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Abstract Background and purpose Particle therapy, mainly including carbon-ion radiotherapy (CIRT) and proton beam therapy (PBT), has dose distribution advantages compared to photon radiotherapy. It has been widely reported as a promising treatment method for early non-small cell lung cancer (NSCLC). However, its application in locally advanced non-small cell lung cancer (LA-NSCLC) is relatively rare, and its efficacy and safety are inconclusive. This study aimed to provide systematic evidence for evaluating the efficacy and safety of particle therapy for inoperable LA-NSCLC. Methods To retrieve published literature, a systematic search was conducted in PubMed, Web of Science, Embase, and Cochrane Library until September 4, 2022. The primary endpoints were local control (LC) rate, overall survival (OS) rate, and progression-free survival (PFS) rate at 2 and 5 years. The secondary endpoint was treatment-related toxicity. The pooled clinical outcomes and 95% confidence intervals (CIs) were calculated by using STATA 15.1. Results Nineteen eligible studies with a total sample size of 851 patients were included. The pooled data demonstrated that the OS, PFS, and LC rates at 2 years of LA-NSCLC treated by particle therapy were 61.3% (95% CI = 54.7-68.7%), 37.9% (95% CI = 33.8-42.6%) and 82.2% (95% CI = 78.7-85.9%), respectively. The pooled 5-year OS, PFS, and LC rates were 41.3% (95% CI = 27.1-63.1%), 25.3% (95% CI = 16.3-39.4%), and 61.5% (95% CI = 50.7-74.6%), respectively. Subgroup analysis stratified by treatment type showed that the concurrent chemoradiotherapy (CCRT, PBT combined with concurrent chemotherapy) group had better survival benefits than the PBT and CIRT groups. The incidence rates of grade 3/4 esophagitis, dermatitis, and pneumonia in LA-NSCLC patients after particle therapy were 2.6% (95% CI = 0.4-6.0%), 2.6% (95% CI = 0.5-5.7%) and 3.4% (95% CI = 1.4-6.0%), respectively. Conclusions Particle therapy demonstrated promising efficacy and acceptable toxicity in LA-NSCLC patients.

Japanese national oncological experts convened to evaluate the efficacy and safety of particle beam therapy (PT) for pulmonary, liver and lymph node oligometastases (P-OM, L-OM and LN-OM, respectively) and to conduct a statistically comparative analysis of the local control (LC) rate and overall survival (OS) rate of PT versus those of X-ray stereotactic body radiotherapy (X-SBRT) and X-ray intensity-modulated radiotherapy (X-IMRT). They conducted [1] an analysis of the efficacy and safety of metastasis-directed therapy with PT for P-OM, L-OM and LN-OM using a Japanese nationwide multi-institutional cohort study data set; [2] a systematic review of X-ray high-precision radiotherapy (i.e. X-SBRT/X-IMRT) and PT for P-OM, L-OM and LN-OM; and [3] a statistical comparison between LC and OS of the cohort data set in PT and that of the extracted historical data set in X-SBRT/X-IMRT from the preceding systematic review. Safety was evaluated as the incidence of grade ≥ 3 adverse events, while statistical comparisons of LC and OS were conducted by estimating the incidence rate ratios (IRR) for local progression and mortality, respectively. This study demonstrated that PT provided durable LC (3-year LC rate: 72.8–83.2%) with acceptable OS (3-year OS rate: 38.5–68.1%) and risk of severe toxicity incidence of 0.8–3.5% in radical metastasis-directed therapy for P-OM, L-OM and LN-OM. Compared to LC with X-SBRT or X-IMRT, LC with PT was potentially superior for P-OM; superior for L-OM; and equivalent for LN-OM. In particular, this study demonstrated that PT may be a new treatment option for L-OM tumors measuring > 5 cm. [ABSTRACT FROM AUTHOR]

We reviewed the outcomes of glioma patients enrolled in a prospective observational registry study of proton beam therapy (PBT) in Japan. The inclusion criteria were glioma patients registered in the Electronic Data Capture system, the Proton-net, between May 2016 and July 2019. Data on patient characteristics, treatments, late adverse events, survival status, recurrence and secondary tumors were extracted and statistically analyzed. The primary endpoint was the overall survival (OS) rate, and the secondary endpoints were the progression-free survival (PFS) rate and cumulative local recurrence rate (cLRR). Of the 65 primary brain tumor patients registered, 29 glioma patients from eight of 19 PBT facilities met the inclusion criteria. There were 19 glioblastoma patients, eight of other malignant gliomas, and two of low-grade gliomas. For glioblastomas, with a median follow-up period of 16 months, the median survival time was 21.2 months and the OS at 1, 2, 3 and 4 years were 77.4%, 44.9%, 23.9% and 23.9%, respectively. The median PFS period was 10.1 months, the 1, 2, 3 and 4-year PFS were 32.4%, 19.4%, 9.7% and 9.7%, respectively. The 1, 2, 3 and 4-year cLRR were 56.1%, 68.8%, 78.4 and 78.4%, respectively. Grade 3 brain necrosis was observed in two patients. No secondary tumor was observed. This is the first report on the current status of PBT for gliomas in Japan. For glioblastomas, the outcomes of PBT are estimated to be equivalent to historical data of photon therapy. The results of a prospective comparative evaluation of PBT and photon therapy are awaited. [ABSTRACT FROM AUTHOR]

