 56% in electron boost fields immediately downstream of the implant. The effects of the silicon elastomer are also much more apparent in an electron beam than a photon beam.ConclusionsEvidently, each component of the TTE attenuates the radiation beam to different degrees. This study has demonstrated that the accuracy of photon and electron treatments of post-mastectomy patients is influenced by the presence of a tissue expander for various beam orientations. The impact of TTEs on dose distributions establishes the importance of an accurately modelled high-density implant in the treatment planning system for post-mastectomy patients.     

Boosting runtime-performance of photon pencil beam algorithms for radiotherapy treatment planning

Pencil beam algorithms are still considered as standard photon dose calculation methods in Radiotherapy treatment planning for many clinical applications. Despite their established role in radiotherapy planning their performance and clinical applicability has to be continuously adapted to evolving complex treatment techniques such as adaptive radiation therapy (ART). We herewith report on a new highly efficient version of a well-established pencil beam convolution algorithm which relies purely on measured input data. A method was developed that improves raytracing efficiency by exploiting the capability of modern CPU architecture for a runtime reduction. Since most of the current desktop computers provide more than one calculation unit we used symmetric multiprocessing extensively to parallelize the workload and thus decreasing the algorithmic runtime. To maximize the advantage of code parallelization, we present two implementation strategies – one for the dose calculation in inverse planning software, and one for traditional forward planning. As a result, we could achieve on a 16-core personal computer with AMD processors a superlinear speedup factor of approx. 18 for calculating the dose distribution of typical forward IMRT treatment plans.     

Treatment of high-grade glioma with radiolabeled peptides

The management of high-grade glioma (HGG) patients in clinical routine represents a challenging task. HGG has a poor prognosis because of early recurrence or therapy-refractory disease following first-line standard therapy, which includes a multidisciplinary approach involving radical surgical resection followed by external beam radiation therapy in combination with chemotherapy.Glioma cells are known to express specific receptors or glycoproteins on their surface which can be used as biological targets for treatment. The application of radiopharmaceuticals consisting of a targeting and an effector domain has led to the introduction of new treatment approaches, aiming at a tumor-specific treatment sparing normal brain tissue.One of these new modalities is the peptide receptor radionuclide therapy (PRRT). Peptides labeled with radioactive nuclides can bind directly to the tumor cells and deliver high doses of radioactivity directly to the tumor tissue.This article reviews the literature for PRRT in HGG.     

Retrospective comparison of rectal toxicity between carbon-ion radiotherapy and intensity-modulated radiation therapy based on treatment plan,normal tissue complication probability model,and clinical outcomes in prostate cancer

This retrospective study assessed the treatment planning data and clinical outcomes for 152 prostate cancer patients: 76 consecutive patients treated by carbon-ion radiation therapy and 76 consequtive patients treated by moderate hypo-fractionated intensity-modulated photon radiation therapy. These two modalities were compared using linear quadratic model equivalent doses in 2 Gy per fraction for rectal or rectal wall dose–volume histogram, 3.6 Gy per fraction-converted rectal dose–volume histogram, normal tissue complication probability model, and actual clinical outcomes. Carbon-ion radiation therapy was predicted to have a lower probability of rectal adverse events than intensity-modulated photon radiation therapy based on dose–volume histograms and normal tissue complication probability model. There was no difference in the clinical outcome of rectal adverse events between the two modalities compared in this study.     

Influence of the Presence of Tissue Expanders on Energy Deposition for Post-Mastectomy Radiotherapy

