Conventional Photon Radiotherapy Research Articles

Risk of Secondary Malignant Neoplasms in Children Following Proton Therapy vs. Photon Therapy for Primary CNS Tumors

<h3>Purpose/Objective(s)</h3> Central nervous system tumors are the second most common primary neoplasms seen in children and radiation therapy is a key component in management of most of these tumors. Secondary malignant neoplasms (SMNs) are rare but dreaded complications, particularly in the pediatric population. Proton beam therapy (PBT) can potentially minimize the risk of SMNs compared to conventional photon radiation therapy (RT). Multiple recent studies with mature data have reported the risk of SMNs after PBT. We performed this systematic review and meta-analysis to characterize and compare the incidence of SMNs after proton and photon-based radiation for pediatric CNS tumors. <h3>Materials/Methods</h3> A systematic search of literature on electronic (PubMed, Cochrane Central, and Embase) databases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We included studies reporting incidence and nature of SMNs in pediatric patients with primary CNS tumors. The crude incidence of SMNs and all secondary neoplasms were separately extracted, the random-effects model was used for pooled analysis and subgroup comparison was performed between studies using photons vs protons. <h3>Results</h3> Twenty-four studies (21 with conventional RT and 4 with PBT) were included for meta-analysis after performing the systematic review. A total of 418 SMNs and 645 any secondary neoplasms were seen in 38163 patients overall. The most common secondary neoplasms seen were gliomas (40.6%) followed by meningiomas (38.7%), sarcomas (4.8%), thyroid cancers (4.2%), and basal cell carcinomas (1.3%). The overall median follow-up was 8.8 years (range: 3.3 to 23.2 years), while the median latency to a secondary cancer was 9.8 years (range: 5 to 23 years). The median latency to a secondary cancer for photons and protons was 11.9 years (range: 5 to 23 years) and 5.9 years (range: 5 to 6.7 years), respectively. The pooled incidence of SMNs was 1.8% (95% CI: 1.1% – 2.6%, I²=94%) with photons and 1.5% (95% CI: 0 - 4.5%, I²=81%) with protons. There was no significant difference among the two subgroups (p = 0.91). Similarly, the pooled incidence of all secondary neoplasms was not different among the two subgroups [photons: 3.6% (95% CI: 2.5% – 4.8%, I²=96%) vs protons: 1.5% (95% CI: 0 – 4.5%, I²=80%); p = 0.21]. <h3>Conclusion</h3> We observed a slightly lower rate of SMN with PBT at 1.5% compared to 1.8% with photon-based RT for pediatric CNS tumors, although the difference was not statistically significant. We observed a shorter latency to secondary cancers with proton therapy compared to photon-based radiation, which may be related to secondary neutron exposure. With increasing use of techniques that decrease the irradiated tissue volume outside the clinical target volume, like pencil beam scanning proton therapy and VMAT, further studies with longer follow-up are warranted to evaluate the risk of secondary cancers in patients treated with these newer modalities.

Trends and Predictors of Proton Therapy Utilization in Early-Stage Hodgkin Lymphoma: A National Cancer Database Analysis