Background and purpose: Particle therapy, mainly including carbon-ion radiotherapy (CIRT) and proton beam therapy (PBT), has dose distribution advantages compared to photon radiotherapy. It has been widely reported as a promising treatment method for early non-small cell lung cancer (NSCLC). However, its application in locally advanced non-small cell lung cancer (LA-NSCLC) is relatively rare, and its efficacy and safety are inconclusive. This study aimed to provide systematic evidence for evaluating the efficacy and safety of particle therapy for inoperable LA-NSCLC. Methods: To retrieve published literature, a systematic search was conducted in PubMed, Web of Science, Embase, and Cochrane Library until September 4, 2022. The primary endpoints were local control (LC) rate, overall survival (OS) rate, and progression-free survival (PFS) rate at 2 and 5 years. The secondary endpoint was treatment-related toxicity. The pooled clinical outcomes and 95% confidence intervals (CIs) were calculated by using STATA 15.1. Results: Nineteen eligible studies with a total sample size of 851 patients were included. The pooled data demonstrated that the OS, PFS, and LC rates at 2 years of LA-NSCLC treated by particle therapy were 61.3% (95% CI = 54.7-68.7%), 37.9% (95% CI = 33.8-42.6%) and 82.2% (95% CI = 78.7-85.9%), respectively. The pooled 5-year OS, PFS, and LC rates were 41.3% (95% CI = 27.1-63.1%), 25.3% (95% CI = 16.3-39.4%), and 61.5% (95% CI = 50.7-74.6%), respectively. Subgroup analysis stratified by treatment type showed that the concurrent chemoradiotherapy (CCRT, PBT combined with concurrent chemotherapy) group had better survival benefits than the PBT and CIRT groups. The incidence rates of grade 3/4 esophagitis, dermatitis, and pneumonia in LA-NSCLC patients after particle therapy were 2.6% (95% CI = 0.4-6.0%), 2.6% (95% CI = 0.5-5.7%) and 3.4% (95% CI = 1.4-6.0%), respectively. Conclusions: Particle therapy demonstrated promising efficacy and acceptable toxicity in LA-NSCLC patients. [ABSTRACT FROM AUTHOR]

Lymphocytes play an important role in the cancer immune system. In the present study, we aimed to evaluate the associations of lymphopenia during proton beam therapy (PBT) and concurrent chemotherapy with clinical outcomes and to determine whether lung or bone is more influential on lymphopenia during PBT. Data from 41 patients with stage III non-small cell lung cancer (NSCLC) who received PBT of 74 GyE with concurrent chemotherapy between 2007 and 2017 were reviewed retrospectively. The correlation between dosimetry parameters obtained from dose–volume histograms of the bone and lung and lymphopenia during PBT were analyzed. Minimum absolute lymphocyte count (ALCmin) and maximum neutrophil/lymphocyte ratio (NLRmax) were used as indicators of lymphopenia. Bone V5–20 and lung V5–50 were significantly correlated with the ALCmin and NLRmax during PBT. Multivariable analysis showed that the NLRmax, but not the ALCmin, was associated with overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). The 3-year rates of OS, PFS and DMFS of patients with a low (≤ 6.3) versus high (> 6.3) NLRmax were 73.9% vs 44.4% (P  = 0.042), 26.1% vs 5.6% (P  = 0.022) and 39.1% vs 5.6% (P  < 0.001), respectively. Lung V20 was significantly associated with DMFS on multivariable analyses (hazard ratio: 1.094, P  = 0.008), whereas bone V5 had no impact on survival outcomes. We concluded that the NLRmax was a better prognostic indicator than the ALCmin, and the lung dose had more influence than the bone dose on the main survival outcomes in stage III NSCLC patients treated with PBT combined with concurrent chemotherapy. [ABSTRACT FROM AUTHOR]