An increasing number of studies have shown that post-mastectomy radiotherapy presents benefits associated with the patients survival and a significant fraction of the treated patients makes use of tissue expanders for breast reconstruction. Some models of tissue expanders have a magnetic disk on their surface that constitutes heterogeneity in the radiation field, which can affect the dose distribution during the radiotherapy treatment. In this study, the influence of a metallic heterogeneity positioned in a breast tissue expander was evaluated by means of Monte Carlo simulations using the MCNPX code and using Eclipse treatment planning system. Deposited energy values were calculated in structures which have clinical importance for the treatment. Additionally, the effect in the absorbed energy due to backscattering and attenuation of the incident beam caused by the heterogeneity, as well as due to the expansion of the prosthesis, was evaluated in target structures for a 6 MV photon beam by simulations. The dose distributions for a breast treatment were calculated using a convolution/superposition algorithm from the Eclipse treatment planning system. When compared with the smallest breast expander volume, underdosage of 7% was found for the largest volume of breast implant, in the case of frontal irradiation of the chest wall, by Monte Carlo simulations. No significant changes were found in dose distributions for the presence of the heterogeneity during the treatment planning of irradiation with an opposed pair of beams. Even considering the limitation of the treatment planning system, the results obtained with its use confirm those ones found by Monte Carlo simulations for a tangent beam irradiation. The presence of a heterogeneity didńt alters the dose distributions on treatment structures. The underdosage of 7% observed with Monte Carlo simulations were found for irradiation at 0°, not used frequently in a clinical routine.     

Real-time tumor tracking with an artificial neural networks-based method: A feasibility study

The purpose of this study was to develop and assess the performance of a tumor tracking method designed for application in radiation therapy. This motion compensation strategy is currently applied clinically only in conventional photon radiotherapy but not in particle therapy, as greater accuracy in dose delivery is required.We proposed a tracking method that exploits artificial neural networks to estimate the internal tumor trajectory as a function of external surrogate signals. The developed algorithm was tested by means of a retrospective clinical data analysis in 20 patients, who were treated with state of the art infra-red motion tracking for photon radiotherapy, which is used as a benchmark. Integration into a hardware platform for motion tracking in particle therapy was performed and then tested on a moving phantom, specifically developed for this purpose.Clinical data show that a median tracking error reduction up to 0.7 mm can be achieved with respect to state of the art technologies. The phantom study demonstrates that a real-time tumor position estimation is feasible when the external signals are acquired at 60 Hz.The results of this work show that neural networks can be considered a valuable tool for the implementation of high accuracy real-time tumor tracking methodologies.     

Proton beam therapy with concurrent chemotherapy is feasible in children with newly diagnosed rhabdomyosarcoma

BackgroundThe optimal treatment for rhabdomyosarcoma (RMS) requires multidisciplinary treatment with chemotherapy, surgery, and radiotherapy. Surgery and radiotherapy are integral to the local control (LC) of RMS. However, postsurgical and radiotherapy-related complications could develop according to the local therapy and tumor location. In this study, we conducted a single-center analysis of the outcomes and toxicity of multidisciplinary treatment using proton beam therapy (PBT) for pediatric RMS.Materials and methodsRMS patients aged younger than 20 years whose RMS was newly diagnosed and who underwent PBT at University of Tsukuba Hospital (UTH) during the period from 2009 to 2019 were enrolled in this study. The patients’ clinical information was collected by retrospective medical record review.ResultsForty-eight patients were included. The 3-year progression-free survival (PFS) and overall survival (OS) rates of all the patients were 68.8% and 94.2%, respectively. The 3-year PFS rates achieved with radical resection, conservative resection, and biopsy only were 65.3%, 83.3%, and 67.6%, respectively (p = 0.721). The 3-year LC rates achieved with radical resection, conservative resection, and biopsy only were 90.9%, 83.3%, and 72.9%, respectively (p = 0.548). Grade 3 or higher mucositis/dermatitis occurred in 14 patients. Although the days of opioid use due to mucositis/dermatitis during the chemotherapy with PBT were longer than those during the chemotherapy without PBT [6.1 and 1.6 (mean), respectively, p = 0.001], the frequencies of fever and elevation of C-reactive protein were equivalent.ConclusionsMultidisciplinary therapy containing PBT was feasible and provided a relatively fair 3-year PFS, even in children with newly diagnosed RMS without severe toxicity.     

Tailor-made treatment combined with proton beam therapy for children with genitourinary/pelvic rhabdomyosarcoma

Background

Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas among children. Patients who developed genitourinary/pelvic rhabdomyosarcoma (GU/P-RMS) have a higher complication ratio and relatively poorer event free survival, with local therapy being very important. While proton beam therapy (PBT) is expected to reduce co-morbidity, especially for children, this lacks firm evidence and analysis. We analyzed GU/P-RMS children who had undergone multimodal therapy combined with PBT at a single institution.