<h3>Purpose/Objective(s)</h3> Early stage (ES) Hodgkin Lymphoma (HL) is a highly curable malignancy for which consolidative radiotherapy (RT) is often recommended. HL frequently affects young adults, who are at elevated risk of late RT toxicity. Proton therapy (PT), which can offer a more optimal integral dose distribution compared to conventional photon radiotherapy (XRT), is often pursued in this population when available. We aimed to report trends in PT utilization using the National Cancer Database (NCDB) over a period of increasing modality availability. <h3>Materials/Methods</h3> The NCDB was used to identify adult patients with stage I or II classical HL treated with multiagent chemotherapy and consolidative RT (XRT or PT) between 2004 and 2018. PT utilization was analyzed over time using Pearson's Chi-squared test, with confidence intervals (CI) around the annual percentage of patients treated with PT calculated using the Clopper-Pearson method. Predictors of PT utilization were determined using Chi-squared tests and multivariable logistic regression. <h3>Results</h3> From 2004 to 2018, 14,344 patients met inclusion criteria, of which 51.5% were male, 86.5% were white, and the median age was 36 years old (ranging from 18 to 90 with most patients (59.4%) within the category of 18 to 40 years old). Only 198 (1.4%) patients received PT. The most common histologies were nodular sclerosing (78%) and mixed cellularity (13%). Of those with adequately coded data: the most common total RT doses (cGy) were 3060 (28%), 3000 (18%), 3600 (14%), and 2000 (10%); 56% were treated with IMRT vs 3D conformal RT (44%); RT site included head and neck in 50% and thorax in 44%, and 70% had RT at nonacademic centers distributed throughout the US (south 25%, northeast 24%, midwest 34%, west 17%). From 2004 to 2018, the percentage of PT receipt increased from 1% (n=9, 95% CI 0-1%) to 4% (n=34, 95% CI 3-6%), with an inflection point at 2012. From 2004 to 2012 an average of 3.8 patients were treated with PT per year, whereas from 2013 to 2018 the average was 27.3 per year (p < 0.001). Of those receiving PT, 79% were 18-40 years ole while the oldest was 78, and 58% were female. On univariable analysis, receipt of PT was associated with younger age (p<0.001), female gender (p=0.01), private insurance (p<0.001), Medicaid (p<0.001), and above median income quartile by zip code (MIQBZ) (p=0.003). Charlson-Comorbidity Index score 0 (vs. ≥1; p=0.10) trended towards significance in predicting PT and was included in the multivariable model. Variables remaining significant for predicting PT receipt on multivariable logistic regression included age ≤ 40 (OR 2.1, CI 1.4-3.0, p<0.001), above MIQBZ (OR 1.6, CI 1.1-2.2, p=0.01), and female gender (OR 1.5, CI 1.1-2.0, p=0.01). <h3>Conclusion</h3> PT utilization in ES HL patients has gradually but significantly increased since 2004, with an inflection point at 2013. Female patients under 40 with above MIQBZ are most likely to be receiving PT.

Carbon ion irradiation plus CTLA4 blockade elicits therapeutic immune responses in a murine tumor model

Radiotherapy can act as an in situ vaccine, activating preventive tumor-specific immune responses in patients. Although carbon ion radiotherapy has superior biophysical properties over conventional photon irradiation, the immunological effects induced by this radiation type are poorly understood. Multiple strategies combining radiotherapy with immune checkpoint inhibition (radioimmunotherapy) to enhance antitumor immunity have been described; however, immune cell composition in tumors following radioimmunotherapy with carbon ions remains poorly explored. We developed a bilateral tumor model based on time-shifted subcutaneous injection of murine Her2+ EO771 tumor cells into immune-competent mice followed by selective irradiation of the primary tumor. αCTLA4-, but not αPD-L1-based radioimmunotherapy, induced complete tumor rejection and mediated the eradication of even non-irradiated, distant tumors. Cured mice were protected against the EO771 rechallenge, indicating long-lasting, tumor-specific immunological memory. Single-cell RNA sequencing and flow cytometric analyses of irradiated tumors revealed activation of NK cells and distinct tumor-associated macrophage clusters with upregulated expression of TNF and IL1 responsive genes. Distant tumors in the irradiated mice showed higher frequencies of naïve T cells activated upon the combination with CTLA4 blockade. Thus, radioimmunotherapy with carbon ions plus CTLA4 inhibition reshapes the tumor-infiltrating immune cell composition and can induce complete rejection even of non-irradiated tumors. Our data suggest combining radiotherapy approaches with CTLA4 blockade to achieve durable antitumor immunity. Evaluation of future radioimmunotherapy approaches should not be restricted to immunological impact at the irradiation site but should also consider systemic immunological effects on non-irradiated tumors.

P01.07.A Neurocognitive outcomes after proton beam therapy for skull base tumours