Disregarding the increase of relative biological effectiveness (RBE) may raise the risk of acute and late adverse events after proton beam therapy (PBT). This study aims to explore the relationship between variable RBE (above 1.1)-induced normal tissue complication probabilities (NTCP) and patient-specific factors, identify patients at high risk of RBE-induced NTCP increase, and assess risk mitigation by incorporating RBE variability into treatment planning. We retrospectively analyzed 105 primary brain tumor patients treated with PBT (RBE = 1.1). We calculated differences in estimated NTCP (ΔNTCP) using a variable RBE-weighted dose (D RBE , Wedenberg model) and a constant RBE-weighted dose (D RBE=1.1), across 16 NTCP models. These differences were correlated with patient-specific characteristics. Based on ΔNTCP, patients were classified as high risk (32 %) or low risk (68 %) for adverse events due to RBE-induced NTCP. This classification was compared with alternative classifications based on (a) relevant patient-specific characteristics, (b) D RBE=1.1 , and (c) the difference between D RBE and D RBE=1.1 (ΔD), assessing the balanced accuracy. The potential to reduce RBE-induced NTCP through track-end and linear energy transfer (LET) optimization was evaluated in six example patients. Using a variable RBE instead of a constant one resulted in NTCP increases (up to 32 percentage points). Variable-RBE-induced NTCP increases were strongly negatively correlated with the distance between the clinical target volume (CTV) and the organ at risk (OAR) for most side-effects, and positively correlated with CTV volume for certain side-effects. High increases were associated with (a) specific patient factors, particularly the proximity of the CTV to OARs, (b) D RBE=1.1 , and (c) ΔD, with a balanced accuracy of 0.88, 0.94, and 0.86, respectively. Optimization of track-ends and LET considerably reduced NTCP values, achieving a mean reduction of 31 % for optimized OARs. The risk of variable-RBE-induced NTCP strongly depends on patient-specific factors and the considered side-effect. A small distance between the tumor and OARs notably increases the risk. Integrating biologically-guided objectives into treatment planning can effectively mitigate the risk. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) is an integral component of potentially curative management of esophageal cancer (EC). However, RT can cause significant acute and late morbidity due to excess radiation exposure to nearby critical organs, especially the heart and lungs. Sparing these organs from both low and high radiation dose has been demonstrated to achieve clinically meaningful reductions in toxicity and may improve long-term survival. Accruing dosimetry and clinical evidence support the consideration of proton beam therapy (PBT) for the management of EC. There are critical treatment planning and delivery uncertainties that should be considered when treating EC with PBT, especially as there may be substantial motion-related interplay effects. The Particle Therapy Co-operative Group Thoracic and Gastrointestinal Subcommittees jointly developed guidelines regarding patient selection, treatment planning, clinical trials, and future directions of PBT for EC.

Radiation therapy (RT) is an integral component of potentially curative management of esophageal cancer (EC). However, RT can cause significant acute and late morbidity due to excess radiation exposure to nearby critical organs, especially the heart and lungs. Sparing these organs from both low and high radiation dose has been demonstrated to achieve clinically meaningful reductions in toxicity and may improve long-term survival. Accruing dosimetry and clinical evidence support the consideration of proton beam therapy (PBT) for the management of EC. There are critical treatment planning and delivery uncertainties that should be considered when treating EC with PBT, especially as there may be substantial motion-related interplay effects. The Particle Therapy Co-operative Group Thoracic and Gastrointestinal Subcommittees jointly developed guidelines regarding patient selection, treatment planning, clinical trials, and future directions of PBT for EC. [ABSTRACT FROM AUTHOR]

ObjectiveRadiotherapy (RT) is an integral part of the interdisciplinary treatment of patients with high-risk neuroblastoma (NB). With the continuous improvements of outcome, the interest in local treatment strategies that reduce treatment-related side effects while achieving optimal oncological results is growing. Proton beam therapy (PBT) represents a promising alternative to conventional photon irradiation with regard to the reduction of treatment burden.MethodRetrospective analysis of children with high or intermediate risk NB receiving PBT of the primary tumor site during first-line therapy between 2015 and 2020 was performed. Data from the prospective in-house registry Standard Protonentherapie WPE – Kinder- (KiProReg) with respect to tumor control and treatment toxicity were analyzed. Adverse events were classified according to CTCAE Version 4 (V4.0) before, during, and after PBT.ResultsIn total, 44 patients (24 male, 20 female) with high (n = 39) or intermediate risk NB (n = 5) were included in the analysis. Median age was 3.4 years (range, 1.4–9.9 years). PBT doses ranged from 21.0 to 39.6 Gray (Gy) (median 36.0 Gy). Five patients received PBT to the MIBG-avid residual at the primary tumor site at time of PBT according to the NB-2004 protocol. In 39 patients radiation was given to the pre-operative tumor bed with or without an additional boost in case of residual tumor. After a median follow-up (FU) of 27.6 months, eight patients developed progression, either local recurrence (n = 1) or distant metastases (n = 7). Four patients died due to tumor progression. At three years, the estimated local control, distant metastatic free survival, progression free survival, and overall survival was 97.7, 84.1, 81.8, and 90.9%, respectively. During radiation, seven patients experienced higher-grade (CTCAE ≥ °3) hematologic toxicity. No other higher grade acute toxicity occurred. After PBT, one patient developed transient myelitis while receiving immunotherapy. No higher grade long-term toxicity was observed up to date.ConclusionPBT was a well tolerated and effective local treatment in children with high and intermediate risk NB. The role of RT in an intensive multidisciplinary treatment regimen remains to be studied in the future in order to better define timing, doses, target volumes, and general need for RT in a particularly sensitive cohort of patients.