Method

We retrospectively reviewed charts of children with GU/P-RMS treated from January 2007 to May 2013 at the University of Tsukuba Hospital who had undergone multimodal therapy with PBT.

Results

There were 5 children and their median age at diagnosis was 2.8 years (0.6–4.4 years). Primary sites were the bladder (2) and the prostate (3). All received neo-adjuvant chemotherapy and 3 underwent chemotherapy during PBT (Group Cx). All patients of Group Cx developed leukocytopenia (WBC <1000/μL). The median dose of PBT was 47.7 GyE (41.4–50.4 GyE). All patients survived by their last hospital visit (median, 36 months).

Conclusions

We analyzed multimodal treatment combined with PBT applied for GU/P-RMS. PBT was well tolerated and could be a plausible choice instead of photon therapy for this population.     

Monte Carlo Study of Radiation Dose Enhancement by Gadolinium in Megavoltage and High Dose Rate Radiotherapy

MRI is often used in tumor localization for radiotherapy treatment planning, with gadolinium (Gd)-containing materials often introduced as a contrast agent. Motexafin gadolinium is a novel radiosensitizer currently being studied in clinical trials. The nanoparticle technologies can target tumors with high concentration of high-Z materials. This Monte Carlo study is the first detailed quantitative investigation of high-Z material Gd-induced dose enhancement in megavoltage external beam photon therapy. BEAMnrc, a radiotherapy Monte Carlo simulation package, was used to calculate dose enhancement as a function of Gd concentration. Published phase space files for the TrueBeam flattening filter free (FFF) and conventional flattened 6MV photon beams were used. High dose rate (HDR) brachytherapy with Ir-192 source was also investigated as a reference. The energy spectra difference caused a dose enhancement difference between the two beams. Since the Ir-192 photons have lower energy yet, the photoelectric effect in the presence of Gd leads to even higher dose enhancement in HDR. At depth of 1.8 cm, the percent mean dose enhancement for the FFF beam was 0.38±0.12, 1.39±0.21, 2.51±0.34, 3.59±0.26, and 4.59±0.34 for Gd concentrations of 1, 5, 10, 15, and 20 mg/mL, respectively. The corresponding values for the flattened beam were 0.09±0.14, 0.50±0.28, 1.19±0.29, 1.68±0.39, and 2.34±0.24. For Ir-192 with direct contact, the enhanced were 0.50±0.14, 2.79±0.17, 5.49±0.12, 8.19±0.14, and 10.80±0.13. Gd-containing materials used in MRI as contrast agents can also potentially serve as radiosensitizers in radiotherapy. This study demonstrates that Gd can be used to enhance radiation dose in target volumes not only in HDR brachytherapy, but also in 6 MV FFF external beam radiotherapy, but higher than the currently used clinical concentration (>5 mg/mL) would be needed.     

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.     

On the Use of Optically Stimulated Luminescent Dosimeter for Surface Dose Measurement during Radiotherapy

This study was carried out to investigate the suitability of using the optically stimulated luminescence dosimeter (OSLD) in measuring surface dose during radiotherapy. The water equivalent depth (WED) of the OSLD was first determined by comparing the surface dose measured using the OSLD with the percentage depth dose at the buildup region measured using a Markus ionization chamber. Surface doses were measured on a solid water phantom using the OSLD and compared against the Markus ionization chamber and Gafchromic EBT3 film measurements. The effect of incident beam angles on surface dose was also studied. The OSLD was subsequently used to measure surface dose during tangential breast radiotherapy treatments in a phantom study and in the clinical measurement of 10 patients. Surface dose to the treated breast or chest wall, and on the contralateral breast were measured. The WED of the OSLD was found to be at 0.4 mm. For surface dose measurement on a solid water phantom, the Markus ionization chamber measured 15.95% for 6 MV photon beam and 12.64% for 10 MV photon beam followed by EBT3 film (23.79% and 17.14%) and OSLD (37.77% and 25.38%). Surface dose increased with the increase of the incident beam angle. For phantom and patient breast surface dose measurement, the response of the OSLD was higher than EBT3 film. The in-vivo measurements were also compared with the treatment planning system predicted dose. The OSLD measured higher dose values compared to dose at the surface (Hp(0.0)) by a factor of 2.37 for 6 MV and 2.01 for 10 MV photon beams, respectively. The measurement of absorbed dose at the skin depth of 0.4 mm by the OSLD can still be a useful tool to assess radiation effects on the skin dermis layer. This knowledge can be used to prevent and manage potential acute skin reaction and late skin toxicity from radiotherapy treatments.     