Abstract Background Evidence suggests that Proton Beam Therapy (PBT) may lessen the risk of neurocognitive decline (NCD) by reducing the dose to the normal brain as compared to conventional photon radiotherapy (XRT). We report the incidence of moderate-severe (Grade ≥3) NCD in adults treated for skull base chordomas and chondrosarcomas within the United Kingdom’s Proton Overseas Programme (POP). Material and Methods Baseline (pre-PBT) and follow-up clinical outcomes data were prospectively collected as part of a national PBT-outcomes registry, which started in 2008 . This registry is curated by a dedicated Proton Clinical Outcomes Unit. Specifically, late toxicities ≥G3 as per CTCAE (Common Terminology Criteria for Adverse Events) v4.0 definition, occurring later than 90 days after treatment completion, were recorded. This study focuses on the incidence of memory impairment (MI) in the adult (≥25 y) cohort. Results Between 2008-2018, 141 adult patients were treated for skull base chordomas (77 patients, 54.6%) and chondrosarcomas (64 patients, 45.4%) via the POP (the majority -62.8%- treated at the University of Florida PBT Institute). Median age at treatment was 51 years (range 26-77). Median prescription dose was 73.8 GyRBE (70-75.6), with a median dose per fraction of 1.8 Gy (1.2-2.1). Of note, the median dose for chondrosarcomas was 70.2 GyRBE (70-75.6), whereas the median dose for chordomas was 73.8 GyRBE (72-75.6). Median follow up was 39 months (0-138). On clinical assessment, 4 patients (2 chordomas, 2 chondrosarcomas) were reported with G3 MI after a median time of 43 months (27-49). None of them had impaired memory at baseline, nor relevant neurological comorbidities. Median age of those who developed G3 MI was 63 y (39-70). Median prescription dose was 72.9 GyRBE (70-73.8). Plans were available for 3 of these 4 patients. Relevant dose statistics to hippocampi and temporal lobes were extracted. Dmean to the omo- and contralateral hippocampi in these 3 patient plans were: patient 1) 33.7 and 11.6 GyRBE; patient 2) 28.1 and 24.4 Gy; patient 3) 8.7 and 8.2 GyRBE, respectively. V20 to the omo- and contralateral temporal lobes in the same patients were: patient 1) 47% and 10%; patient 2) 29% and 28.7%; patient 3) 30% and 28%, respectively. Suggested constraints for these structures are: Dmean &amp;lt; 20 Gy to the hippocampi and V20Gy &amp;lt;10% to the temporal lobes. Conclusion Our results indicate that adult patients undergoing high dose radiation for radioresistant tumours may experience detrimental effects on memory. Neurocognitive baseline and follow-up assessment is not routinely performed in this age group but might be appropriate to explore which domains of cognitive function are mainly affected. Larger cohorts are warranted to establish predictive factors and better understand dose volume effect of brain structures and neurocognitive sequelae.

Serial Measurement of Global Longitudinal Strain Among Women With Breast Cancer Treated With Proton Radiation Therapy: A Prospective Trial for 70 Patients

Conventional photon radiation therapy (RT) for breast cancer is associated with a reduction in global longitudinal strain (GLS) and an increase in troponin, N-terminal pro hormone B-type natriuretic peptide (NT-proBNP), and incident heart failure. The cardiac radiation exposure with proton-RT is much reduced and thus may be associated with less cardiotoxicity. The objective was to test the effect of proton-RT on GLS, troponin, and NT-proBNP. We conducted a prospective, observational, single-center study of 70 women being treated with proton-RT for breast cancer. Serial measurements of GLS, high-sensitivity troponin I, and NT-proBNP were performed at prespecified intervals (before proton-RT, 4 weeks after completion of proton-RT, and again at 2 months after proton-RT). The mean age of the patients was 46 ± 11 years, and the mean body mass index was 25.6 ± 5.2 kg/m2; 32% of patients had hypertension, and the mean radiation doses to the heart and the left ventricle (LV) were 0.44 Gy and 0.12 Gy, respectively. There was no change in left ventricular ejection fraction (65 ± 5 vs 66 ± 5 vs 64 ± 4%; P=.15), global GLS (-21.7 ± 2.7 vs -22.7 ± 2.3 vs -22.8 ± 2.1%; P=.24), or segmental GLS from before to after proton-RT. Similarly, there was no change in either high-sensitivity troponin or NT-proBNP with proton-RT. However, in a post hoc subset analysis, women with hypertension had a greater decrease in GLS after proton-RT compared with women without hypertension (-21.3 ± 3.5 vs -24.0 ± 2.4%; P=.006). Proton-RT did not affect LV function and was not associated with an increase in biomarkers. These data support the potential cardiac benefits of proton-RT compared with conventional RT.

Can We Compare the Health-Related Quality of Life of Childhood Cancer Survivors Following Photon and Proton Radiation Therapy? A Systematic Review.