Background: Radiobiological model-based studies of photon-modulated radiotherapy for pancreatic cancer have reported reduced gastrointestinal (GI) toxicity, although the risk is still high. The purpose of this study was to investigate the potential of 3D-passive scattering proton beam therapy (3D-PSPBT) in limiting GI organ at risk (OAR) toxicity in localized pancreatic cancer based on dosimetric data and the normal tissue complication probability (NTCP) model.Methods: The data of 24 pancreatic cancer patients were retrospectively analyzed, and these patients were planned with intensity-modulated radiotherapy (IMRT), volume-modulated arc therapy (VMAT), and 3D-PSPBT. The tumor was targeted without elective nodal coverage. All generated plans consisted of a 50.4-GyE (Gray equivalent) dose in 28 fractions with equivalent OAR constraints, and they were normalized to cover 50% of the planning treatment volume (PTV) with 100% of the prescription dose. Physical dose distributions were evaluated. GI-OAR toxicity risk for different endpoints was estimated by using published NTCP Lyman–Kutcher–Burman (LKB) models. Analysis of variance (ANOVA) was performed to compare the dosimetric data, and ΔNTCPIMRT−PSPBT and ΔNTCPVMAT−PSPBT were also computed.Results: Similar homogeneity and conformity for the clinical target volume (CTV) and PTV were exhibited by all three planning techniques (P > 0.05). 3D-PSPBT resulted in a significant dose reduction for GI-OARs in both the low-intermediate dose range (below 30 GyE) and the highest dose region (Dmax and V50 GyE) in comparison with IMRT and VMAT (P < 0.05). Based on the NTCP evaluation, the NTCP reduction for GI-OARs by 3D-PSPBT was minimal in comparison with IMRT and VMAT.Conclusion: 3D-PSPBT results in minimal NTCP reduction and has less potential to substantially reduce the toxicity risk of upper GI bleeding, ulceration, obstruction, and perforation endpoints compared to IMRT and VMAT. 3D-PSPBT may have the potential to reduce acute dose-limiting toxicity in the form of nausea, vomiting, and diarrhea by reducing the GI-OAR treated volume in the low-to-intermediate dose range. However, this result needs to be further evaluated in future clinical studies.

The “Laser-hybrid Accelerator for Radiobiological Applications,” LhARA, is conceived as a novel, flexible facility dedicated to the study of radiobiology. The technologies demonstrated in LhARA, which have wide application, will be developed to allow particle-beam therapy to be delivered in a new regimen, combining a variety of ion species in a single treatment fraction and exploiting ultra-high dose rates. LhARA will be a hybrid accelerator system in which laser interactions drive the creation of a large flux of protons or light ions that are captured using a plasma (Gabor) lens and formed into a beam. The laser-driven source allows protons and ions to be captured at energies significantly above those that pertain in conventional facilities, thus evading the current space-charge limit on the instantaneous dose rate that can be delivered. The laser-hybrid approach, therefore, will allow the radiobiology that determines the response of tissue to ionizing radiation to be studied with protons and light ions using a wide variety of time structures, spectral distributions, and spatial configurations at instantaneous dose rates up to and significantly beyond the ultra-high dose-rate “FLASH” regime. It is proposed that LhARA be developed in two stages. In the first stage, a programme of in vitro radiobiology will be served with proton beams with energies between 10 and 15 MeV. In stage two, the beam will be accelerated using a fixed-field alternating-gradient accelerator (FFA). This will allow experiments to be carried out in vitro and in vivo with proton beam energies of up to 127 MeV. In addition, ion beams with energies up to 33.4 MeV per nucleon will be available for in vitro and in vivo experiments. This paper presents the conceptual design for LhARA and the R&D programme by which the LhARA consortium seeks to establish the facility.

Objective: Radiotherapy (RT) is an integral part of the interdisciplinary treatment of patients with high-risk neuroblastoma (NB). With the continuous improvements of outcome, the interest in local treatment strategies that reduce treatment-related side effects while achieving optimal oncological results is growing. Proton beam therapy (PBT) represents a promising alternative to conventional photon irradiation with regard to the reduction of treatment burden. Method: Retrospective analysis of children with high or intermediate risk NB receiving PBT of the primary tumor site during first-line therapy between 2015 and 2020 was performed. Data from the prospective in-house registry Standard Protonentherapie WPE – Kinder- (KiProReg) with respect to tumor control and treatment toxicity were analyzed. Adverse events were classified according to CTCAE Version 4 (V4.0) before, during, and after PBT. Results: In total, 44 patients (24 male, 20 female) with high (n = 39) or intermediate risk NB (n = 5) were included in the analysis. Median age was 3.4 years (range, 1.4–9.9 years). PBT doses ranged from 21.0 to 39.6 Gray (Gy) (median 36.0 Gy). Five patients received PBT to the MIBG-avid residual at the primary tumor site at time of PBT according to the NB-2004 protocol. In 39 patients radiation was given to the pre-operative tumor bed with or without an additional boost in case of residual tumor. After a median follow-up (FU) of 27.6 months, eight patients developed progression, either local recurrence (n = 1) or distant metastases (n = 7). Four patients died due to tumor progression. At three years, the estimated local control, distant metastatic free survival, progression free survival, and overall survival was 97.7, 84.1, 81.8, and 90.9%, respectively. During radiation, seven patients experienced higher-grade (CTCAE ≥ °3) hematologic toxicity. No other higher grade acute toxicity occurred. After PBT, one patient developed transient myelitis while receiving immunotherapy. No higher grade long-term toxicity was observed up to date. Conclusion: PBT was a well tolerated and effective local treatment in children with high and intermediate risk NB. The role of RT in an intensive multidisciplinary treatment regimen remains to be studied in the future in order to better define timing, doses, target volumes, and general need for RT in a particularly sensitive cohort of patients. [ABSTRACT FROM AUTHOR]