Palliative brachytherapy to axilla and hypopharynx in elderly patient with hypopharyngeal squamous cell carcinoma — case report

Brachytherapy (BT) is an important local treatment of tumor and it can be applied to different anatomical sites either in a curative or palliative setting. BT can deliver large dose of radiation to the tumor while sparing the surrounding normal tissue which translates into a better therapeutic ratio compared to external beam radiotherapy. However, the evidence for the use of brachytherapy in the palliative setting is lacking in the literature. In this case report, we describe the brachytherapy technique and outcome of a patient with squamous cell carcinoma of the hypopharynx who underwent palliative brachytherapy to the hypopharynx and metastatic tumor at the right axilla.     

放射性药物在肿瘤靶向治疗中的应用

放射性药物指供临床诊断或治疗用的放射性核素制剂或其标记化合物。放射性核素靶向治疗是利用对肿瘤细胞具有特异高亲和力的分子载体将核素定向导入特定的肿瘤组织,对肿瘤进行治疗。与传统的放疗和化疗相比,其具有选择性杀伤肿瘤细胞的特点。随着核医学的发展,SPECT/CT、PET/CT的普及,新靶点的发现和新型放射性药物的研发,利用放射性药物进行靶向治疗在肿瘤临床治疗中占据的地位越来越重要。本文简述了放射性药物的分类、组成及特点;综述了针对肿瘤相关抗原的放射免疫药物在非霍奇金淋巴瘤、结直肠癌和前列腺癌中的应用;受体介导的放射性核素药物在治疗神经内分泌肿瘤、前列腺癌和乳腺癌中的临床应用以及基于基因修饰的放射性药物在肿瘤靶向治疗中的实验研究进展。最后总结了放射性药物在肿瘤靶向治疗中的应用前景与面临的挑战,以期为靶向治疗肿瘤的放射性药物的开发和临床应用提供一些参考。     

食管癌三维适形放疗和常规放疗比较

目的对比研究三维适形放疗（3DCRT）和常规模拟机定位放疗两种不同方法在食管癌放射治疗中的优缺点。方法 20例食管癌患者采用3DCRT方法进行治疗,应用同一治疗计划系统,制定适形放疗和常规模拟机定位放疗方案。结果与常规模拟定位机定位放疗相比,食管癌照射中3DCRT有最好的剂量分布,既可明显提高靶区的剂量,同时能较好地保护正常组织。结论食管癌的适形放疗技术能降低正常组织的放射损伤和并发症,提高放疗治疗的适形度,改善靶区的剂量分布。     

A realistic utilization of nanotechnology in molecular imaging and targeted radiotherapy of solid tumors

Precise dose delivery to malignant tissue in radiotherapy is of paramount importance for treatment efficacy while minimizing morbidity of surrounding normal tissues. Current conventional imaging techniques, such as magnetic resonance imaging (MRI) and computerized tomography (CT), are used to define the three-dimensional shape and volume of the tumor for radiation therapy. In many cases, these radiographic imaging (RI) techniques are ambiguous or provide limited information with regard to tumor margins and histopathology. Molecular imaging (MI) modalities, such as positron emission tomography (PET) and single photon-emission computed-tomography (SPECT) that can characterize tumor tissue, are rapidly becoming routine in radiation therapy. However, their inherent low spatial resolution impedes tumor delineation for the purposes of radiation treatment planning. This review will focus on applications of nanotechnology to synergize imaging modalities in order to accurately highlight, as well as subsequently target, tumor cells. Furthermore, using such nano-agents for imaging, simultaneous coupling of novel therapeutics including radiosensitizers can be delivered specifically to the tumor to maximize tumor cell killing while sparing normal tissue.     