Simple SummaryProton radiation therapy is a radiation oncology innovation expected to produce superior health-related quality of life (HRQoL) outcomes for children with cancer, compared to conventional photon radiation therapy. The review aim is to identify if clinical evidence exists to support the anticipated HRQoL improvements for children receiving proton radiation therapy. HRQoL outcomes of 1986 childhood cancer survivors are described. There is insufficient quality evidence to compare HRQoL outcomes between proton and photon radiation therapy. Therefore, the current state of the literature does not conclude that proton radiation therapy produces superior HRQoL outcomes for childhood cancer survivors. Despite recommendations, no evidence of routine HRQoL assessment using patient-reported outcomes in paediatric radiation oncology are identified. Further rigorous collection and reporting of HRQoL data is essential to improve patient outcomes, and to adequately compare HRQoL between radiation therapy modalities.Paediatric cancer patients have a risk of late side effects after curative treatment. Proton radiation therapy (PRT) has the potential to reduce the incidence and severity of toxicities produced by conventional photon radiation therapy (XRT), which may improve the health-related quality of life (HRQoL) in children. This systematic review aimed to identify the evidence of HRQoL outcomes in childhood cancer survivors following XRT and PRT. Medline, Embase, and Scopus were systematically searched. Thirty studies were analysed, which described outcomes of 1986 childhood cancer survivors. Most studies (n = 24) described outcomes for children with a central nervous system (CNS) tumour, four studies reported outcomes for children with a non-CNS tumour, and two studies combined CNS and non-CNS diagnoses within a single cohort. No studies analysed routine HRQoL collection during paediatric radiation oncology clinical practice. There is insufficient quality evidence to compare HRQoL outcomes between XRT and PRT. Therefore, the current state of the literature does not conclude that PRT produces superior HRQoL outcomes for childhood cancer survivors. Standardised clinical implementation of HRQoL assessment using patient-reported outcomes is recommended to contribute to improvements in clinical care whilst assisting the progression of knowledge comparing XRT and PRT.

Abstract 1289: Systemic immune response of prostate cancer patients to alpha-emitting radiotherapy

Abstract Targeted alpha therapy (TAT) is a type of radiotherapy (RT) that uses alpha-emitting radionuclides. These radionuclides have a natural affinity for areas of bone metastases (i.e., radium-223, Ra-223) or can label specific tumour targets (i.e., prostate-specific membrane antigen). Conventional photon irradiation (i.e., external beam) can activate or suppress immune responses. The resulting immune response is dictated by the release of soluble markers such as cytokines (i.e., IL-6) and damage associated molecular patterns, DAMPs (calreticulin). Less is known about the immune response induced by alpha-emitters. With increased interest in using TAT for cancer patients, it is important to gain a more in depth knowledge regarding the immune response of alpha emitters. Aim: Explore the systemic immune response of prostate cancer (PCa) patients to alpha-emitting RT by studying circulating cytokines, checkpoint molecules, matrix metalloproteinases (MMPs) and DAMPs. Methods: The cohort comprised of 43 patients with metastatic castration-resistant PCa treated with up to six four-weekly injections of the alpha emitter, Ra-223. We measured longitudinal changes in 61 plasma markers using the Luminex assay. The plasma markers included cytokines, checkpoint molecules and DAMPs. Results: Ra-223 induced longitudinal changes in 14 plasma markers over the course of treatment (T2-T6) compared with pre-treatment levels (T1). Most of the observed RT-induced changes occurred after four injections of Ra-223 (T5), where 9 of the 14 plasma markers changed significantly. The table summarises T5 findings (presented as mean concentration, pg/ml; statistical analysis using Wilcoxon matched-pairs signed rank test). Conclusion: Our data demonstrates that alpha-emitting RT induces systemic immune responses that can be measured in the plasma of patients. Given the diverse role of these markers, further study is needed to explore the biological implications of these systemic changes on patient outcome. Changes in plasma markers in patients treated with Ra-223 T1 T5 P value IL-8 6.7±0.9 9.7±1.3 0.0009 IL-2R 293.5±42.9 364.5±69.7 0.0247 IP-10 18.4±2.3 21.8±2.5 0.0243 RANTES 2668.8±173.4 2944.7±164.6 0.0455 BTLA 549.9±153.5 527.7±265.2 0.0319 CD137 49.6±8.9 39.1±13.5 0.0099 Calreticulin 7868±3514.9 9238.4±808.5 0.0386 RAGE 63.9±4.7 52.3±5.1 0.0014 MMP1 66.1±7.5 84.9±12.6 0.0245 Citation Format: Sapna Lunj, Hitesh Mistry, YeePei Song, Kamlesh Patel, Hannah Nightingale, Tim Smith, Peter Hoskin, Catharine West, Ananya Choudhury. Systemic immune response of prostate cancer patients to alpha-emitting radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1289.

Combined proton-photon therapy for non-small cell lung cancer.