Background: Radiobiological model-based studies of photon-modulated radiotherapy for pancreatic cancer have reported reduced gastrointestinal (GI) toxicity, although the risk is still high. The purpose of this study was to investigate the potential of 3D-passive scattering proton beam therapy (3D-PSPBT) in limiting GI organ at risk (OAR) toxicity in localized pancreatic cancer based on dosimetric data and the normal tissue complication probability (NTCP) model. Methods: The data of 24 pancreatic cancer patients were retrospectively analyzed, and these patients were planned with intensity-modulated radiotherapy (IMRT), volume-modulated arc therapy (VMAT), and 3D-PSPBT. The tumor was targeted without elective nodal coverage. All generated plans consisted of a 50.4-GyE (Gray equivalent) dose in 28 fractions with equivalent OAR constraints, and they were normalized to cover 50% of the planning treatment volume (PTV) with 100% of the prescription dose. Physical dose distributions were evaluated. GI-OAR toxicity risk for different endpoints was estimated by using published NTCP Lyman–Kutcher–Burman (LKB) models. Analysis of variance (ANOVA) was performed to compare the dosimetric data, and ΔNTCPIMRT−PSPBT and ΔNTCPVMAT−PSPBT were also computed. Results: Similar homogeneity and conformity for the clinical target volume (CTV) and PTV were exhibited by all three planning techniques (P > 0.05). 3D-PSPBT resulted in a significant dose reduction for GI-OARs in both the low-intermediate dose range (below 30 GyE) and the highest dose region (D max and V 50 GyE) in comparison with IMRT and VMAT (P < 0.05). Based on the NTCP evaluation, the NTCP reduction for GI-OARs by 3D-PSPBT was minimal in comparison with IMRT and VMAT. Conclusion: 3D-PSPBT results in minimal NTCP reduction and has less potential to substantially reduce the toxicity risk of upper GI bleeding, ulceration, obstruction, and perforation endpoints compared to IMRT and VMAT. 3D-PSPBT may have the potential to reduce acute dose-limiting toxicity in the form of nausea, vomiting, and diarrhea by reducing the GI-OAR treated volume in the low-to-intermediate dose range. However, this result needs to be further evaluated in future clinical studies. [ABSTRACT FROM AUTHOR]

Purpose of Review: Proton beam therapy (PBT) allows for improved sparing of surrounding normal tissues compared with X-ray-based radiation therapy. This is especially important in the setting of liver malignancies, where an increase in integral dose leads to a higher risk of radiation-induced liver disease (RILD) as well as close proximity to vital gastrointestinal (GI) organs. Recent Findings: We have data from multiple centers demonstrating that PBT can safely deliver high, ablative doses of radiation therapy conferring excellent local control with good tolerance of treatment. Summary: PBT is an effective treatment with longstanding evidence of efficacy that is increasing in availability. [ABSTRACT FROM AUTHOR]

A 27-year-old woman was admitted to our hospital due to a liver tumor. She had been born late at 41 weeks of gestation and had heterotaxy syndrome, polysplenia, and complete transposition of the great arteries. She underwent percutaneous balloon angioplasty at 5 years of age and the Fontan procedure at 6 years of age. At 25 years of age, computed tomography detected liver congestion. Her alpha-fetoprotein level increased from 13 to 2098 ng/dL (L3 fraction 1.8%) at 27 years of age. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging showed a 22-mm liver tumor in the second liver segment. The liver tumor was enhanced in the arterial phase and washed-out in the hepatobiliary phase; the patient was, therefore, diagnosed with hepatocellular carcinoma. Radiofrequency ablation and surgery were not indicated due to the proximity of the tumor to the inferior vena cava. Therefore, proton beam therapy was selected as conservative therapy, and a dose of 74 Gray equivalents in 37 fractions was administered at the University of Tsukuba Hospital. There were no severe adverse events and she survived for 38 months after treatment without recurrence. [ABSTRACT FROM AUTHOR]

Abstract Aim To assess the feasibility of transferring to the University of Tsukuba Hospital for proton beam therapy (PBT) during intensive chemotherapy in children with Ewing sarcoma family of tumors (ESFT) who had been diagnosed and started their first-line treatment at prefectural or regional centers for pediatric oncology. Background The treatment of ESFT relies on a multidisciplinary approach using intensive neoadjuvant and adjuvant chemotherapies with surgery and radiotherapy. Multi-agent chemotherapy comprising vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC-IE) is widely used for ESFT, and the interval between each course is very important for maintaining the intensity and effect of chemotherapy. Materials and methods Clinical information of patients who received PBT and VDC-IE between April 2009 and May 2016 was collected retrospectively. The intervals between each course of VDC-IE and adverse events were assessed. Results Fifteen patients were evaluated. No delays in the intervals of chemotherapy due to transfer were observed. There were no adverse events caused during/just after transfer and no increases in adverse events. The estimated 4-year overall and event-free survival rates were 94.6% and 84.8%, respectively. Discussion Although the results of efficacy are preliminary, survival rates were comparable with past studies. More experience and follow-up are required to further assess the efficacy of PBT for patients with ESFT. Conclusion Multidisciplinary therapy for children with ESFT involving transfer to our hospital for PBT during VDC-IE was feasible without treatment delay or an increase in adverse events. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cancer cause of death in the United States. Radiotherapy is an essential component of the definitive treatment of early-stage and locally-advanced lung cancer, and the palliative treatment of metastatic lung cancer. Proton beam therapy (PBT), through its characteristic Bragg peak, has the potential to decrease the toxicity of radiotherapy, and, subsequently improve the therapeutic ratio. Herein, we provide a primer on the physics of proton beam therapy for lung cancer, present the existing data in early-stage and locally-advanced non-small cell lung cancer (NSCLC), as well as in special situations such as re-irradiation and post-operative radiation therapy. We then present the technical challenges, such as anatomic changes and motion management, and future directions for PBT in lung cancer, including pencil beam scanning. [ABSTRACT FROM AUTHOR]