Heavy ion radiography and tomography

In the latest years, radiation therapy with ion beams has been rapidly spreading worldwide. This is mainly due to the favourable interaction properties of ion beams with matter, offering the possibility of more conformal dose deposition with superior sparing of healthy tissue in comparison to conventional photon radiation. Moreover, heavier ions like carbon offer a selective increase of biological effectiveness which can be advantageous for the treatment of tumours being resistant to sparsely ionizing radiation. However, full clinical exploitation of the advantages offered by ion beams is still challenged by the lack of exact knowledge of the beam range within the patient. Therefore, increasing research efforts are being devoted to the goal of reducing range uncertainties in ion beam therapy. In this context, ion transmission imaging is being recognized as a promising modality capable of providing valuable pre- (or even “in-between”) treatment information on the patient-specific stopping properties for indirect in-vivo range verification and low dose image guidance at the treatment site. The more recent availability of energetic ion beam sources at therapeutic treatment facilities, in combination with the advances in detector technologies and computational power, have considerably renewed the interest in this imaging technique. Nowadays, many research efforts are being devoted to the development of novel detector prototypes for heavy ion radiography and tomography, as will be reviewed in this contribution.     

Partial breast irradiation techniques in early breast cancer

Whole breast irradiation represents an integral part of combined breast-conserving treatment of early breast cancer. A new concept includes replacing traditionally fractionated whole breast postoperative radiotherapy by accelerated partial breast irradiation. The latter involves a variety of techniques and may be applied intraoperatively or shortly after the surgery. The intraoperative techniques include photon or electron external beam irradiation and interstitial high dose rate (HDR) brachytherapy, whereas the postoperative techniques comprise interstitial brachytherapy, be it HDR, pulse dose rate (PDR) or low dose rate (LDR), intracavitary brachytherapy and external beam radiotherapy using electrons, photons or protons. This article presents accelerated partial breast irradiation techniques, ongoing phase III trials evaluating their value and recommendations for clinical practice.     

Intermediate Megavoltage Photon Beams for Improved Lung Cancer Treatments

The goal of this study is to evaluate the effects of intermediate megavoltage (3-MV) photon beams on SBRT lung cancer treatments. To start with, a 3-MV virtual beam was commissioned on a commercial treatment planning system based on Monte Carlo simulations. Three optimized plans (6-MV, 3-MV and dual energy of 3- and 6-MV) were generated for 31 lung cancer patients with identical beam configuration and optimization constraints for each patient. Dosimetric metrics were evaluated and compared among the three plans. Overall, planned dose conformity was comparable among three plans for all 31 patients. For 21 thin patients with average short effective path length (< 10 cm), the 3-MV plans showed better target coverage and homogeneity with dose spillage index R_50% = 4.68±0.83 and homogeneity index = 1.26±0.06, as compared to 4.95±1.01 and 1.31±0.08 in the 6-MV plans (p < 0.001). Correspondingly, the average/maximum reductions of lung volumes receiving 20 Gy (V_20Gy), 5 Gy (V_5Gy), and mean lung dose (MLD) were 7%/20%, 9%/30% and 5%/10%, respectively in the 3-MV plans (p < 0.05). The doses to 5% volumes of the cord, esophagus, trachea and heart were reduced by 9.0%, 10.6%, 11.4% and 7.4%, respectively (p < 0.05). For 10 thick patients, dual energy plans can bring dosimetric benefits with comparable target coverage, integral dose and reduced dose to the critical structures, as compared to the 6-MV plans. In conclusion, our study indicated that 3-MV photon beams have potential dosimetric benefits in treating lung tumors in terms of improved tumor coverage and reduced doses to the adjacent critical structures, in comparison to 6-MV photon beams. Intermediate megavoltage photon beams (< 6-MV) may be considered and added into current treatment approaches to reduce the adjacent normal tissue doses while maintaining sufficient tumor dose coverage in lung cancer radiotherapy.     

Intraoperative radiation therapy-induced sarcomas in dogs

In a canine model the tolerance of normal and surgically manipulated tissue to intraoperative radiotherapy (IORT) was investigated to provide guidelines for the clinical use of IORT in human cancer patients. A dose of 20 Gy IORT, with or without external beam radiotherapy, was generally well tolerated without significant increased treatment morbidity. Higher doses of IORT (over 30 Gy) have produced radiation-induced sarcomas in some animals followed over a long period. Therefore IORT should be used only in human cancer patients in well controlled studies, in which complications are well documented, and the possibility of radiation-induced malignancies in long-term survival should be considered.