PurposeAdvanced non‐small cell lung cancer (NSCLC) is still a challenging indication for conventional photon radiotherapy. Proton therapy has the potential to improve outcomes, but proton treatment slots remain a limited resource despite an increasing number of proton therapy facilities. This work investigates the potential benefits of optimally combined proton–photon therapy delivered using a fixed horizontal proton beam line in combination with a photon Linac, which could increase accessibility to proton therapy for such a patient cohort.Materials and methodsA treatment planning study has been conducted on a patient cohort of seven advanced NSCLC patients. Each patient had a planning computed tomography scan (CT) and multiple repeated CTs from three different days and for different breath‐holds on each day. Treatment plans for combined proton–photon therapy (CPPT) were calculated for individual patients by optimizing the combined cumulative dose on the initial planning CT only (non‐adapted) as well as on each daily CT respectively (adapted). The impact of inter‐fractional changes and/or breath‐hold variability was then assessed on the repeat breath‐hold CTs. Results were compared to plans for IMRT or IMPT alone, as well as against combined treatments assuming a proton gantry. Plan quality was assessed in terms of dosimetric, robustness and NTCP metrics.ResultsCombined treatment plans improved plan quality compared to IMRT treatments, especially in regard to reductions of low and medium doses to organs at risk (OARs), which translated into lower NTCP estimates for three side effects. For most patients, combined treatments achieved results close to IMPT‐only plans. Inter‐fractional changes impact mainly the target coverage of combined and IMPT treatments, while OARs doses were less affected by these changes. With plan adaptation however, target coverage of combined treatments remained high even when taking variability between breath‐holds into account.ConclusionsOptimally combined proton‐photon plans improve treatment plan quality compared to IMRT only, potentially reducing the risk of toxicity while also allowing to potentially increase accessibility to proton therapy for NSCLC patients.

Iron oxide nanoparticle-mediated radiation delivery for glioblastoma treatment

Radiotherapy is a mainstay adjunctive therapy for glioblastoma (GBM). Despite the outcome improvement achieved with radiation, GBM prognosis remains dismal. Here we introduce a tumor-targeted iron oxide nanoparticle (NP) that intensifies the energy transfer of conventional photon radiotherapy on a selective cellular basis. Several NPs were formulated with systematic architectural variation to study and optimize reactive oxygen species (ROS) production. Selected from this screening stage, a biocompatible tumor-targeted NP was tested in vitro using two models of GBM, and then in vivo, using an orthotopic human primary GBM xenograft mouse model. Animals that received intravenous NP before irradiation demonstrated a 3-fold reduction in tumor growth and a 2-fold increase in survival. Cellular damage was investigated using in vivo magnetic resonance spectroscopy, which demonstrated increased therapeutic cytotoxicity specific to the tumor mass. Our work presents a viable therapeutic strategy to improve radiation therapy for GBM.

Flourish of Proton and Carbon Ion Radiotherapy in China.

Proton and heavy ion therapy offer superior relative biological effectiveness (RBE) in the treatment of deep-seated tumors compared with conventional photon radiotherapy due to its Bragg-peak feature of energy deposition in organs. Many proton and carbon ion therapy centers are active all over the world. At present, five particle radiotherapy institutes have been built and are receiving patient in China, mainly including Wanjie Proton Therapy Center (WPTC), Shanghai Proton Heavy Ion Center (SPHIC), Heavy Ion Cancer Treatment Center (HIMM), Chang Gung Memorial Hospital (CGMH), and Ruijin Hospital affiliated with Jiao Tong University. Many cancer patients have benefited from ion therapy, showing unique advantages over surgery and chemotherapy. By the end of 2020, nearly 8,000 patients had been treated with proton, carbon ion or carbon ion combined with proton therapy. So far, there is no systemic review for proton and carbon ion therapy facility and clinical outcome in China. We reviewed the development of proton and heavy ion therapy, as well as providing the representative clinical data and future directions for particle therapy in China. It has important guiding significance for the design and construction of new particle therapy center and patients’ choice of treatment equipment.

Out-of-field doses in pediatric craniospinal irradiations with 3D-CRT, VMAT, and scanning proton radiotherapy: A phantom study.