We assessed the development of lymphopenia during concurrent chemoradiotherapy (CRT) using X-ray versus proton beams and the impact on survival in patients with esophageal cancer. Among patients with esophageal cancer who were administered concurrent CRT with a curative intent at our institute from 2014 to 2018, 69 (15 receiving X-ray radiotherapy (XRT) and 54 receiving proton beam therapy [PBT]) who underwent weekly blood testing during treatment were enrolled. The absolute lymphocyte counts (ALC) at 1, 5 and 6 weeks were significantly higher in the patients who received PBT than in those who received XRT (p = 0.002, p = 0.006 and p = 0.009, respectively), and a similar trend in the neutrophil-to-lymphocyte ratio (NLR) was observed (p = 0.003 at 5 weeks). The 2-year overall survival (OS) and progression-free survival (PFS) rates tended to be higher in the patients who maintained an ALC ≥200 compared with those who did not (p = 0.083 and p = 0.053, respectively), and similar trends were observed in the NLR (p = 0.061 and p = 0.038, respectively). Dose-volume analysis revealed significant correlations between volumes of the thoracic bones irradiated by 5-50 Gy and minimum ALCs and maximum NLR. These findings suggested that PBT prevented the development of lymphopenia during CRT by reducing the irradiated volume of the thoracic bone, and the maintained lymphocyte count is possibly one of the early predictors for survival in patients with esophageal cancer., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The prediction of liver Dmean with 3-dimensional radiation treatment planning (3DRTP) is time consuming in the selection of proton beam therapy (PBT), and deep learning prediction generally requires large and tumor-specific databases. We developed a simple dose prediction tool (SDP) using deep learning and a novel contour-based data augmentation (CDA) approach and assessed its usability. We trained the SDP to predict the liver Dmean immediately. Five and two computed tomography (CT) data sets of actual patients with liver cancer were used for the training and validation. Data augmentation was performed by artificially embedding 199 contours of virtual clinical target volume (CTV) into CT images for each patient. The data sets of the CTVs and OARs are labeled with liver Dmean for six different treatment plans using two-dimensional calculations assuming all tissue densities as 1.0. The test of the validated model was performed using 10 unlabeled CT data sets of actual patients. Contouring only of the liver and CTV was required as input. The mean relative error (MRE), the mean percentage error (MPE) and regression coefficient between the planned and predicted Dmean was 0.1637, 6.6%, and 0.9455, respectively. The mean time required for the inference of liver Dmean of the six different treatment plans for a patient was 4.47±0.13 seconds. We conclude that the SDP is cost-effective and usable for gross estimation of liver Dmean in the clinic although the accuracy should be improved further if we need the accuracy of liver Dmean to be compatible with 3DRTP., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Hepatocellular carcinoma (HCC) located in the caudate lobe (caudate HCC) is rare; however, patients with this type of tumour have poorer prognoses than those with HCC in other segments. Despite many published reports on the clinical usefulness of proton beam therapy (PBT) for HCC, data on the clinical outcomes of patients undergoing PBT for caudate HCC remain scarce. Therefore, the present study aimed to investigate the outcomes of this group of patients. Thirty patients with caudate HCC who underwent definitive PBT between February 2002 and February 2014 were retrospectively analysed. The total irradiation doses ranged from 55 to 77 (median 72.6) Gy relative biological dose. The median follow-up period was 37.5 (range, 3.0-152.0) months. The overall survival (OS) rates at one, three and five years were 86.6%, 62.8% and 46.1%, respectively. According to univariate and multivariate analyses, Child-Pugh A (P < 0.01), having a single tumour (P = 0.02) and a low serum alpha-fetoprotein level (AFP; P < 0.01) were significant factors predicting longer survival. The local control (LC) rates at one, three and five years were 100%, 85.9% and 85.9%, respectively, while the corresponding progression-free survival (PFS) rates were 65%, 27.5% and 22%, respectively. No grade 3 or worse adverse events were observed. PBT is effective and safe for the treatment of caudate HCC, and should therefore be considered a feasible option for intervention in patients with this disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Although lung cancer rates are decreasing nationally, lung cancer remains the leading cause of cancer related death. Despite advancements in treatment and technology, overall survival (OS) for lung cancer remains poor. Proton beam therapy (PBT) is an advanced radiation therapy (RT) modality for treatment of lung cancer with the potential to achieve dose escalation to tumor while sparing critical structures due to higher target conformality. In early and late-stage non-small cell lung cancer (NSCLC), dosimetric studies demonstrated reduced doses to organs at risk (OARs) such as the lung, spinal cord, and heart, and clinical studies report limited toxicities with PBT, including hypofractionated regimens. In limited-stage SCLC, studies showed that regimens chemo RT including PBT were well tolerated, which may help optimize clinical outcomes. Improved toxicity profiles may be beneficial in post-operative radiotherapy, for which initial dosimetric and clinical data are encouraging. Sparing of OARs may also increase the proportion of patients able to complete reirradiation for recurrent disease. However, there are various challenges of using PBT including a higher financial burden on healthcare and limited data supporting its cost-effectiveness. Further studies are needed to identify subgroups that benefit from PBT based on prognostic factors, and to evaluate PBT combined with immunotherapy, in order to elucidate the benefit that PBT may offer future lung cancer patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-2501). TTS reports that he provides strategic and scientific recommendations as a member of the Advisory Board and speaker for Novocure, Inc., which is not in any way associated with the content or disease site as presented in this manuscript. SES reports that he writes and edits for UpToDate on various subjects related to radiation oncology. The other authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