Craniospinal irradiation (CSI) has greatly increased survival rates for patients with a diagnosis of medulloblastoma and other primitive neuroectodermal tumors. However, as it includes exposure of a large volume of healthy tissue to unwanted doses, there is a strong concern about the complications of the treatment, especially for the children. To estimate the risk of second cancers and other unwanted effects, out-of-field dose assessment is necessary. The purpose of this study is to evaluate and compare out-of-field doses in pediatric CSI treatment using conventional and advanced photon radiotherapy (RT) and advanced proton therapy. To our knowledge, it is the first such comparison based on in-phantom measurements. Additionally, for out-of-field doses during photon RT in this and other studies, comparisons were made using analytical modeling. In order to describe the out-of-field doses absorbed in a pediatric patient during actual clinical treatment, an anthropomorphic phantom, which mimics the 10-year-old child, was used. Photon 3D-conformal RT (3D-CRT) and two advanced, highly conformal techniques: photon volumetric-modulated arc therapy (VMAT) and active pencil beam scanning (PBS) proton RT were used for CSI treatment. Radiophotoluminescent and poly-allyl-diglycol-carbonate nuclear track detectors were used for photon and neutron dosimetry in the phantom, respectively. Out-of-field doses from neutrons were expressed in terms of dose equivalent. A two-Gaussian model was implemented for out-of-field doses during photon RT. The mean VMAT photon doses per target dose to all organs in this study were under 50% of the target dose (i.e.,<500mGy/Gy), while the mean 3D-CRT photon dose to oesophagus, gall bladder, and thyroid, exceeded that value. However, for 3D-CRT, better sparing was achieved for eyes and lungs. The mean PBS photon doses for all organs were up to three orders of magnitude lower compared to VMAT and 3D-CRT and exceeded 10mGy/Gy only for the oesophagus, intestine, and lungs. The mean neutron dose equivalent during PBS for eight organs of interest (thyroid, breasts, lungs, liver, stomach, gall bladder, bladder, prostate) ranged from 1.2mSv/Gy for bladder to 23.1 mSv/Gy for breasts. Comparison of out-of-field doses in this and other phantom studies found in the literature showed that a simple and fast two-Gaussian model for out-of-field doses as a function of distance from the field edge can be applied in a CSI using photon RT techniques. PBS is the most promising technique for out-of-field dose reduction in comparison to photon techniques. Among photon techniques, VMAT is a preferred choice for most of out-of-field organs and especially for the thyroid, while doses for eyes, breasts, and lungs are lower for 3D-CRT. For organs outside the field edge, a simple analytical model can be helpful for clinicians involved in treatment planning using photon RT but also for retrospective data analysis for cancer risk estimates and epidemiology in general.

Cellular plasticity upon proton irradiation determines tumor cell radiosensitivity.

Proton radiotherapy has been implemented into the standard-of-care for cancer patients within recent years. However, experimental studies investigating cellular and molecular mechanisms are lacking, and prognostic biomarkers are needed. Cancer stem cell (CSC)-related biomarkers, such as aldehyde dehydrogenase (ALDH), are known to influence cellular radiosensitivity through inactivation of reactive oxygen species, DNA damage repair, and cell death. In a previous study, we found that ionizing radiation itself enriches for ALDH-positive CSCs. In this study, we analyze CSC marker dynamics in prostate cancer, head and neck cancer, and glioblastoma cells upon proton beam irradiation. We find that proton irradiation has a higher potential to target CSCs through induction of complex DNA damages, lower rates of cellular senescence, and minor alteration in histone methylation pattern compared with conventional photon irradiation. Mathematical modeling indicates differences in plasticity rates among ALDH-positive CSCs and ALDH-negative cancer cells between the two irradiation types.

Normal Tissue Complication Probability Modelling for Toxicity Prediction and Patient Selection in Proton Beam Therapy to the Central Nervous System: A Literature Review

Normal tissue complication probability (NTCP) models can guide clinical decision making in radiotherapy. In recent years, they have been used for patient selection for proton beam therapy (PBT) for some anatomical tumour sites. This review synthesizes the published evidence regarding the use of NTCP models to predict the toxicity of PBT, for different end points in patients with brain tumours. A search of Medline and Embase using the Patients, Intervention, Comparison, Outcome (PICO) criteria was undertaken. In total, 37 articles were deemed relevant and were reviewed in detail. Nineteen articles on NTCP modelling of toxicity end points were included. Of these, 11 were comparative NTCP studies of PBT versus conventional photon radiotherapy (XRT), which evaluated differences in plan dosimetry and then assumed that XRT-derived literature estimates of NTCP would be applicable to both. Seven papers derived NTCP models based on PBT outcome data, two of which provided model parameters. Among analysed end points, the reduced risk of secondary tumours with PBT as compared with XRT is estimated – through modelling studies – to be considerable and was highlighted by most authors. For other analysed end points, the clinical benefit of PBT mainly depends on tumour location in relation to organs at risk as well as prescription doses. NTCP models can be useful tools for treatment plan comparison. However, most published toxicity data were derived from XRT cohorts; this review has highlighted the need for further studies relating dose-volume parameters to observed toxicity in PBT-treated patients. Specifically, there is a need for PBT-specific NTCP models that can be implemented in the clinical practice. NTCP models built on robust clinical data for the most common radiotherapy toxicities in the brain would potentially redefine the current indications for PBT.

64Cu-ATSM Predicts Efficacy of Carbon Ion Radiotherapy Associated with Cellular Antioxidant Capacity

Simple SummaryCarbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. Here we show that the carbon ion RBE in human cancer cells correlates with the cellular uptake of 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. High RBE/64Cu-ATSM cells show greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts. These data suggest that the cellular antioxidant activity is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake.Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. We addressed this issue by focusing on cellular antioxidant capacity and investigated 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with 64Cu-ATSM uptake both in vitro and in vivo. High RBE/64Cu-ATSM cells showed greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts; this upregulation of antioxidant systems was associated with downregulation of TCA cycle intermediates. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) sensitized high RBE/64Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/64Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake. These new findings highlight the potential clinical utility of 64Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.

Intensity-modulated proton radiation therapy as a radical treatment modality for nasopharyngeal carcinoma in China: Cost-effectiveness analysis.

Compared to conventional intensity-modulated photon radiation therapy (IMRT), intensity-modulated proton radiation therapy (IMPT) has potential to reduce irradiation-induced late toxicities while maintaining excellent tumor control in patients with nasopharyngeal carcinoma (NPC). However, the relevant cost-effectiveness remains controversial. A Markov decision tree analysis was performed under the assumption that IMPT offered normal tissue complication probability reduction (NTCP reduction) in long-term dysphagia, xerostomia, and hearing loss, compared to IMRT. Base-case evaluation was performed on T2N2M0 NPC of median age (43 years old). A Chinese societal willingness-to-pay threshold (33558 US dollars [$])/quality-adjusted life-year [QALY]) was adopted. For patients at median age and having NTCP reduction of 10%, 20%, 30%, 40%, 50%, and 60%, their incremental cost-effectiveness ratios were $102684.0/QALY, $43161.2/QALY, $24134.7/QALY, $13991.6/QALY, $8259.8/QALY, and $4436.1/QALY, respectively; IMPT should provide an NTCP reduction of ≥24% to be considered cost-effective. IMPT has potential to be cost-effective for average Chinese NPC patients and should be validated clinically.

Proton therapy for prostate cancer: current state and future perspectives.

Localized prostate cancer can be treated with several radiotherapeutic approaches. Proton therapy (PT) can precisely target tumors, thus sparing normal tissues and reducing side-effects without sacrificing cancer control. However, PT is a costly treatment compared with conventional photon radiotherapy, which may undermine its overall efficacy. In this review, we summarize current data on the dosimetric rationale, clinical benefits, and cost of PT for prostate cancer. An extensive literature review of PT for prostate cancer was performed with emphasis on studies investigating dosimetric advantage, clinical outcomes, cost-effective strategies, and novel technology trends. PT is safe, and its efficacy is comparable to that of standard photon-based therapy or brachytherapy. Data on gastrointestinal, genitourinary, and sexual function toxicity profiles are conflicting; however, PT is associated with a low risk of second cancer and has no effects on testosterone levels. Regarding cost-effectiveness, PT is suboptimal, although evolving trends in radiation delivery and construction of PT centers may help reduce the cost. PT has several advantages over conventional photon radiotherapy, and novel approaches may increase its efficacy and safety. Large prospective randomized trials comparing photon therapy with proton-based treatments are ongoing and may provide data on the differences in efficacy, toxicity profile, and quality of life between proton- and photon-based treatments for prostate cancer in the modern era. PT provides excellent physical advantages and has a superior dose profile compared with X-ray radiotherapy. Further evidence from clinical trials and research studies will clarify the role of PT in the treatment of prostate cancer, and facilitate the implementation of PT in a more accessible, affordable, efficient, and safe way.

Carbon Ion Radiotherapy in the Management of Hepatocellular Carcinoma.

Localized hepatocellular carcinoma (HCC) that is unresectable and non-transplantable can be treated by several liver-directed therapies. External beam radiation therapy (EBRT) is an increasingly accepted and widely utilized treatment modality in this setting. Accelerated charged particles such as proton beam therapy (PBT) and carbon ion radiation therapy (CIRT) offer technological advancements over conventional photon radiotherapy. In this review, we summarize the distinct advantages of CIRT use for HCC treatment, focusing on physical and biological attributes, and outline dosimetric and treatment planning caveats. Based on these considerations, we posit that HCC may be among the best indications for use of CIRT, as it allows for maximizing tumoricidal doses to the target volume while minimizing the dose to the organs at risk.

Adenoid cystic carcinoma. An indolent but aggressive tumour. Part B: treatment and prognosis.