The majority of esophageal cancer patients are diagnosed with locoregionally confined disease, which is often amenable to curative intent therapy. Chemoradiotherapy (CRT) improves overall survival (OS) in stage II and III esophagus cancer in the neoadjuvant and definitive settings. Due to the close proximity of organs at risk (OARs), including lungs, heart, stomach, bowel, kidneys, and spinal cord, esophageal CRT can result in profound acute and late toxicities. Acute toxicities can include esophagitis, nausea, vomiting, fatigue, and cytopenias. Late complications may also occur months or years after completion of thoracic radiotherapy, including significant cardiac, pulmonary, liver, kidney, or bowel toxicities, which can be life-threatening or fatal. Photon-based radiotherapy exposes OARs to significant doses of radiation, whereas proton beam therapy (PBT) has unique physical properties, as it lacks an exit dose. This allows PBT to deliver, a more conformal dose to the target and minimize the volume of OARs exposed to radiation. This dosimetric advantage may portend an increased therapeutic ratio of CRT for esophagus cancer. The objective of this review is to discuss the evolution of photon and proton-based radiotherapy techniques, rationale, dosimetric and clinical studies comparing outcomes of photon- and proton-based techniques, ongoing prospective trials, and future directions of PBT as a means of reducing toxicity and improving oncologic outcomes for patients with esophagus cancer., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: http://dx.doi.org/10.21037/jtd-2019-cptn-06). The series “Contemporary Practice in Thoracic Neoplasm Diagnosis, Evaluation and Treatment” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Proton beam therapy (PBT) delivers less dose to nearby normal organs compared to X-ray therapy (XRT), which is particularly relevant for treating liver cancers given that both mean and low liver dose are among the most significant predictors of radiation induced liver disease (RILD). High-dose PBT has been shown to achieve excellent long-term tumor control with minimal toxicity in hepatocellular carcinoma (HCC) patients. Increasing data support ablative PBT for patients with unresectable cholangiocarcinoma or liver metastases, especially those with larger tumors not suitable for XRT., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Journal of Gastrointestinal Oncology. All rights reserved.)

Despite the conformality of modern X-ray therapy limiting high dose received by normal tissues the physical properties of X-rays make it impossible to avoid dose being delivered distal to the target. This "exit dose" is likely clinically significant especially for patients with gastrointestinal (GI) cancers when considering that even low dose received by the heart, lungs, bowel, and other radiosensitive structures can lead to morbidity and even may affect long-term tumor control. In contrast, proton beam therapy (PBT) delivers no "exit dose" and a growing body of literature suggests that this may improve clinical outcomes by reducing toxicity and even allowing for safe dose intensification to enhance tumor control. While there are not yet robust prospective data demonstrating the role of PBT for GI cancers, emerging retrospective data provide a strong rationale for continued study of how PBT may improve the therapeutic ratio for these patients. Here we review these data as well as discuss ongoing clinical trials of PBT for GI cancers., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The role of radiation therapy (RT) in thymic malignancies has long been subject to considerable controversy. The main role for RT is in the setting of adjuvant therapy after surgical tumor resection, especially in advanced or incompletely resected cases. However, recent studies with larger patient numbers and cleaner study populations than previous studies have indicated a potentially clearer than previously assumed benefit after post-operative RT (PORT) even for completely resected patients with earlier stages of thymoma. In marginally resectable patients RT may be used in combination with neoadjuvant chemotherapy to shrink tumors and thereby potentially enable resection. In unresectable patients concurrent or sequential chemotherapy and RT can be employed as the definitive nonsurgical approach. The tendency of thymic tumors to recur in the pleural space highlights the necessity for more effective approaches to identify and treat high risk patients. Experiences in other pleural malignancies may pave the way to novel treatment modalities, for example pleural IMRT. The role of these techniques in thymic malignancies has yet to be determined and is not advisable at the current time outside of a clinical study. As the disease often takes an indolent course with excellent long-term local control (LC) and survival, late toxicities related to radiation of the mediastinum and adjacent organs at risk (OARs) have to be taken into consideration and may jeopardize the benefit patients experience from RT, especially in younger patients with a long-anticipated life expectancy. Radiation techniques, such as intensity modulated RT (IMRT) and proton beam therapy (PBT), have substantially reduced the exposure of OARs to ionizing radiation which is expected to translate into reduced long-term toxicities. Hence, the risk-benefit ratio of RT in early stage thymoma patients may be shifted favorably., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Locoregional failure in non-small cell lung cancer (NSCLC) remains high, and the management for recurrent disease in the setting of prior radiotherapy is difficult. Retreatment options such as surgery or systemic therapy are typically limited or frequently result in suboptimal outcomes. Reirradiation (reRT) of thoracic malignancies may be an optimal strategy for providing definitive local control and offering a new chance of cure. Yet, retreatment with radiation therapy can be challenging for fear of excessive toxicities and the inability to safely deliver definitive (≥60 Gy) doses of reRT. However, with recent improvements in radiation delivery techniques and image-guidance, dose-escalation with reRT is possible and outcomes are encouraging. Here, we present a review of various radiation techniques, clinical outcomes and associated toxicities in patients with locoregionally recurrent NSCLC treated primarily with reRT., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Randomized esophageal cancer (EC) trials have utilized two- or three-dimensional conformal radiotherapy (3DCRT). Advanced radiotherapy (RT) techniques [(ARTs): intensity-modulated radiotherapy (IMRT) and proton beam therapy (PBT)] may have benefits, but are relatively unproven. This is the first study to date evaluating utilization of ARTs versus 3DCRT in the trimodality setting in the United States., Methods: The National Cancer Data Base (NCDB) was queried (2004-2013) for newly-diagnosed cT1b-T4bN0/N+M0 EC receiving neoadjuvant CRT followed by esophagectomy. The primary objective was to assess temporal trends, with multivariable logistic regression analysis assessing factors predictive of receiving ARTs. Secondarily, Kaplan-Meier analysis evaluated overall survival (OS), Cox proportional hazards modeling determined variables associated with OS, and postoperative complications were compared between cohorts., Results: Altogether, 3,138 patients met criteria; 1,398 (45%) received 3DCRT, and 1,740 (55%) received ARTs (99% IMRT, 1% PBT). Temporally, utilization of ARTs is steadily rising in the United States, from 20% in 2004 to 69% in 2013, corresponding with a progressive decrease in utilization of 3DCRT. ARTs were more often delivered with advancing age, squamous cell histology, N2+ disease, and at academic centers (P<0.05 for all). Centers in the Southwest were more likely to use ARTs, and those in the Midwest least likely (P<0.05 for both). As expected, there were no OS differences (P=0.8477); there were also no differences in postoperative events (P>0.05 for all). Treatment at an academic center independently correlated with improved OS (P<0.001)., Conclusions: Utilization of ARTs (IMRT in the vast majority) is steadily rising in the United States; 3DCRT is now used in a minority of patients. This has implications for payers and insurance coverage. ART use is impacted by not only age and disease factors, but also regional and facility differences. Treatment at an academic facility independently correlated with higher survival, which has implications for patient counseling., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The prognosis of limited-stage small cell lung cancer (LS-SCLC) continues to improve and is now roughly comparable to that of locally advanced non-small cell lung cancer (NSCLC). This shift, taken together with the decreased toxicities of modern radiotherapy (RT) for LS-SCLC compared with those reported in historical trials, necessitates further evaluation of whether proton beam therapy (PBT) could further reduce both acute and late toxicities for patients receiving concurrent chemoradiotherapy for LS-SCLC. These notions are discussed theoretically, with an emphasis on cardiac events. This is followed by a review of the published evidence to date demonstrating improved dosimetry with PBT over intensity-modulated RT and encouraging safety and efficacy profiles seen in early clinical reports. In addition to covering technical aspects of PBT for LS-SCLC such as intensity-modulated PBT, image-guidance for PBT, and adaptive planning, this review also discusses the need for increased data on intensity-modulated PBT for LS-SCLC, economic and quality of life analyses for future PBT SCLC studies, careful categorization of cardiac events in these patients, and the role for immunotherapy combined with photon- or proton-based RT for LS-SCLC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Intrahepatic cholangiocarcinoma (ICC) is one of the few gastrointestinal cancers with increasing incidence and mortality worldwide. Unlike hepatocellular carcinoma (HCC) which arises usually in a cirrhotic environment ICC frequently arises in the context of normal hepatic parenchyma. Surgical resection represents the mainstay of curative treatment, with minimally invasive approaches being increasingly utilized. Despite good surgical outcomes, most patients suffer from disease recurrence and eventually succumb to their disease. Effective adjuvant treatments are therefore needed. For unresectable disease hepatic artery utilization techniques are becoming more widely used. New treatments for non metastatic disease such as proton beam therapy (PBT) are also emerging. Systemic chemotherapy is also changing and targeted biologic agents are being added to conventional chemotherapeutic agents.

Local tumor control remains challenging in many cases of non-small cell lung cancer (NSCLC), particularly those that involve large or centrally located tumors. Concurrent chemotherapy and radiation can maximize tumor control and survival for patients with locally advanced disease, but a substantial proportion of such patients cannot tolerate this therapy, and sequential chemoradiation regimens or radiation given alone at conventionally fractionated doses produces suboptimal results. An alternative approach is the use of hypofractionated proton beam therapy (PBT). The energy distribution of protons can be exploited to reduce involuntary irradiation of normal tissues, particularly the low-dose irradiation problematic in intensity-modulated (photon) radiation therapy (IMRT). Here we summarize current evidence on the use of hypofractionated PBT for both early-stage and locally advanced NSCLC, and the possibility of using hypofractionated regimens for patients who are not candidates for concurrent chemotherapy.