SUMMARYThe purpose of this review is to analyse the very large number of studies (sometimes contradictory) on adenoid cystic carcinoma (ACC). This second part provides a critical analysis of various treatment described in the literature. Anywhere the primary tumour is located, the most common treatment for ACC is complete surgical resection, with or without post-operative radiotherapy (PORT), while conventional photon and/or electron radiotherapy alone and chemotherapy are commonly used in unresectable or metastatic disease. Fast neutron radiotherapy was used in the past with good local results, but the risk of late effects was high and tended to increase over time. Modern carbon-ion radiotherapy seems to be a valid option in selected cases. The quite universally accepted poor prognostic factors are advanced stage, perineural and intraneural invasion, involved margins, and initial presence or later development of neck metastases. The impact of histologic grade on prognosis is controversial. Owing to the long natural history of ACC, the follow-up for patients must be at least 10 years long.

Proton Beam Therapy for Local Recurrence of Rectal Cancer.

Curing local recurrence of rectal cancer (LRRC) is difficult with conventional photon radiotherapy. Proton beam therapy (PBT) on the other hand, has unique physical characteristics that permit higher doses to LRRC while minimizing side effects on surrounding organs. However, the efficacy of PBT on controlling rectal cancer recurrence has not yet been reported. This study aimed to evaluate clinical outcomes and toxicities of PBT for LRRC. Clinical outcomes were retrospectively evaluated for 12 patients with 13 total lesions that had received PBT for LRRC at our institute. The median follow-up period from the initiation of PBT was 35.6 months. The 3-year local control, progression-free survival and overall survival rates were 80.2%, 10.4% and 73.8%, respectively. Median survival time was 67.1 months. There were no severe acute or late adverse events. PBT could be a safe and effective treatment method for LRRC.

Quality assurance method for monitoring of lateral pencil beam positions in scanned carbon-ion radiotherapy using tracking of secondary ions.

Ion beam radiotherapy offers enhances dose conformity to the tumor volume while better sparing healthy tissue compared to conventional photon radiotherapy. However, the increased dose gradient also makes it more sensitive to uncertainties. While the most important uncertainty source is the patient itself, the beam delivery is also subject to uncertainties. Most of the proton therapy centers used cyclotrons, which deliver typically a stable beam over time, allowing a continuous extraction of the beam. Carbon-ion beam radiotherapy (CIRT) in contrast uses synchrotrons and requires a larger and energy-dependent extrapolation of the nozzle-measured positions to obtain the lateral beam positions in the isocenter, since the nozzle-to-isocenter distance is larger than for cyclotrons. Hence, the control of lateral pencil beam positions at isocenter in CIRT is more sensitive to uncertainties than in proton radiotherapy. Therefore, an independent monitoring of the actual lateral positions close to the isocenter would be very valuable and provide additional information. However, techniques capable to do so are scarce, and they are limited in precision, accuracy and effectivity. The detection of secondary ions (charged nuclear fragments) has previously been exploited for the Bragg peak position of C-ion beams. In our previous work, we investigated for the first time the feasibility of lateral position monitoring of pencil beams in CIRT. However, the reported precision and accuracy were not sufficient for a potential implementation into clinical practice. In this work, it is shown how the performance of the method is improved to the point of clinical relevance. To minimize the observed uncertainties, a mini-tracker based on hybrid silicon pixel detectors was repositioned downstream of an anthropomorphic head phantom. However, the secondary-ion fluence rate in the mini-tracker rises up to 1.5×105 ions/s/cm2 , causing strong pile-up of secondary-ion signals. To solve this problem, we performed hardware changes, optimized the detector settings, adjusted the setup geometry and developed new algorithms to resolve ambiguities in the track reconstruction. The performance of the method was studied on two treatment plans delivered with a realistic dose of 3Gy (RBE) and averaged dose rate of 0.27Gy/s at the Heidelberg Ion-Beam Therapy Center (HIT) in Germany. The measured lateral positions were compared to reference beam positions obtained either from the beam nozzle or from a multi-wire proportional chamber positioned at the room isocenter. The presented method is capable to simultaneously monitor both lateral pencil beam coordinates over the entire tumor volume during the treatment delivery, using only a 2-cm2 mini-tracker. The effectivity (defined as the fraction of analyzed pencil beams) was 100%. The reached precision of (0.6 to 1.5) mm and accuracy of (0.5 to 1.2) mm are in line with the clinically accepted uncertainty for QA measurements of the lateral pencil beam positions. It was demonstrated that the performance of the method for a non-invasive lateral position monitoring of pencil beams is sufficient for a potential clinical implementation. The next step is to evaluate the method clinically in a group of patients in a future observational clinical study.